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Development of adamantane scaffold containing 1,3,4-thiadiazole

derivatives: Design, synthesis, anti-proliferative activity and molecular
docking study targeting EGFR

Article  in  Bioorganic Chemistry · March 2021

DOI: 10.1016/j.bioorg.2021.104794

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 Bioorganic Chemistry 110 (2021) 104794

Contents lists available at ScienceDirect

Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg

Development of adamantane scaffold containing 1,3,4-thiadiazole

derivatives: Design, synthesis, anti-proliferative activity and molecular
docking study targeting EGFR
Mohammed M.S. Wassel a, Yousry A. Ammar b, *, Gameel A.M. Elhag Ali b, Amany Belal c, d,
Ahmed B.M. Mehany e, Ahmed Ragab b, *
a
Department of Foot and Mouth Disease, Veterinary Serum and Vaccine Research Institute (VSVRI), Abbasia, Cairo, Egypt
b
Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City, 11884 Cairo, Egypt
c
Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
d
Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
e
Zoology Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt

A R T I C L E I N F O A B S T R A C T

Keywords: A new series of 1,3,4-thiadiazolo-adamantane derivatives were synthesized through molecular hybridization
Adamantane approach, then used as starting material to synthesize chloro and cyano acetamide-thiadiazole derivatives 2, 3.
1,3,4-Thiadiazole derivatives The newly designed compounds 1–3 were treated with different reagents to design 5-adamantyl thiadiazole
Anti-proliferative activity
derivatives 4–17 and evaluate their in vitro anti-proliferative activity against three cancer cell lines (MCF-7,
EGFR
Apoptosis and molecular docking
HepG-2 and A549). Doxorubicin was used as a positive control. The most promising compounds 5, 6, 10a, 10b,
14b, 14c, and 17 showed up-regulation for BAX and down-regulation of Bcl-2, these findings proved their role as
hopeful apoptotic inducers. In addition, the inhibitory activity against both wild EGFRWT and mutant EGFRL858R-
TK
for these derivatives revealed that compounds 5, 14c, and 17 have IC50 value ranging from 85 nM to 71.5 nM
against wild EGFRWT and 37.85–41.19 nM against the mutant type, Lapatinib was used as a reference standard
with IC50 values of 31.8 nM and 39.53 nM, respectively. The most potent derivatives were subjected to further
evaluation against double mutant EGFR L858R/T790M and showed good IC50 values between (0.27–0.78 nM)
compared to Lapatinib (0.18 nM) and Erlotinib (0.21 nM). Among them, thiazolo-thiadiazole adamantane de­
rivative 17 exhibited the strongest inhibitory activity to the EGFR. Molecular docking studies were performed
inside the active site of EGFR (1M17), and binding energy scores ranged between (− 19.19 to –22.07 Kcal/mol)
compared to Erlotinib (− 19.10 Kcal/mol). Furthermore, oral bioavailability beside some pharmacokinetics
properties of these derivatives were also investigated in this research work.

1. Introduction increased anticancer drug resistance and decreased apoptosis capacity

Cancer is emerging as one of the fastest-growing diseases in the
world and a leading cause of death following cardiovascular diseases
[1–3]. Cancer is the world’s second-largest cause of death, accounting
for 9.6 million deaths in 2018, with approximately one in nine deaths
due to cancer [4,5]. Current cancer care approaches include surgery,
radiotherapy, and chemotherapy either alone or in combination, how­
ever, metastasis (spread of disease to other areas in the body) is still
representing a challenge [6]. DNA-damaging agents, such as radiation
and chemotherapeutic drugs, can induce programmed cell death
(apoptosis) [7]. Many studies have shown a close association between
[8–13]. Hence, inhibition of apoptosis will play a major role in cancer
progression during carcinogenesis. There are different types of molec­
ular pathways used by the cancer cells to inhibit apoptosis [12]. BAX
and Bcl-2 are respectively apoptotic and anti-apoptotic proteins, and the
ratio of those two proteins determines the frequency in apoptosis in cells
[14–17]. An important determinant of cell survival is the relationship
between the apoptotic and anti-apoptotic levels [18]. EGFR belongs to a
family of four related receptor tyrosine kinases including EGFR (HER1/
ErbB1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4) that act
as a key mediator in cell signaling pathways involving cell proliferation,
apoptosis, angiogenesis, and metastatic spread [19,20]. Although each

* Corresponding authors.
E-mail addresses: yossry@azhar.edu.eg (Y.A. Ammar), ahmed_ragab@azhar.edu.eg (A. Ragab).

https://doi.org/10.1016/j.bioorg.2021.104794
Received 9 June 2020; Received in revised form 28 February 2021; Accepted 1 March 2021
Available online 5 March 2021
0045-2068/© 2021 Published by Elsevier Inc.
M.M.S. Wassel et al.
member of the EGFR family is the potent mediator of normal cell growth
and development, overexpression of EGFR appears in various human
tumors [21,22]. The advantage of the adamantyl group confers addi­
tional potency in drugs in which it was present. The property underlined
was the lipophilicity of adamantane which increases the ease with,
which the compound reaches the activity site as well as the bulkiness
property that indicates a steric factor is also necessary at the activity site
for the interactions[23]. Adamantane derivatives have several enticing
pharmacological activities, such as antibacterial [24,25], antifungal
[26], antiviral [27–29], antidiabetic [30], carbonic anhydrase inhibitors
[31], and anticancer effects [32–35]. Amantadine and many similar
compounds with three-dimensional ‘box-like’ adamantane structure are
employed in the treatment of certain neurological disorders [36]. It was
found that N-1-adamantylcitraconimide (ACI) (I), N-1-ada­
mantylmaleimide (AMI) (II) and dimethyl adamantyl maleimide
(DMAMI) (III) exhibited modest growth-inhibitory activity against four
cancer cell lines (Colo 205, HepG-2, SK-BR-3 and Molt-4). Also, AMI was
also successful in inhibiting the growth of both in vitro and in vivo
human gastric cancer cells and induced in vitro apoptosis [37]. Dimethyl
adamantyl maleimide (DMAMI), the AMI derivative, induces apoptosis
and inhibits the development of human colon cancer Colo 205 in SCID
mice [38]. In addition, 1,3,4-thiadiazoles are heterocyclic scaffolds
found in several compounds that have various pharmacological activ­
ities as such as fungicidal [39], insecticidal [40], anticonvulsant [41],
anti-tuberculosis [42], anticancer [43,44], antiviral [45], antibacterial
[46]. The wide range of pharmaceutically suitable biological activities is
due to the existence of the NCS group, a hydrogen-binding domain with
two-electron donor systems, as well as sulfur atom that enhances the
liposolubility of the molecule [47–49]. The broad and wide biological
activities of 1,3,4-thiadiazole derivatives are due to the aromaticity of
the ring, which also provides great in vivo stability to this five-
membered ring system and low toxicity for higher vertebrates,
Fig. 1. Rationale design for the target molecules.
2
Bioorganic Chemistry 110 (2021) 104794
including human beings [50,51] (Fig. 1).
Molecular hybridization has become an appealing technique for the
rational design of anticancer agents with improved affinity and efficacy
in comparison with parent drugs and increased activity [52]. The hybrid
drug is a new term in development which involves combining two or
more pharmaceutical cores to produce a new hybrid drug which can
interact with multiple targets or minimize side effects using single-target
agents [53,54]. Based on the previous findings and our ongoing efforts
to develop a new heterocyclic compound with biological activity
[55–59]. It was conceived that binding more than one pharmacophores
as adamantane and thiadiazole moieties to design one scaffold using
drug design strategy would be of great interest developing potent anti­
cancer agents as described previously [60,61]. Nowadays, the creation
of hybrid molecules is a phenomenon that aims to combine multiple
pharmacophore fragments in the same molecule with different biolog­
ical potentials [62–68,84,85]. Our study’s rationale came up from the
great importance and synthetic accessibility of adamantly-thiadiazole
hybrids incorporating some amide, azomethane, amine, pyridine de­
rivatives, and some new fused ring with thiadiazole as imidazo and
pyrimidino derivatives. The synthesized derivatives were evaluated as
anti-proliferative activity against three cell lines, mitochondrial
apoptosis by regulating BAX and Bcl-2 proteins’ expression, and EGFR
inhibition. Besides, study cell cycle, apoptosis assay, and finally, some
physicochemical and pharmacokinetic properties as well as molecular
docking study for the most active derivatives were determined hoping to
generate potential anticancer molecules.
2. Results and discussion
2.1. Chemistry
The synthetic procedures adopted to obtain the target compounds
M.M.S. Wassel et al.
are depicted in Schemes 1–3. The starting compound, 5-(adamantan-1-
yl)-1,3,4-thiadiazol-2-amine (1) was prepared according to the previ­
ously reported procedure [69]. Thus, 2-aminothiadiazole derivative 1
was subjected to chloroacetylation through its reaction with chlor­
oacetyl chloride in the presence of trimethylamine as a catalyst to afford
the corresponding 2-chloro acetamide derivative 2. Structure of the
latter product was confirmed based on analytical and spectral data. The
IR spectrum showed absorption bands at ν 3160, 2905, 2849, and 1714
cm− 1 due to NH, aliphatic-CH and C– – O groups. Its 1H NMR spectrum
showed two singlet signals at δ 12.79 and 4.42 ppm corresponding to NH
and CH2 groups. The adamantane protons were observed at δ 2.06, 2.01,
and 1.76 ppm. 13C NMR for this compound exhibited signals at δ 174.6,
165.66, 157.88, and 43.12 ppm corresponding for C– – O, two C–– N, and
CH2 groups respectively, while the adamantane-C were observed at δ
42.76, 37.77, 36.28, and 28.30 ppm.
In addition, N-(5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-2-cyanoa­
cetamide (3) was obtained through cyano-acetylation of compound 1
with 3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxopropane-nitrile in toluene.
Elemental analysis, IR, 1H NMR, and 13C NMR are in agreement with the
proposed structure. Its IR spectrum exhibited two new bands at 2263
and 1720 cm− 1 due to CN and C– – O respectively. 1H NMR spectrum
displayed a singlet signal at δ 4.07 ppm attributed to CH2. The 13C NMR
spectrum characterized signals at δ 174.48, 115.63, and 56.48 ppm
assigned to the C–– O, CN, and CH2 groups, respectively.
N-(5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl)benzamide (4) was ob­
tained by reaction of 2-aminothiadiazole derivative 1 with benzoyl
chloride under reflux condition. The IR spectrum of compound 4 showed
a new absorption band at 1670 cm− 1 due to the carbonyl group. Its 1H
NMR spectrum revealed a singlet signal at δ 12.62 ppm due to NH proton
Scheme 1. Synthesis of thiadiazole amide, indolin-2-one and acyclic derivatives containing adamantane pharmacophore.
3
Bioorganic Chemistry 110 (2021) 104794
that exchangeable by D2O, in addition to three signals at δ 8.03, 7.59,
and 7.49 ppm for aromatic protons. The 13C NMR spectrum exhibited
signals for carbonyl carbon at δ 174.22 and aromatic at δ 133.31,
132.27, 129.72, 129.08, 129.02, and 128.80 ppm as well as two singlet
signal at δ 167.78 and 159.17 ppm for two C– – N groups in thiadiazole
moiety. Condensation of compound 1 with isatin in boiling ethanol
furnished Schiff’s base 5 in a good yield. The chemical structure of
compound 5 was elucidated based on elemental analysis and spectral
data. The IR spectrum indicated the presence of a strong absorption
band at 1727 cm− 1 due to the carbonyl group. The 1H NMR spectrum
showed the presence of indolinone part at 11.02, 7.48, 7.39, 6.96, and
6.83 ppm for NH and four aromatic protons. Although, its 13C NMR
exhibited signals at 168.89, 168.27, 138.84, 130.84, 125.13, 123.21,
118.28, and 112.71 ppm due to the indolinone core.
Furthermore, we investigated the reactivity of 2-aminothiadiazole
derivative 1 towards some halogenated compounds to prepare imi­
dazo[2,1-b][1,3,4]thiadiazole derivatives. Thus, the reaction of thia­
diazole derivative 1 with 3-chloroacetylacetone and ethyl 3-
chloroacetoacete in ethanol containing piperidine as a catalyst for
obtaining the cyclic structure but a cyclic structures 6 and 7 were ob­
tained. Structure of the latter products was confirmed on the basis of
correct elemental analyses and spectral data. The IR spectrum of com­
pound 6 indicated the presence of two strong absorption bands at 1699
and 1676 cm− 1 due to two carbonyl groups, while the carbonyl of ester
group in compound 7 was observed at 1698 cm− 1. The 1H NMR spec­
trum of compound 6 showed the presence of NH proton at δ 9.48 and
three singlet signals at δ 3.10, 2.15, and 2.04 ppm corresponding for two
methyl groups and methine proton in addition to the expected signals for
thiadiazole adamantane moiety. In the similar manner compound 7
M.M.S. Wassel et al. Bioorganic Chemistry 110 (2021) 104794

Scheme 2. Reaction of 2-chloroacetamide with a different reagent to produce imidazo[2,1-b]thiadiazol, substituted amide derivatives as well as thiazole containing
thiadiazolo-adamantane amine moiety.

Scheme 3. Condensation and cyclization reactions of cyno-acetamide derivative into pyrimidinone, aryl cyan-acrylamide, pyridine, chromenone and thiazolidinone
derivatives containing adamantyl thiadiazole moiety.

showed signals at δ 2.87 and 3.03 ppm for methine proton and methyl
group in addition to ester group that observed as quartet and triplet at δ
4.23 and 1.45 ppm with coupling constant (J = 6.8 Hz). In addition, its
13
C NMR exhibited signals at δ 175.15, 168.29, 158.92, and 151.27 ppm
for two carbonyls and C–– N respectively. Moreover, methine carbon and
ethyl group carbons appear at δ 77.82, 60.56, and 14.66 ppm as well as
adamantane carbons.
N-(5-(Adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-2-chloroacetamide (2)
is a versatile reagent and has been extensively used as a synthetic in­
termediate for the synthesis of thiadiazole derivatives of potential

4
M.M.S. Wassel et al.
biological activity. It was thus of interest to study the reactivity of
compound 2 towards a variety of chemical reagents. Thus, upon
refluxing of compound 2 in dioxane containing trimethylamine as a
catalyst caused self-cyclization to furnish the corresponding 2-(ada­
mantan-1-yl)imidazo[2,1-b][1,3,4]thiadiazol-6-one (8). The chemical
structure of compound 8 was established on the basis of its elemental
analysis and spectral data. Its 1H NMR spectrum displayed two singlet
signals at δ 12.82, and 4.05 ppm for hydroxy and methine proton and its
13
C NMR spectrum was characterized by signal at δ 174.61 assigned to
the carbon attached to the hydroxyl group. Amination of compound 2
with piperidine as secondary amine and p-anisidine as well as p-tolui­
dine as primary amine afforded the corresponding amino derivatives
compounds 9 and 10. The structure of the amino products 9, and 10
were verified by elemental analyses and spectroscopic methods. For
example, 1H NMR spectrum of compound 10a displayed aromatic pro­
ton signals which appeared as two doublets with coupling constant (J =
8.8 Hz) at 6.71, and 6.52 ppm. Addition to four singlet signals at δ 12.40,
5.67, 3.98, and 3.62 ppm characteristic for the 2NH, CH2, and OCH3,
respectively, besides the expected protons of adamantane moiety and its
13
C NMR showed signals at δ 174.08, 170.65, 157.89, 55.74 and 47.41
ppm corresponding to C– – O, two C– – N, OCH3, and CH2 groups. Treat­
ment of 2-chloro acetamide derivative 2 with ammonium thiocyanate in
absolute ethanol afforded the thiazolidinone derivative 11 containing
thiadiazolo-adamantane Scheme 2. The IR spectrum of compound 11
revealed a strong absorption band at 1740 cm− 1 due to thiazolidine
carbonyl function. Its 1H NMR revealed one D2O exchangeable proton at
δ 12.24 and a singlet signal at δ 4.07 ppm due to CH2 protons. Moreover,
its 13C NMR exhibited signals at δ 177.10, 174.49, and 66.82 ppm for
two carbonyl group moreover endocyclic methylene group of thiazol-4-
one derivative.
Furthermore, we also investigated the reactivity of N-(5-(ada­
mantan-1-yl)-1,3,4-thiadiazol-2-yl)-2-cyanoacetamide (3) towards
some selective reagents with the aim of preparing some bioactive de­
rivatives. Thus, compound 3 underwent cyclization when heated under
reflux in dioxane to afford thiadiazolo[3,2-a]pyrimidin-7-one derivative
12. The structure of 12 was confirmed based on its elemental analysis
and spectral data. The IR spectrum of compound 12 showed absorption
bands at 3156 and 1718 cm− 1 indicating the presence of NH and C– –O
groups, respectively and absent of the cyan-group. Moreover, its 1H
NMR showed two singlets at δ 12.80 and 4.42 ppm due to the presence of
NH and CH2 protons. Furthermore, 13C NMR exhibited the presence of
C–– O and CH2 carbons at δ 174.57 and 46.72 ppm, respectively in
addition to the expected carbons of the thiadiazolo-adamantane moiety.
Condensation of cyano-acetanilide thiadiazole derivative 3 with
some aromatic aldehydes namely 4-methoxy or 4-chloro or 4-fluoro
benzaldehyde afforded the corresponding acrylamide derivatives 13a-
c. The chemical structure of 13 was assigned on the basis of the spectral
and elemental analyses. The IR spectrum of compound 13a as an
example showed absorption bands at 3175 and 1652 cm− 1 due to NH
and amidic carbonyl functions, respectively. The 1H NMR spectrum of
compound 13a revealed the lack of CH2 signal and the presence of one
singlet signal exchangeable with D2O at δ 13.89 ppm due to NH proton,
beside a singlet signal at δ 8.38 for –
– CH methine and two doublets at δ
8.05 and δ 7.16 ppm with coupling constant (J = 8.8 Hz) for aromatic
protons and singlet signal at δ 3.88 corresponding for OCH3. In addition,
13
C NMR of compound 13a exhibited signals at δ 177.11, 115.41, and
56.17 ppm corresponding for C– – O, CN and OCH3 carbons over the
presence of aromatic and adamantane carbons. On the other hand, the
interaction of cyano-acetamide derivative 3 with arylidenemalononi­
triles in the presence of piperidine affected cyclization to yield the
corresponding pyridine carbonitrile derivatives 14a-c. The structure of
compound 14 was confirmed on the basis of its elemental analysis and
spectral data. The IR spectrum of 14a as the example showed absorption
bands at 3314, 3172, 2223, and 1706 cm− 1 indicating the presence of
amino, two CN, and carbonyl groups, respectively. The 1H NMR spec­
trum revealed the lack of CH2 signal and the presence of singlet signal at
5
Bioorganic Chemistry 110 (2021) 104794
δ 3.88 ppm due to OCH3 protons beside signals in the region of δ 7.15 to
8.39 ppm for Aromatic and NH2 protons as well as the expected ada­
mantane protons that appear as three singlet signals at δ 1.74, 1.99 and
2.18 ppm.
Reactivity of cyano-acetamide derivative with the 1,3-dicarbonyl
compound was studied in the aim of formation of pyridine derivatives
with potential biological activities [70,71]. Thus, compound 3 reacted
with acetylacetone to give the pyridine derivative 15. Structure of the
latter product was based on analytical and spectral data. The IR spec­
trum of compound 15 showed the exchangeable NH band and exhibited
two absorption bands at 2223 and 1668 cm− 1 due to CN and C– –O
groups. The 1H NMR spectrum revealed the appearance of three new
singlets at δ 2.09, 2.42 and 6.56 ppm assigned to two methyl protons and
the pyridinone H-5. Furthermore, cyclocondensation of compound 3
with salicylaldehyde in boiling ethanol containing a catalytic amount of
piperidine afforded the coumarin derivative 16. The IR spectrum of
compound 16 showed the absence of cyano band that already present in
the starting compound and the formed product exhibited the presence of
two strong absorption bands at 1712 and 1695 cm− 1 which prove the
formation chromone ring. Its 1H NMR spectrum revealed the absence of
methylene signal and the presence of two singlet signals at δ 8.99 and
4.35 ppm due to chromone H-4, NH of amide derivatives. Besides, the
presence of aromatic and adamantane protons. Its 13C NMR spectrum is
an agreement with the expected structure.
Finally, treatment of cyano-acetanilide thiadiazole derivative 3 with
phenyl isothiocyanate in DMF, in alkaline medium followed by treat­
ment with methyl chloroacetate afforded the corresponding thiazolidi­
none derivative 17. The structure of thiazolidinone containing
thiadiazolo-adamantane 17 was established by the appearance of a
strong absorption band at 1732 cm− 1 for new carbonyl formed in the IR
spectrum. This band displayed a strong confirmation for the thiazolidi­
none nucleus formation. Another evidence for the cyclization occurred is
the presence of a singlet signal at δ 4.05 ppm in the 1H NMR spectrum
equivalent to two protons for endocyclic methylene as well as signals at
δ 7.13 to 7.52 ppm related to phenyl group and in 13C NMR spectra
aromatic carbons displayed between δ 124.05 to 136.44 ppm.
2.2. Biological evaluations
2.2.1. Effect of 1,3,4-thiadiazole derivatives on anti-proliferative activity
and SAR study
The in vitro anti-proliferative activity of twenty-one 1,3,4-thiadiazole
derivatives, 2 to 17 containing adamantane moiety were evaluated
against a panel of three cell lines including mammary gland breast
cancer cell line (MCF-7), human hepatocellular carcinoma cell line
(HepG-2) as well as human lung adenocarcinoma epithelial cells (A549)
by using sulforhodamine B colorimetric (SRB) assay according to re­
ported methods [17,72]. Doxorubicin (DOX) is one of the commonly
used small molecular anti-cancer drugs, was selected to be the reference
drug. The in vitro cytotoxicity of all the synthetized compounds are
summarized in Table 1 and IC50 values expressed by (μM) that means the
concentration of compound or drug required to inhibit the growth of
cancer cells by 50%.
The resulting data from Table 1 showed that adamantane-containing
1,3,4-thiadiazole had moderate to potent growth inhibitory effect
against tested cell lines (MCF-7, HepG-2 and A549) with IC50 values
ranged between (5.71 ± 0.37 μM to 21.47 ± 1.5 μM), (4.28 ± 0.35 μM to
17.38 ± 1.35 μM) and (4.11 ± 0.28 μM to 16.31 ± 1.2 μM) μM in
comparison to Doxorubicin (8.19 ± 0.72 μM, 7.46 ± 0.12 μM and 3.58
± 0.03 μM), respectively. Compounds 2, 3, 4, 9, 10a, and 10b that
containing thiadiazole having amide derivatives in position two showed
that aromatic acetamide 10a, 10b revealed the highest activity de­
rivatives followed by benzamide, piperidinyl, chloro and cyanoaceta­
mide derivatives (10a ˃ 10b ˃ 4 ˃ 9 ˃ 2 ˃ 3), and 4-methoxy phenyl
acetamide derivative 10a was more active than 4-methyl derivative 10b
with IC50 values (6.44 ± 0.52 μM, 4.92 ± 0.35 μM, and 4.61 ± 0.31 μM)
M.M.S. Wassel et al. Bioorganic Chemistry 110 (2021) 104794

Table 1 cells. The most potent compounds showed IC50 values from 89.75 to
Cytotoxic screening of the newly designed compounds 2–17 and Doxorubicin 225.7 μM. From Table 2, the selectivity index (SI) data indicated that
against three cancer cell lines (IC50 values are expressed in μM ± S.E). adamantane core that attached to 1,3,4-thiadiazole derivatives exhibits
Compound no. IC50 μM ± S.E* a high degree of cytotoxic selectivity. For instance, compound 6 with
MCF-7 HepG-2 A 549
pentane-2,3-dione alkyl group attached to the amino of 2-aminothiadia­
zole adamantane derivatives exhibited the safest compound with IC50
2 14.32 ± 1.13 11.46 ± 0.93 10.67 ± 0.84
(225.7 μM) and highest SI (26.84, 36.70 and 39.12) respectively.
3 17.44 ± 1.32 15.72 ± 1.1 16.31 ± 1.2
4 12.37 ± 0.97 9.45 ± 0.76 10.18 ± 0.82 Simultaneously, N-1,2,4-thiadiazolo-di-cyanopyridine derivative 14c
5 7.27 ± 0.68 5.83 ± 0.42 4.26 ± 0.35 with 4-chlorophenyl moiety in position four of pyridine showed IC50
6 8.41 ± 0.74 6.15 ± 0.5 5.77 ± 0.4 (89.75 μM) with SI (15.72, 20.97, and 21.84) to the tested cell line
7 18.22 ± 1.41 15.37 ± 1.05 13.81 ± 0.98 respectively.
8 11.28 ± 0.95 10.17 ± 0.92 9.74 ± 0.86
9 17.55 ± 1.23 13.64 ± 0.97 11.37 ± 0.95
10a 6.44 ± 0.52 4.92 ± 0.35 4.61 ± 0.31 2.2.1.2. Effect of compounds on mitochondrial apoptosis by regulating the
10b 9.31 ± 0.85 7.67 ± 0.64 5.74 ± 0.44 expression of BAX and Bcl-2 proteins. The effect of the new designed
11 14.61 ± 1.1 10.36 ± 0.91 9.38 ± 0.84 compounds on the induced apoptotic process via mitochondria medi­
12 15.84 ± 1.14 13.49 ± 0.97 10.75 ± 0.85
13a 12.45 ± 0.98 10.77 ± 0.95 8.49 ± 0.75
ated pathway up-regulation of BAX and down-regulation of Bcl-2 was
13b 17.62 ± 1.35 14.92 ± 1.14 15.02 ± 1.16 evaluated and the obtained data are represented in Table 3. Treatment
13c 10.45 ± 0.93 8.22 ± 0.7 6.75 ± 0.55 of human lung adenocarcinoma epithelial cells (A549) with the most
14a 12.41 ± 1.1 10.37 ± 0.92 9.12 ± 0.76 promising compounds 5, 6, 10a, 10b, 14b, 14c, and 17 expressed high
14b 8.16 ± 0.69 6.75 ± 0.57 5.79 ± 0.41
levels of BAX and lower levels of Bcl-2 compared to untreated cells.
14c 5.71 ± 0.37 4.28 ± 0.35 4.11 ± 0.28
15 17.39 ± 1.4 14.89 ± 1.1 12.55 ± 0.95 From Table 3, the condensation of 2-aminothiadiazole with isatin to
16 21.47 ± 1.5 17.38 ± 1.35 14.62 ± 1.2 produce thiadiazole containing 2-oxoindole 5 exhibited the highest
17 6.51 ± 0.48 4.47 ± 0.3 4.32 ± 0.25 apoptosis induced by (BAX = 415.84 pg/mL with 8.57 folds) than un­
Dox. 8.19 ± 0.72 7.46 ± 0.12 3.58 ± 0.03 treated cells, followed by enaminonitrile containing thiadiazole 14c
*
Three independent experiments were performed for each tested compound (BAX = 411.32 pg/mL, 8.47 folds), and thiadiazole hybridized with N-
for each concentration. phenyl thiazole 17 (BAX = 375.19 pg/mL, 7.73 folds) and the other
derivatives induced apoptosis from 6.13 to 7.02 folds higher than con­
(9.31 ± 0.85 μM, 7.67 ± 0.64 μM, and 5.74 ± 0.44 μM), respectively. trol. By the same way, the most promising derivative among the thia­
Thiazol-4-one derivatives 11 and 17 that were obtained from chloro and diazole derivatives that demonstrated the highest value in suppressing
cyanoacetamide of thiadiazole adamantane derivatives by reacting them apoptosis against BCL-2 is thiadiazole containing enaminonitrile deriv­
with different reagents, and it was found that N-phenyl thiazol-4-one ative 14c with Bcl-2 value 1.42 pg/mL (4.13 folds). Whereas compounds
derivative 17 exhibited cytotoxic activity higher than its analogue 11 5, 6, 10a, 10b, 14b, and 17 showed decrease in Bcl-2 levels from 3.06
with IC50 values ranged between (4.32 ± 0.25 μM to 6.51 ± 0.48 μM), pg/mL to 1.75 pg/mL that decreased the level by 1.92 to 3.35 folds.
and in comparison, to Doxorubicin (3.58 ± 0.03 μM to 8.19 ± 0.72 μM). Our study indicated that compounds 5, 6, 10a, 10b, 14b, 14c, and
Amino thiadiazole derivatives with diacetyl derivative 6 demonstrated a 17 exhibited chemo suppression/induction cancerous cells to apoptosis
significant activity than 2-aminothiazole 7 with ethyl acetoacetate core induction by changes in Bcl-2 and BAX gene levels, depending on the
where IC50 values (8.41 ± 0.74, μM 6.15 ± 0.5 μM, and 5.77 ± 0.4 μM) variety of substituents that were attached to 1,3,4-thiadiazolo
and (18.22 ± 1.41 μM, 15.37 ± 1.05 μM, and 13.81 ± 0.98 μM) against adamantane.
the tested cell line (MCF-7, HepG-2, and A549), respectively. That is due
to the presence of ethyl acetate group that decrease activity than acetyl 2.2.1.3. Effect of compounds on EGFR inhibition. Epidermal growth
group. factor receptor (EGFR) are considered as an attractive and clinically
2-Cyanoacrylamide 1,3,4-thiadiazolo-adamantane derivatives 13a validated drug targets in cancer therapy because it is important for
to 13c showed moderate activity and chloro derivatives showed to be various biological processes and cancers development and progression,
the most active member with IC50 values (10.45 ± 0.93 μM, 8.22 ± 0.7 such as cell proliferation, adhesion, migration, differentiation, and
μM, and 6.75 ± 0.55 μM) for MCF-7, HepG-2, and A549 cell lines, survival. EGFR can cause dysregulation by two different mechanisms
respectively. N-thiadiazole pyridine derivatives 14 and 15 exhibited one of them is the high expression of EGFR that lead to increase in re­
variable activity, and the presence of dicyanopyridine derivative 14 ceptor signaling output. In contrast, the second mechanism involves
exhibited more activity than mono-cyano derivative 15, as well as the overexpression of the ligand and therefore increase in EGFR signaling
presence of aryl derivatives in compounds 14a to 14c. Also, the presence activity despite normal or even low levels of receptor expression
of chloro-derivative caused higher activity than both fluro- and methoxy [73–75]. Depending on the results of antiproliferative activity, we
derivatives in position four in dicyanopyridine derivative 14. Simulta­ selected the most promising compounds 5, 6, 10a, 10b, 14b, 14c and 17
neously, the 3-amide-2-oxo-chromene derivative 16 decreased the po­ for EGFR enzymatic activity assays by using A549 cancer cell to
tency than other adamantane derivatives.
Finally, seven compounds 5, 6, 10a, 10b, 14b, 14c, and 17 with 5-
(adamantan-1-yl)-1,3,4-thiadiazole backbone core showed potent cyto­ Table 2
toxicity with low micromolar (<10 μM) and most of these derivatives IC50 values in μM ± S.E. for WI-38 cell line for the most promising compounds.
showed IC50 lower than Doxorubicin on both MCF-7 and HepG-2 and Cpd. No. IC50 μM WI-38 Cells SI*
nearly to the reference drug against A 549 cell line with growth inhib­ MCF-7 HepG-2 A 549
itory ranged from 4.11 μM to 5.79 μM, besides, compounds 8, 11, 13a,
5 97.55 ± 0.68 13.42 16.73 22.90
13c, and 14a with IC50 values from 6.75 μM to 9.74 μM. 6 225.7 ± 1.25 26.84 36.70 39.12
10a 128.39 ± 0.98 19.94 26.10 27.85
2.2.1.1. Effects of compounds on normal cells. The cytotoxic activities of 10b 178.41 ± 0.67 19.16 23.26 31.08
the new promising compounds 5, 6, 10a, 10b, 14b, 14c and 17 were 14b 185.9 ± 1.75 22.78 27.54 32.11
14c 89.75 ± 0.24 15.72 20.97 21.84
evaluated on normal non-cancer cells (WI-38 cells) to determine the 17 112.75 ± 0.55 17.32 25.22 26.10
selectivity of the 2-amino-1,3,4-thidiazole derivatives against cancer
*
SI: Selectivity index = (IC50 of WI-38)/(IC50 of the tested cancer cell line).

6
M.M.S. Wassel et al. Bioorganic Chemistry 110 (2021) 104794

Table 3 except for 6, and 14b against EGFR L858R-TK.

Effect of compounds 5, 6, 10a, 10b, 14b, 14c, and 17 on expression of BAX and To study the most promising three derivatives 5, 14c, and 17 against
Bcl-2 that expressed by IC50 values in pg/mL ± S.E. for apoptosis markers. further kinase EGFR L858R/T790M double mutant with Lapatinib and
Cpd. No Bax (Pg/mL) Fold Bcl2 (Pg/mL) Fold Erlotinib as reference drugs (both drugs are known to target EGFR so
5 415.84 ± 3.53 8.57 1.75 ± 0.12 3.35
that they were selected to act as positive controls in this assay) and as
6 331.75 ± 2.19 6.83 2.54 ± 0.24 2.31 expected they inhibited the enzymatic activity against EGFR L858R/T790M
10a 340.55 ± 1.98 7.02 2.19 ± 0.17 2.64 with IC50 values ranged between (0.27 nM to 0.78 nM) compared to
10b 329.71 ± 2.98 6.79 2.71 ± 0.36 2.16 Lapatinib (0.18 nM) and Erlotinib (0.22 nM). Thiazolidinone derivative
14b 297.46 ± 3.10 6.13 3.06 ± 0.19 1.92
17 exhibited the highest value with 0.28 nM in comparison to enami­
14c 411.32 ± 1.25 8.47 1.42 ± 0.11 4.13
17 375.19 ± 2.65 7.73 1.88 ± 0.27 3.12 nonitrile pyridine derivative 14c (0.47 nM) and Schiff bases 5 (0.79
A549 cells 48.51 ± 1.04 1 5.87 ± 0.31 1 nM), and that may be due to presence of thiazolidinone moiety beside
thiadiazolo-adamantane backbone core.

elucidate the mechanism of these active compounds.

2.2.1.4. Cell cycle analysis. Depending on the antiproliferative activ­
From Table 4, the results of wide type EGFR on A549 cancer cells
ities, BAX, Bcl-2 gene expression as well as single and double mutant
expressed as the half-maximal inhibitory concentration IC50 (μM). All
EGFR results obtained previously. The most promising three derivatives
the promising compounds were investigated in EGFRWT inhibitory assay
5, 14c, and 17 were selected and investigated for cell cycle progression
and showed values <2 μM. The 3,5-dicyano-pyridine that containing 4-
and the apoptosis percentage induced by the help of adamantane de­
chlorophenyl derivatives as well as backbone core 1,3,4-thiadiazole
rivatives on human lung adenocarcinoma epithelial cells A549 cell when
adamantane 14c exhibited the most potent activity with IC50 value
treated with 5 μM. The obtained data represented in Table 5 and Fig. 2
85 nM while the fluro derivative 14b showed to be the least inhibitor
and Fig. 3.
towards EGFR in comparison to the tested compounds and Lapatinib
It is observed after 24 h; that the tested compounds exhibited PreG1
that used as a positive control due to its declared activity as a drug that
apoptosis and cell growth arrest in A549 at G2/M phase. Thiadiazole
can target EGFR, its IC50 (31.8 nM) against EGFRWT. Schiff base deriv­
containing both isatin or thiazole as hybrid molecule derivatives 5 and
ative 5 of 1,3,4-thiadiazole adamantane with isatin displayed 50% in­
17 beside adamantane core causes accumulation of A549 cell at G0-G1
hibition of EGFRWT expression at 35.2 nM. Moreover, compound 17
phases by 41.29% and 39.58%, respectively as well as, increasing G2/M
bearing 2-cyano-2(N-phenylthiazolidin-2-ylidene-4-one)acetamide de­
phase percentage by 26.64% and 26.29% in comparison to untreated
rivatives were found to be active inhibition (IC50 = 71.5 nM) against
cells 14.38%. While, enaminonitrile pyridine derivatives that are having
overexpression of EGFRWT. Compounds 6, 10a, and 10b inhibited the
both p-chlorophenyl moiety and adamantyl thiadiazole core revealed
enzymatic activity against EGFRWT with IC50 values (1.32, 0.954, and
cell cycle arrest by 42.09%, 29.67%, and 28.24% for G2/M, S, and G0-
1.27 μM).
G1 phases respectively. Also, enaminonitrile pyridine derivative 14c
Due to the importance of EGFR that can be defined as member of the
cause apoptosis and detain the cell cycle in both G2/M and preG1 by
membrane-bound receptor tyrosine kinase family and when activated,
74.50%. Although, both thiadiazole adamantane derivatives 5 and 17
transduce mitogenic signals [48]. The most promising compounds were
causes increase the content of DNA in G0-G1 and S phases by nearly
selected for further in vitro mutant EGFR L858R-TK that were expressed by
73.36% and 73.71%, respectively. Surprisingly, compounds 5, 14c, and
IC50 (nM) to evaluate the activity and selectivity of newly designed
17 induced apoptosis at pre-G1 phases by ranged from 16.59% to
compounds. Compound 14c showed the most potent inhibitory activity
32.41% in comparison to A549 cell by 1.86%.
against EGFR L858R-TK with IC50 (37.85 nM) in comparison to Lapatinib
Finally, the thiadiazolo-adamantane derivatives with different sub­
as a positive control (IC50 = 39.53 nM). Both compounds 5 and 17
stituent 5, 14c and 17 used as inhibitors for cancer cell and induced
showed equipotent to the standard drug with IC50 values (41.19 nM, and
apoptosis in different phases.
40.58 nM), respectively compared to Erlotinib (59.56 nM). Chlor­
oacetamide thiadiazole derivatives 2, when reacted with different aro­
2.2.1.5. Effect of compounds on apoptotic assay. To determine the
matic amines (4-methoxy and 4-methyl) to produce acetamide
mechanism of cell death and apoptosis-inducing effect double staining
derivative with aromatic core reveled activity with 52.11 nM and 55.28
Annexin V/propidium iodide was used through follow cytometry
nM with 30% less than Lapatinib and still having inhibitory activity
method [16,17], where apoptosis can be defined as an active and regular
better than Erlotinib 59.56 nM. Surprisingly, compound 14b demon­
pathway. At the same time, necrosis is a passive and accident cell death
strated the least inhibition towards EGFRWT, the observed IC50 = 70.49
[76]. Three thiadiazolo-adamantane derivatives 5, 14c, 17 were treated
nM against EGFR L858R-TK with nearly 56% less than the positive control.
with 5 μM and incubated for 24 h on A549 cell, and the obtained data
Most of the tested compounds reveled IC50 values higher than Erlotinib
showed in Table 6 and Fig. 4.
We detected an increase in the total percentage of apoptosis because
of the adamantane derivatives that exhibited total apoptosis ranged
Table 4
IC50 values in μM ± S.E. for EGFR kinases assay for the active compounds.
from 16.59% to 32.41% as compared to 1.86% for standard A549 cells.
By the same way, the enaminonitrile pyridine derivative 14c was the
Cpd. No. Enzyme inhibitory activity IC50 *
highest induction of total cell apoptosis (32.41%) by nearly 17.42 folds.
EGFRWT (μM) EGFR L858R-TK (nM) EGFR L/T**

5 0.0352 ± 0.008 41.19 ± 3.08 0.788

Table 5
6 1.323 ± 0.024 63.48 ± 2.89 –
Cell cycle analysis by percentage in different phases after treatment the lung
10a 0.954 ± 0.014 52.11 ± 3.54 –
10b 1.274 ± 0.026 55.28 ± 2.98 – cancer cell A549 with 10 μM of thiadiazolo-adamantane derivatives 5, 14c, and
14b 1.961 ± 0.023 70.49 ± 2.71 – 17.
14c 0.085 ± 0.010 37.85 ± 1.54 0.467 Compound No. Results
17 0.0715 ± 0.019 40.58 ± 1.25 0.278
Lapatinib 0.0318 ± 0.014 39.53 ± 1.62 0.182 %G0-G1 %S %G2/M %Pre-G1
Erlotinib 0.0656 ± 0.009 59.56 ± 2.31 0.218 5 41.29 32.07 26.64 19.11
*
Data are average of three independent results. 14c 28.24 29.67 42.09 32.41
** 17 39.58 34.13 26.29 16.59
EGFR L/T = double mutant EGFR L858R/T790M, (− ) mean not
cont. A549 46.93 38.69 14.38 1.86
determined.

7
M.M.S. Wassel et al.
Fig. 2. Diagram illustrated the percentage of cell cycle arrest for the most potency thiadiazole-adamantane derivatives 5, 14c, and 17 at different phases.
Moreover, the percentage in early-stage varies from 2.61%, 5.13% and
8.26% for 5, 17, and 14c, respectively.
Finally, the effect of three derivatives 5, 17, and 14c treated with
A549 cell lead to an increase in the sensitivity to apoptosis by different
percentage in different stages and therefore increased total apoptosis
percentage and these data support the higher values on antiproliferative
against A549 cell (<5 μM). Besides, the thiazolo-thiadiazole ada­
mantane derivative 17 exhibited the most active derivative (Fig. 5).
2.2.1.6. In silico studies
2.2.1.6.1. Evaluation of physicochemical, and pharmacokinetic pre­
diction on active compounds. Physicochemical parameters (oral
bioavailability) for both Lipinski’s and Veber rules were determined for
the most promising compounds as well as Lapatinib and Erlotinib using
Swiss ADME: a free web tool [77]. From data in Table 7, the most active
compounds 5, 14c, and 17 obey RO5 criteria without no violations from
Lipinski’s Rule, and both enaminonitrile 14c and thiazolo-thiadiazole
adamantane derivative 17 failed to pass through Veber rule by Topo­
logical polar surface area (TPSA) higher than 140 Å2. For two standard
drugs, Erlotinib pass in both rule of five and Veber rule while Lapatinib
met the RO5 with one violation in MW > 500 and passed in Veber rule.
By the same way, some Pharmacokinetic properties were studies
depending on Swiss ADME: a free web tool involving gastrointestinal
absorption and blood brain barrier. Compounds 14c and 17, as well as
Lapatinib, showed low gastrointestinal absorption with no permeation
to blood brain barrier while Schiff’s base 5 and Erlotinib exhibited high
absorption to gastrointestinal track. Furthermore, Erlotinib pass through
the blood brain barrier but the most promising displayed no promotion.
Finally, our new compounds exhibited not only promising activity,
but also some oral bioavailability beside pharmacokinetic properties as
Lapatinib and Erlotinib.
2.2.1.6.2. Effect of compounds on molecular docking study. To
explore the possible binding conformation and got deeper insights of the
structure activity relationship as well as understanding the potency of
the newly designed thiadiazolo-adamantane derivatives 5, 14c and 17
molecular docking simulation was performed with the ATP binding
pocket of EGFR PDB (1M17) [78]. From Table 8, it was found the co-
crystalized ligand 4-anilinoquinazoline inhibitor (Erlotinib) exhibited
self-docking process with small RMSD = 1.99 ◦ A and binding energy S =
− 19.10 Kcal/mol, through one hydrogen bond backbone acceptor with
Met769 with the nitrogen of quinazoline with bond length 3.13 ◦ A and
bound strength 16% (Figs. 6a and 6b). All the tested compound inside
8
Bioorganic Chemistry 110 (2021) 104794
the active site revealed binding energy between –22.07 to − 19.19 Kcal/
mol higher than Erlotinib (Figs. 6–9 and Table 8). Hydrazone containing
2-oxo-indole as well as thiadiazolo-adamantane derivative demonstrate
one hydrogen bond donor from side chain Asp831 with NH of isatin
moiety through bond length (2.54 ◦ A) and displayed binding energy S =
− 19.19 Kcal/mol (Figs. 7a and 7b). Enaminonitrile pyridine derivative
14c showed the highest binding energy score S = –22.07 Kcal/mol with
one hydrogen bond backbone acceptor between Met769 (the same
amino acid binding with Erlotinib) with cyano group in enaminonitrile
derivative with bond length 3.18◦ A (22%) (Figs. 8a and 8b). Hybrid
structure 17 that containing N-phenyl thiazole beside backbone moiety
(thiadiazolo-adamantane) displayed binding energy S = − 21.78 Kcal/
mol through two amino acid residue Asp 831 and Lys721 with bond
length 2.81◦ A (45%), 2.60◦ A (51%) respectively (Figs. 9a and 9b).
Finally, the most promising derivatives investigated binding energy
higher than the co-crystalized inhibitor (Erlotinib) as well as ada­
mantane moiety displayed hydrophobic interaction inside the active site
of pocket.
3. Conclusion
A novel series of twenty-one 1,3,4-thiadiazolo-adamantane de­
rivatives were designed and synthetized starting from 5-(adamantan-1-
yl)-1,3,4-thiadiazol-2-amine (1). The newly synthetized derivatives 2 to
17 were evaluated in vitro for their anti-proliferative activity against the
selected three cancer cell lines. The structure of the new designed
compounds was established and confirmed based on its elemental
analysis and spectral data. Cytotoxic values showed a broad spectrum of
the designed compounds against the tested cell lines (MCF-7, HepG-2
and A 549), and seven compounds 5, 6, 10a, 10b, 14b, 14c and 17
with 5-(adamantan-1-yl)-1,3,4-thiadiazole backbone core showed
potent cytotoxicity with low IC50 values (<10 μM). Moreover, the most
potent compounds showed IC50 values from 89.75 to 225.7 μM against
normal non-cancer cells WI-38. Besides, they have exhibited chemo
suppression/induction to cancers cells e.g. apoptosis induction by
making changes in Bcl-2 and BAX gene levels. All promising compounds
investigated EGFRWT inhibitory assay<2 μM. Besides, compound 14c
showed the most potent inhibitory activity against EGFR L858R-TK with
IC50 (37.85 nM) in comparison to Lapatinib as a positive control (IC50 =
39.53 nM) and Erlotinib (IC50 = 59.56 nM). Both compounds 5 and 17
showed equipotent activity to the standard drug with IC50 values (41.19
nM, and 40.58 nM), respectively. Furthermore, the most promising
M.M.S. Wassel et al. Bioorganic Chemistry 110 (2021) 104794

Fig. 3. Cell cycle analysis (a) Control A549, (b) 5/A549, (c) 14c/A549 and (d) 17/A549.

derivatives 5, 14c, and 17 exhibited IC50 values ranged between (0.27 induced apoptosis and arrested the cell cycle by 74.50% in both G2/M
nM to 0.78 nM) compared to Lapatinib (0.18 nM) and Erlotinib (0.22 and preG1. While both thiadiazole adamantane derivatives 5 and 17 had
nM) against EGFR L858R/T790M double mutant kinase. Studying cell cycle caused increase in DNA content in G0-G1 and S phases by nearly
analysis revealed that the enaminonitrile pyridine derivative 14c 73.36%, and 73.71%, respectively. The most potent adamantane

9
M.M.S. Wassel et al. Bioorganic Chemistry 110 (2021) 104794

Table 6 1,3,4-thiadiazol-2-yl)-2-cyano-2-(4-oxo-3-phenylthiazo-lidin-2-ylidene)
Percentage of cell death after treatment with compounds 5, 14c, and 17. acetamide (17) that has exhibited good EGFR inhibitors with lower IC50
Cpd. No. Apoptosis Necrosis values, that may be attributed to the presence of thiazolidinone moiety
beside thiadiazolo-adamantane backbone core. Finally, molecular
Total Early Late
docking study revealed that the promising compounds deeply bounded
5 19.11 2.61 5.41 11.09 inside the active site of the pocket as Erlotinib with binding energy
14c 32.41 8.26 14.79 9.36
17 16.59 5.13 7.35 4.11
between –22.07 to − 19.19 Kcal/mol which is higher than Erlotinib S =
A549 1.86 0.31 0.15 1.4 − 19.10 Kcal/mol, as well as the assessment of oral bioavailability
(Lipinski’s and Veber rules) beside other pharmacokinetics properties.

derivatives 5, 14c, and 17 showed increase in the total percentage of

apoptosis from 16.59% to 32.41% compared to 1.86% for standard A549
cells. Among the three promising derivatives, N-(5-(adamantan-1-yl)-

Fig. 4. Illustrated the different percentage of cell death by thiadiazolo-adamantane derivatives 5, 14c, and 17.

Fig. 5. Showed the results of the most active thiazolo-thiadiazole adamantane derivative 17.

Table 7
In silico the physicochemical and pharmacokinetic properties of the thiadiazolo-adamantane derivatives 5, 14c, and 17 as well as standard drugs (Lapatinib and
Erlotinib).
Cpd. No. Lipinski’s Rule Veber filter Pharmacokinetics

MW < 500 MLogP ≤ 4.15 nHBA ≤ 10 nHBD ≤ 5 nRB ≤ 10 TPSA ≤ 140 Å2 GI BBB

5 364.46 3.35 4 1 2 95.48 High No

14c 488.99 3.26 5 1 3 149.62 Low No
17 477.60 2.46 5 1 5 152.52 Low No
Lapatinib 581.06 3.44 8 2 11 114.73 Low No
Erlotinib 393.44 1.89 6 1 10 74.73 High yes

* MW; Molecular weight, MLogP; an octanol–water partition coefficient, nHBA; no. of hydrogen bond acceptor, nHBD; no of hydrogen bond donor, nRB; no. of
rotatable bond.

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M.M.S. Wassel et al. Bioorganic Chemistry 110 (2021) 104794

Table 8 4. Experimental section

Docking results of the adamantane derivatives with binding energy and inter­
acting group with specific amino acids in residue inside active side 1M17. 4.1. Chemistry
Cpd. No. (S) Amino Interacting groups Length Strength
(Kcal/ acids (◦ A) % Uncorrected melting points were recorded on digital Gallen Kamp
mol) MFB-595 instrument. The IR spectra (KBr) (cm− 1) were measured on a
Erlotinib − 19.10 Met769 N of quinazoline 3.13 16 Shimadzu 440 spectrophotometer.1H NMR spectra (δ, ppm) were ob­
5 − 19.19 Asp831 NH of isatin 2.54 49 tained in deuterated dimethyl sulfoxide (DMSO–d6) and 13C NMR at
14c Met769 CN of 3.18 22
–22.07
101 MHz, spectra were obtained on a Bruker spectrometer (400 MHz)
Enaminonitrile
17 − 21.78 Asp831 NH of 2- 2.81 45 spectrometer, using TMS as an internal standard; chemical shifts are
Lys721 aminothiazole 2.60 51 reported as δ ppm units. The data were presented as follows: chemical
CN of shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
cyanoacetanilide multiplet, br = broad, app = apparent), coupling constant(s) in Hertz
(Hz), and integration. Mass spectra were recorded on Thermo Scientific

Fig. 6a. 2D interaction maps of Erlotinib inside 1M17 active site.

Fig. 6b. 3D interaction maps of Erlotinib inside 1M17 active site.

11
M.M.S. Wassel et al.
Fig. 7a. 2D interaction maps of compound 5 inside 1M17 active site.
Fig. 7b. 3D interaction maps of compound 5 inside 1M17 active site.
ISQLT mass spectrometer at the Regional Center for Mycology and
Biotechnology, Al-Azhar University. Elemental analyses were carried
out at Micro Analytical Unit, Cairo University, Cairo, Egypt.
5-(Adamantan-1-yl)-1,3,4-thiadiazol-2-amine (1) was prepared
according to the reported methods [23,69].
Synthesis of N-(5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-2-
chloroacetamide (2) [23]
To a solution of the 5-(adamantan-1-yl)-1,3,4-thiadiazol-2-amine (1)
(5 mmol) in dioxane (20 mL) containing triethylamine (3 drops) as a
catalyst, (5 mmoL) of chloro-acetyl chloride in dioxane (5 mL) was
added the reaction mixture was stirred for 2hs, then poured into crushed
ice and the solid product was filtered off, washed with water to afford
the desired product.
12
Bioorganic Chemistry 110 (2021) 104794
Yield (80%) as white powder from ethanol; mp: 158–160 ◦ C; IR:
ν/cm− 1: 3160 (NH), 2905, 2849 (CH-aliph.), 1714 (C–
– O) 1612 (C–
– N);
1
H NMR (400 MHz, DMSO) δ 12.79 (s, 1H, NH, exchangeable by D2O),
4.42 (s, 2H, CH2), 2.06 (s, 4H, 2CH2), 2.01 (s, 5H, 3CH + CH2), 1.76 (s,
6H, 3CH2); 13C NMR (101 MHz, DMSO) δ 174.60 (C– – O), 165.66,
157.88(2C– – N), 43.12 (CH2), 42.76, 37.77, 36.28, 28.30 (Adamant. Cs);
MS (EI, 70 eV): m/z (%) = 311.81 [M+] (28.75%), 111.18 (100%); Anal.
Calcd for C14H18ClN3OS (311.83): C, 53.93; H, 5.82; N, 13.48; Found: C,
53.88; H, 5.84; N, 13.35%.
Synthesis of N-(5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-2-
cyanoacetamide (3)
A mixture of 5-(adamantan-1-yl)-1,3,4-thiadiazol-2-amine (1) (5
mmol) and 3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxopropanenitrile (5
M.M.S. Wassel et al. Bioorganic Chemistry 110 (2021) 104794

Fig. 8a. 2D interaction maps of compound 14c inside 1M17 active site.

Fig. 8b. 3D interaction maps of compound 14c inside 1M17 active site.

mmol) in toluene (20 mL) was heated under reflux for 30 min., after 162.73, 158.13 (2C–– N), 115.63(CN), 56.48(CH2), 43.10, 37.77, 36.27,
cooling the formed precipitate was filtered off, dried. 28.30, 26.50 (Adamant. Cs); MS (EI, 70 eV): m/z (%) = 302.48 [M+]
Yield (70%) as white powder from ethanol; mp: 180–182 ◦ C; IR: (10.13%), 73.99 (100%); Anal. Calcd for C15H18N4OS (302.40): C,
ν/cm− 1: 3348 (NH), 2965, 2850 (CH-aliph.), 2263 (CN), 1720 (C– – O) 59.58; H, 6.00; N, 18.53; Found: C, 59.78; H, 6.02; N, 18.65%.
1
1617 (C– N); H NMR (400 MHz, DMSO) δ 6.95 (s, 1H, NH, exchange­
– Synthesis of N-(5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl)ben­
able by D2O), 4.07 (s, 2H, CH2), 2.05 (s, 4H, 2CH2), 2.00 (s, 5H, 3CH + zamide (4)
CH2), 1.74 (s, 6H, 3CH2); 13C NMR (101 MHz, DMSO) δ 174.48 (C– – O), A mixture of 5-(adamantan-1-yl)-1,3,4-thiadiazol-2-amine (1) (5

13
M.M.S. Wassel et al. Bioorganic Chemistry 110 (2021) 104794

Fig. 9a. 2D interaction maps of compound 17 inside 1M17 active site.

Fig. 9b. 3D interaction maps of compound 17 inside 1M17 active site.

mmol) and benzoyl chloride (5 mmol) in dioxane (20 mL) was heated
under reflux for 10 hs, and the reaction mixture was left to cool, the
formed precipitate was filtered off then dried.
Yield (65%) as white powder from ethanol; mp: 258–260 ◦ C; IR:
ν/cm− 1: 3138 (NH), 2899, 2847 (CH-aliph.), 1670 (C– – O) 1602 (C– – N);
1
H NMR (400 MHz, DMSO) δ 12.62 (s, 1H, NH, exchangeable by D2O),
8.03 (d, J = 7.2 Hz, 2H, Ar- H), 7.59 (t, J = 7.4 Hz, 1H, Ar- H), 7.49 (t, J
= 7.6 Hz, 2H, Ar- H), 2.00 (s, 4H, 2CH2), 1.97 (s, 5H, 3CH + CH2), 1.69
(s, 6H, 3CH2); 13C NMR (101 MHz, DMSO) δ 174.22(C– – O), 167.78,
159.17(C– – N), 133.31, 132.27, 129.72, 129.08, 129.02, 128.80 (6Ar-
Cs), 43.15, 37.72, 36.32, 28.34 (Adamant. Cs); MS (EI, 70 eV): m/z (%)
= 339.3 [M+] (28.99%), 72.91 (100%); Anal. Calcd for C19H21N3OS
(339.46): C, 67.23; H, 6.24; N, 12.38; Found: C, 67.11; H, 6.28; N,
12.18%.
Synthesis of 3-((5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl)
imino)indolin-2-one (5)
A mixture of 5-(adamantan-1-yl)-1,3,4-thiadiazol-2-amine (1) (5
mmol) and isatin (5 mmol), containing acetic acid (3 drops) as a catalyst
in absolute ethanol (20 mL) was exposed to reflux for 32hs, the reaction
mixture was left to cool, and the solid product so formed was collected
by filtration and crystallized from the proper solvent.
Yield (70%) as Orange powder from ethanol; mp: 155–157 ◦ C; IR:
ν/cm− 1: 3246 (NH), 2890, 2845 (CH-aliph.), 1727 (C– – O) 1614 (C–– N);
1
H NMR (400 MHz, DMSO) δ 11.02 (s, 1H, NH, exchangeable by D2O),

14
M.M.S. Wassel et al.
7.48 (t, J = 7.6 Hz, 1H, Ar- H), 7.39 (d, J = 7.2 Hz, 1H, Ar- H), 6.96 (t, J
= 7.4 Hz, 1H, Ar- H), 6.83 (d, J = 7.6 Hz, 1H, Ar- H), 1.93 (s, 4H, 2CH2),
1.81 (s, 5H, 3CH + CH2), 1.61 (s, 6H, 3CH2); 13C NMR (101 MHz,
DMSO) δ 168.89 (C– – O), 168.27, 159.78, 151.24(3C– – N), 138.84,
130.84, 125.13, 123.21, 118.28, 112.71(6Ar-Cs), 42.29, 38.04, 36.09,
28.11 (Adamant. Cs); MS (EI, 70 eV): m/z (%) = 364.22 [M+] (33.21%),
119.26 (100%); Anal. Calcd for C20H20N4OS (364.47): C, 65.91; H, 5.53;
N, 15.37; Found: C, 65.94; H, 5.68; N, 15.51%.
Synthesis of 3-((5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl)
amino)pentane-2,4-dione (6)
To a solution of 5-(adamantan-1-yl)-1,3,4-thiadiazol-2-amine (1) (5
mmol) in absolute ethanol (20 mL) 3-chloroacetyl acetone (5 mmol)
containing piperidine (2 drops) as a catalyst was added then heated
under reflux for 8 hs, the reaction mixture was left to cool, and the
obtained product was filtered and crystallized from proper solvent.
Yield (72%) as brown powder from ethanol; mp: 120–122 ◦ C; IR:
ν/cm− 1: 3199 (NH), 2948, 2844, 2804 (CH-aliph.), 1699, 1676 (C– – O)
1617 (C– – N); 1H NMR (400 MHz, DMSO) δ 9.48 (s, 1H, NH, exchange­
able by D2O), 3.10 (s, 1H, CH-methylinic), 2.15 (s, 3H, CH3), 2.04 (s, 3H,
CH3), 1.91 (s, 5H, 3CH + CH2), 1.79 (s, 4H, 2CH2), 1.72 (s, 6H, 3CH2);
13
C NMR (101 MHz, DMSO) δ 168.94, 168.15(C– – O), 162.83, 154.89
(C– N), 81.83 (CH ), 43.90, 42.14, 38.07, 36.04, 28.08, 27.97
– –
(Adamant. Cs), 22.49, 22.18 (2CH3); MS (EI, 70 eV): m/z (%) = 333.45
[M+] (9.02%), 123.69 (100%); Anal. Calcd for C17H23N3O2S (333.45):
C, 61.23; H, 6.95; N, 12.60; Found: C, 61.35; H, 7.05; N, 12.51%.
Synthesis of ethyl 2-((5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl)
amino)-3-oxobutanoate (7)
A mixture of 5-(adamantan-1-yl)-1,3,4-thiadiazol-2-amine 1 (5
mmol), ethyl 3-chloroacetoacete (5 mmol) containing piperidine (2
drops) as a catalyst in 20 mL of absolute ethanol was heated under reflux
for 8 hs, the reaction mixture was left to cool, and the formed precipitate
was filtered off, dried, and recrystallized from ethanol.
Yield (65%) as yellow powder; mp: 140–142 ◦ C; IR: ν/cm− 1: 3208
(NH), 2901, 2849 (CH-aliph.), 1698 (C– – O) 1620 (C– – N); 1H NMR (400
MHz, DMSO) δ 8.69 (s, 1H, NH, exchangeable by D2O), 4.23 (q, 2H, J =
6.60, 2H, CH3–CH2–), 3.03 (s, 1H, CH-methylinic), 2.87 (s, 3H, CH3),
1.93 (s, 4H, 2CH2), 1.81 (s, 5H, 3CH + CH2), 1.62 (s, 6H, 3CH2), 1.24 (t,
J = 6.8 Hz, 3H, CH3–CH2–); 13C NMR (101 MHz, DMSO) δ 175.15,
168.29 (2C– – O), 158.92, 151.27(C– – N), 77.82 (CH–), 60.56 (CH3-
CH2–), 43.90, 42.43, 42.25, 37.97, 36.14, 36.06, 28.15 (Adamant. Cs),
22.51(CH3), 14.66(CH3–CH2–); MS (EI, 70 eV): m/z (%) = 363.89
[M+] (14.09%), 56.18 (100%); Anal. Calcd for C18H25N3O3S (363.48):
C, 59.48; H, 6.93; N, 11.58; Found: C, 59.23; H, 7.18; N, 11.48%.
Synthesis of 2-(adamantan-1-yl)imidazo[2,1-b][1,3,4]thiadia­
zol-6-ol (8)
A mixture of N-(5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-2-chlor­
oacetamide (2) (5 mmol) in dioxane (15 mL) containing triethyl amine
(3 drops) was refluxed for 8hs, and then poured into crushed ice to
afford precipitate which was filtered off, washed with water.
Yield (75%) as white powder from ethanol; mp: 320–322 ◦ C; IR:
ν/cm− 1: 3532 (OH), 2901, 2849 (CH-aliph.), 1571 (C– – N); 1H NMR
(400 MHz, DMSO) δ 12.82 (s, 1H, OH, exchangeable by D2O), 4.05 (s,
1H, CH–), 2.04 (s, 4H, 2CH2), 1.99 (s, 5H, 3CH + CH2), 1.74 (s, 6H,
3CH2); 13C NMR (101 MHz, DMSO) δ 174.61(C–OH), 162.67, 158.04
(C–– N), 115.55 (CH–), 43.11, 37.98, 37.78, 36.27, 28.30, 27.92, 26.47
(Adamant. Cs); MS (EI, 70 eV): m/z (%) = 275.40 [M+] (17.17%),
118.98 (100%); Anal. Calcd for C14H17N3OS (275.37): C, 61.06; H, 6.22;
N, 15.26; Found: C, 61.01; H, 6.17; N, 15.16%.
Synthesis of N-(5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-2-
(piperidin-1-yl)acetamide (9)
To a solution of N-(5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-2-
chloroacetamide (2) (5 mmol) in dioxane (10 mL) and piperidine (5
mmol) with three drops of triethyl amine was refluxed for 8 hs, the re­
action mixture was left to cool, and the formed precipitate was filtered
off, dried, and recrystallized from ethanol.
Yield (66%) as creamy powder; mp: 200–202 ◦ C; IR: ν/cm− 1: 3136
15
Bioorganic Chemistry 110 (2021) 104794
(NH), 2900, 2847 (CH-aliph.), 1677 (C– – O) 1627 (C– – N); 1H NMR (400
MHz, DMSO) δ 8.67 (s, 1H, NH, exchangeable by D2O), 4.23 (s, 2H,
CH2), 2.79–2.76 (m, 2H, CH2-Pip.), 2.31–2.28 (m, 2H, CH2-Pip.), 1.85
(s, 4H, 2CH2), 1.79 (m, 5H, 3CH + CH2), 1.55 (s, 6H, 3CH2), 1.49–1.44
(m, 4H, 2CH2-Pip.), 1.38 (m, 2H, CH2-Pip.); 13C NMR (101 MHz, DMSO)
δ 174.25(C– – O), 157.71(C– – N), 60.14(CH2), 53.99 (2CH2-Pip.), 43.97,
43.14, 41.91, 37.72, 36.30, 28.31, 28.06 (Adamant. Cs), 25.04, 22.56,
22.16(3CH2-Pip.); MS (EI, 70 eV): m/z (%) = 360.22 [M+] (50.89%),
205.71 (100%); Anal. Calcd for C19H28N4OS (360.52): C, 63.30; H, 7.83;
N, 15.54; Found: C, 63.14; H, 7.74; N, 15.59%.
Synthesis of 2-amino-substituted-N-(5-(adamantan-1-yl)-1,3,4-
thiadiazol-2-yl)acetamide derivatives (10a, b)
A mixture of N-(5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-2-chlor­
oacetamide (2) (5 mmol), appropriate aromatic amine namely: p-methyl
aniline (5 mmol) and p-anisidine (5 mmol) containing triethylamine (3
drops) as a catalyst in 20 mL of absolute ethanol was heated under reflux
for 12hs, the reaction mixture was left to cool and the formed precipitate
was filtered off, dried, and recrystallized from proper solvent.
N-(5-(Adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-2-((p-methox­
yphenyl)amino)acetamide (10a)
Yield (72%) as dark brown powder from ethanol; mp: 245–247 ◦ C;
IR: ν/cm− 1: 3186 (NH), 2902, 2847 (CH-aliph.), 1705 (C– – O) 1615
(C–– N); 1H NMR (400 MHz, DMSO) δ 12.40 (s, 1H, NH, exchangeable by
D2O), 6.71 (d, J = 8.8 Hz, 2H, Ar-H), 6.52 (d, J = 8.8 Hz, 2H, Ar-H), 5.67
(s, 1H, NH, exchangeable by D2O), 3.98 (s, 2H, CH2), 3.62 (s, 3H, OCH3),
2.03 (s, 4H, 2CH2), 1.98 (s, 5H, 3CH + CH2), 1.73 (s, 6H, 3CH2); 13C
NMR (101 MHz, DMSO) δ 174.08 (C– – O), 170.65, 157.89 (C– – N),
151.72, 142.50, 115.07, 113.74 (6Ar-Cs), 55.74 (OCH3), 47.41(CH2),
43.14, 37.68, 36.29, 28.31(Adamant. Cs); MS (EI, 70 eV): m/z (%) =
398.48 [M+] (10.70%), 102.30 (100%); Anal. Calcd for C21H26N4O2S
(398.53): C, 63.29; H, 6.58; N, 14.06; Found: C, 63.22; H, 6.48; N,
14.18%.
N-(5-(Adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-2-(p-tolylamino)
acetamide (10b)
Yield (82%) as yellow powder from ethanol; mp: 280–282 ◦ C; IR:
ν/cm− 1: 3186 (NH), 2902, 2849 (CH-aliph.), 1708 (C– – O) 1619 (C–
– N);
1
H NMR (400 MHz, DMSO) δ 12.42 (s, 1H, NH, exchangeable by D2O),
6.89 (d, J = 8.4 Hz, 2H, Ar-H), 6.48 (d, J = 8.4 Hz, 2H, Ar-H), 5.83 (s,
1H, NH, exchangeable by D2O), 4.00 (s, 2H, CH2), 2.13 (s, 3H, CH3),
2.03 (s, 4H, 2CH2), 1.98 (s, 5H, 3CH + CH2), 1.72 (s, 6H, 3CH2); 13C
NMR (101 MHz, DMSO) δ 170.51(C– – O), 165.67, 157.89 (C– – N),
146.11, 129.81, 125.48, 112.82 (6Ar-Cs), 46.92 (CH2), 43.14, 42.76,
37.76, 37.68, 36.29, 28.31 (Adamant. Cs), 20.50 (CH3); MS (EI, 70 eV):
m/z (%) = 381.99 [M+] (16.17%), 70.40 (100%); Anal. Calcd for
C21H26N4OS (382.53): C, 65.94; H, 6.85; N, 14.65; Found: C, 65.91; H,
6.73; N, 14.68%.
Synthesis of 2-((5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl)
amino)thiazol-4(5H)-one (11)
A solution of N-(5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-2-chlor­
oacetamide (2) (5 mmol) and ammonium thiocyanate (5 mmol) in
ethanol (20 mL) was heated under reflux for 6 hs. The precipitate formed
upon cooling was isolated by filtration, then dried.
Yield (77%) as faint brown powder from ethanol; mp: 298–300 ◦ C;
IR: ν/cm− 1: 3121 (NH), 2902, 2846 (CH-aliph.), 1740 (C– – O) 1603
(C–– N); 1H NMR (400 MHz, DMSO) δ 12.24 (s, 1H, NH, exchangeable by
D2O), 4.07 (s, 2H, CH2), 2.05 (s, 4H, 2CH2), 1.99 (s, 5H, 3CH + CH2),
1.74 (s, 6H, 3CH2); 13C NMR (101 MHz, DMSO) δ 177.10, 174.49
(C–– O), 169.73, 165.49(C– – N), 66.82 (CH2), 38.34, 36.25, 35.98, 28.29
(Adamant. Cs); MS (EI, 70 eV): m/z (%) = 334.47 [M+] (13.68%), 83.32
(100%); Anal. Calcd for C15H18N4OS2 (334.46): C, 53.87; H, 5.42; N,
16.75; Found: C, 53.82; H, 5.38; N, 16.79%.
Synthesis of 2-(adamantan-1-yl)-5-imino-5,6-dihydro-7H-
[1,3,4]thiadiazolo[3,2-a]pyri-midin-7-one (12)
A mixture of N-(5-(adamantan-1-yl)-1, 3, 4-thiadiazol-2-yl)-2-cya­
noacetamide (3) (5 mmol) in dioxane (15 mL) was refluxed for 8 hs,
and then poured into crushed ice to afford precipitate which was
M.M.S. Wassel et al.
filtered, washed with water.
Yield (72%) as faint yellow powder from ethanol; mp: 302–304 ◦ C;
IR: ν/cm− 1: 3156 (NH), 2903, 2849 (CH-aliph.), 1718(C– – O), 1625
1
(C– N); H NMR (400 MHz, DMSO) δ 12.80 (s, 1H, NH, exchangeable by
– 1-(5-(Adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-6-amino-4-(4-
D2O), 4.42 (s, 2H, CH2), 2.06 (s, 4H, 2CH2), 2.01 (s, 5H, 3CH + CH2),
1.75 (s, 6H, 3CH2); 13C NMR (101 MHz, DMSO) δ 174.57 (C– – O),
165.64, 162.49, 157.90 (C– – N), 46.72 (CH2), 43.12, 37.77, 36.28,
36.08, 28.31, 28.07 (Adamant. Cs); MS (EI, 70 eV): m/z (%) = 303.83
[M+] (12.11%), 135.28 (100%); Anal. Calcd for C15H18N4OS (302.40):
C, 59.58; H, 6.00; N, 18.53; Found: C, 59.42; H, 6.08; N, 18.68%.
Synthesis of 3-substituted N-(5-(adamantan-1-yl)-1,3,4-thiadia­
zol-2-yl)-2-cyanoacrylamide derivatives (13a-c)
A mixture of 2-cyanoacetamide derivative 3 (5 mmol) and the
appropriate benzaldehyde derivatives (namely 4-methoxy or 4-chloro or
4-fluorobenzaldehyde) (5 mmol) in 20 mL absolute ethanol containing
piperidine (2 drops) as a catalyst was heated under reflux for 5 hs. The
obtained product was filtered and recrystallized from the proper solvent.
N-(5-(Adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-2-cyano-3-(4-
methoxyphenyl)acrylamide (13a)
Yield (70%) as yellow crystal from ethanol; mp: 136–138 ◦ C; IR:
ν/cm− 1: 3175 (NH), 3007,3003 (CH-arom), 2903, 2846 (CH-aliph.),
2245(CN), 1652(C– – O), 1586(C– – N); 1H NMR (400 MHz, DMSO) δ
13.89 (s, 1H, NH, exchangeable by D2O), 8.38 (s, 1H, CH-methylinic),
8.05 (d, J = 8.8 Hz, 2H, Ar-H), 7.16 (d, J = 8.8 Hz, 2H, Ar-H), 3.88 (s,
3H, OCH3), 2.07 (s, 4H, 2CH2), 2.00 (s, 5H, 3CH + CH2), 1.76 (s, 6H,
3CH2); 13C NMR (101 MHz, DMSO) δ 177.11 (C– – O), 163.49, 157.46
(C–– N), 152.15, 147.91, 133.45, 131.95, 124.87, 117.52, 115.41(CN),
105.69, 56.17 (OCH3), 42.55, 37.96, 36.21, 28.21 (Adamant. Cs); MS
(EI, 70 eV): m/z (%) = 420.81 [M+] (34.50%), 294.16 (100%); Anal.
Calcd for C23H24N4O2S (420.53): C, 65.69; H, 5.75; N, 13.32; Found: C,
65.69; H, 5.77; N, 13.41%.
N-(5-(Adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-2-cyano-3-(4-flu­
orophenyl) acrylamide (13b)
Yield (78%) as orange crystal from ethanol; mp: 144–146 ◦ C; IR:
ν/cm− 1: 3150 (NH), 3058 (CH-aro), 2901, 2847 (CH-aliph.), 2249(CN),
1678(C– – O), 1621 (C–– N); 1H NMR (400 MHz, DMSO) δ 11.93 (s, 1H,
NH, exchangeable by D2O), 8.76 (s, 1H, CH– methylinic), 8.39–8.25
(m, 1H, Ar-H), 8.04 (m, 1H, Ar-H), 7.80 (s, 1H, Ar-H), 7.38 (d, J = 8.8
Hz, 1H, Ar-H), 1.90 (s, 4H, 2CH2), 1.82 (s, 5H, 3CH + CH2), 1.62 (s, 6H,
3CH2); 13C NMR (101 MHz, DMSO) δ 176.33 (C– – O), 173.87, 168.42
(C–– N), 158.68, 151.39, 133.99, 133.70, 117.15, 116.93, 115.57 (CN),
104.82, 43.99, 43.10, 42.81, 42.48, 37.97, 37.85, 37.59, 36.27, 28.24,
27.91 (Adamant. Cs); MS (EI, 70 eV): m/z (%) = 408.81 [M+] (30.51%),
105.02 (100%); Anal. Calcd for C22H21FN4OS (408.50): C, 64.69; H,
5.18; N, 13.72; Found: C, 64.73; H, 5.11; N, 13.54%.
N-(5-(Adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-3-(4-chlor­
ophenyl)-2-cyanoacryl amide (13c)
Yield (73%) as yellow crystal from ethanol; mp: 112–114 ◦ C; IR:
ν/cm− 1: 3172 (NH), 3049 (CH-aro), 2902, 2847 (CH-aliph.), 2218(CN),
1681(C– – O), 1626 (C–– N); 1H NMR (400 MHz, DMSO) δ 12.52 (s, 1H,
NH, exchangeable by D2O), 8.26 (s, 1H, CH– methylinic), 7.93 (d, J =
8.4 Hz, 2H, Ar-H), 7.56 (d, J = 8.4 Hz, 2H, Ar-H), 1.96 (s, 4H, 2CH2),
1.90 (s, 5H, 3CH + CH2), 1.66 (s, 6H, 3CH2); 13C NMR (101 MHz,
DMSO) δ 171.68 (C– – O), 168.74, 168.03 (C– – N), 165.92, 149.66,
137.17, 132.29, 131.62, 129.79, 117.41, 110.92 (CN), 103.63, 44.06,
43.23, 42.72, 37.90, 36.32, 28.34, 28.28, 27.86 (Adamant. Cs); MS (EI,
70 eV): m/z (%) = 424.20 [M+] (12.54%), 256.57 (100%); Anal. Calcd
for C22H21ClN4OS (424.95): C, 62.18; H, 4.98; N, 13.18; Found: C,
62.22; H, 4.88; N, 13.28%.
Synthesis of 1-(5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-6-
amino-4-(4-substituted)-2-oxo-1, 2-dihydropyridine-3, 5-dicarbo­
nitrile derivatives (14a-c)
Equimolar quantities of 2-cyanoacetamide derivative 3 and the
appropriate 2-(arylidene)malono-nitrile (namely 2-(4-methox­
ybenzylidene)malononitrile, 2-(4-chlorobenzylidene)malono-nitrile,
and 2-(4-fluorobenzylidene)malononitrile (5 mmol) in 20 mL absolute
16
Bioorganic Chemistry 110 (2021) 104794
ethanol containing piperidine (2 drops) as a catalyst was heated under
reflux for 10–16 hs. The resulting solid was filtered off, dried, and
recrystallized from methanol.
methoxyphenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile
(14a)
Yield (69%) as yellow powder from methanol; mp: 160–162 ◦ C; IR:
ν/cm− 1: 3314, 3172 (NH2), 3029 (CH-aro), 2904, 2848 (CH-aliph.),
2223(CN), 1706(C– – O), 1605 (C–– N); 1H NMR (400 MHz, DMSO) δ 8.39
(s, 1H, Ar-H), 8.04 (d, J = 8.0 Hz, 1H, Ar-H), 7.96 (s, 1H, Ar-H), 7.19 (s,
2H, NH2 exchangeable by D2O), 7.15 (d, J = 8.0 Hz, 1H, Ar-H), 3.88 (s,
3H, –OCH3), 2.18 (s, 4H, 2CH2), 1.99 (s, 5H, 3CH + CH2), 1.74 (s, 6H,
3CH2); 13C NMR (101 MHz, DMSO) δ 164.82(C– – O), 163.49, 160.93
(C–– N), 152.18, 150.57, 143.81, 133.84, 133.45, 132.93, 124.84,
124.59, 115.68, 115.40 (2CN), 104.67, 77.32 (C-CN), 56.40(–OCH3),
43.05, 42.55, 37.95, 37.77, 36.26, 36.21, 28.29, 28.21(Adamant. Cs);
MS (EI, 70 eV): m/z (%) = 484.79 [M+] (76.06%), 409.21 (100%); Anal.
Calcd for C26H24N6O2S (484.58): C, 64.44; H, 4.99; N, 17.34; Found: C,
64.34; H, 5.07; N, 17.46%.
1-(5-(Adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-6-amino-4-(4-flu­
orophenyl)-2-oxo-1,2-dihydro-pyridine-3,5-dicarbonitrile (14b)
Yield (66%) as yellow powder from methanol; mp: 170–172 ◦ C; IR:
ν/cm− 1: 3280, 3142(NH2), 3077 (CH-aro), 2903, 2849 (CH-aliph.),
2227(CN), 1679 (C– – O), 1606 (C– – N); 1H NMR (400 MHz, DMSO) δ
8.06–7.97 (m, 1H, Ar-H), 7.73–7.68 (m, 1H, Ar-H), 7.50 (d, J = 8.8 Hz,
1H, Ar-H), 7.43 (s, 2H, NH2 exchangeable by D2O), 7.23 (d, J = 8.8 Hz,
1H, Ar-H), 2.04 (s, 4H, 2CH2), 1.98 (s, 5H, 3CH + CH2), 1.73 (s, 6H,
3CH2); 13C NMR (101 MHz, DMSO) δ 176.33(C– – O), 173.87, 162.28
(C–– N), 158.76, 154.28, 149.77, 134.13, 133.98, 133.53, 133.15,
131.91, 131.87, 130.70, 128.58, 117.51, 116.04, 115.83, 114.47 (2CN),
76.46 (C-CN), 43.16, 37.98, 36.33, 36.22, 28.33, 27.92 (Adamant. Cs);
MS (EI, 70 eV): m/z (%) = 472.13 [M+] (12.29%), 91.64 (100%); Anal.
Calcd for C25H21FN6OS (472.54): C, 63.54; H, 4.48; N, 17.79; Found: C,
63.45; H, 4.52; N, 17.97%.
1-(5-(Adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-6-amino-4-(4-
chlorophenyl)-2-oxo-1,2-dihydro pyridine-3,5-dicarbonitrile (14c)
Yield (68%) as yellow powder from methanol; mp: 150–152 ◦ C; IR:
ν/cm− 1: 3325, 3139 (NH2), 3034 (CH-aro), 2904, 2847 (CH-aliph.),
2226(CN), 1660 (C– – O), 1622 (C– – N); 1H NMR (400 MHz, DMSO) δ
7.94 (d, J = 8.4 Hz, 1H, Ar-H), 7.69 (d, J = 8.8 Hz, 1H, Ar-H), 7.63 (d, J
= 8.4 Hz, 1H, Ar-H), 7.56 (d, J = 8.5 Hz, 1H, Ar-H), 7.43 (s, 2H, NH2
exchangeable by D2O), 2.10 (s, 4H, 2CH2), 1.96 (s, 5H, 3CH + CH2),
1.72 (s, 6H, 3CH2); 13C NMR (101 MHz, DMSO) δ 171.82(C– – O), 168.04,
160.59(C– – N), 157.50, 150.80, 143.14, 139.51, 137.59, 132.60, 130.56,
130.17, 129.11, 116.95, 114.33 (2CN), 103.63, 82.68 (C-CN), 44.01,
43.16, 42.52, 37.99, 36.22, 35.95, 28.30, 28.22, 27.98 (Adamant. Cs);
MS (EI, 70 eV): m/z (%) = 488.12 [M+] (16.83%), 139.21 (100%); Anal.
Calcd for C25H21ClN6OS (488.99): C, 61.41; H, 4.33; N, 17.19; Found: C,
61.28; H, 4.39; N, 17.25%.
Synthesis of 1-(5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-4,6-
dimethyl-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (15)
A mixture of N-(5-(adamantan-1-yl)-1, 3, 4-thiadiazol-2-yl)-2-cya­
noacetamide (3) (5 mmol) and acetylacetone (5 mmol) in absolute
ethanol (20 mL) containing piperidine (2 drops) as catalyst was heated
under reflux for 8 hs, the resulting solid was filtered off, dried, and
recrystallized from ethanol.
Yield (73%) as creamy powder from ethanol; mp: 102–104 ◦ C; IR:
ν/cm− 1: 2905, 2848 (CH-aliph.), 2223(CN), 1668 (C– – O), 1598 (C–– N);
1
H NMR (400 MHz, DMSO) δ 6.56 (s, 1H, –CH pyridine), 2.42 (s, 3H,
–CH3), 2.09 (s, 3H, –CH3), 2.08 (s, 4H, 2CH2), 1.89 (s, 5H, 3CH +
CH2), 1.77 (s, 6H, 3CH2); 13C NMR (101 MHz, DMSO) δ 162.47(C– – O),
160.49, 158.30(C– – N), 151.70, 118.62, 115.41, 110.56, 98.96, 43.23,
43.05, 36.41, 36.11, 28.33, 28.26, 21.48, 20.80 (Adamant. Cs); MS (EI,
70 eV): m/z (%) = 366.27 [M+] (32.49%), 80.31 (100%), Anal. Calcd
for C20H22N4OS (366.48): C, 65.55; H, 6.05; N, 15.29; Found: C, 65.62;
H, 6.21; N, 15.36%.
M.M.S. Wassel et al.
N-(5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-2-oxo-2H-chro­
mene-3-carboxamide (16)
A mixture of N-(5-(adamantan-1-yl)-1, 3, 4-thiadiazol-2-yl)-2-cya­
noacetamide 3 (5 mmol) and salicylaldehyde (5 mmol) in 20 mL abso­
lute ethanol containing piperidine (2 drops) as catalyst was heated
under reflux for 5 hs., the resulting solid was filtered off, dried, and
recrystallized from dioxane.
Yield (77%) as yellow crystal; mp: 128–130 ◦ C; IR: ν/cm− 1: 3349
(NH), 3042 (CH-aro), 2936, 2831 (CH-aliph.), 1712, 1695 (2C– – O),
1610 (C– – N); 1H NMR (400 MHz, DMSO) δ 8.99 (s, 1H, CH-chromene),
8.04 (d, J = 7.5 Hz, 1H, Ar-H), 7.83 (t, J = 7.8 Hz, 1H, Ar-H), 7.58 (d, J
= 8.0 Hz, 1H, Ar-H), 7.51 (t, J = 7.3 Hz, 1H, Ar-H), 4.35 (s, 1H, NH
exchangeable by D2O), 2.08 (s, 4H, 2CH2), 2.05 (s, 5H, 3CH + CH2),
1.78 (s, 6H, 3CH2); 13C NMR (101 MHz, DMSO) δ 175.18, 160.52(C– – O),
157.29, 154.57 (C– – N), 149.16, 135.49, 131.11, 125.98, 118.71,
118.49, 116.91, 43.14, 37.86, 36.28, 28.32 (Adamant. Cs); MS (EI, 70
eV): m/z (%) = 407.33 [M+] (21.25%), 91.55 (100%); Anal. Calcd for
C22H21N3O3S (407.49): C, 64.85; H, 5.19; N, 10.31; Found: C, 64.68; H,
5.09; N, 10.56%.
Synthesis of N-(5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-2-
cyano-2-(4-oxo-3-phenylthiazo-lidin-2-ylidene)acetamide (17)
To a solution of finely powdered potassium hydroxide (0.01 mol) in
dry DMF (10 mL), 2-cyanoacetamide derivative 3 (5 mmol) was added
and stirred for 0.5-1hr., then phenyl isothiocyanate was added slowly
after complete addition, the reaction mixture was stirring for an addi­
tional 6 hs. Then methyl chloroacetate (5 mmol) and the reaction
mixture was stirred for further 4 h, then poured into crushed ice. The
resulting precipitate was filtrated off, dried, and recrystallized from
ethanol.
Yield (72%) as dark green powder ; mp: 250–252 ◦ C; IR: ν/cm− 1:
3136 (NH), 3055 (CH-Aro), 2901, 2847 (CH-aliph.), 2216(CN), 1732,
1677 (C– – O), 1629 (C– – N); 1H NMR (400 MHz, DMSO) δ 9.84 (s, 1H,
NH, exchangeable by D2O), 7.52 (d, J = 7.6 Hz, 2H, Ar-H), 7.34 (d, J =
7.2 Hz, 2H, Ar-H), 7.13 (t, J = 7.3 Hz, 1H, Ar-H), 4.05 (s, 2H, CH2), 2.01
(s, 4H, 2CH2), 1.97 (s, 5H, 3CH + CH2), 1.75 (s, 6H, 3CH2); 13C NMR
(101 MHz, DMSO) δ 180.06 (C– – C–S), 174.00, 169.75 (C– – O), 166.27,
163.09 (C– – N), 150.96, 139.94, 136.44, 135.78, 129.68, 128.88,
127.26, 124.05, 114.68 (CN), 73.58, 43.18, 43.11, 42.26, 41.49, 37.99,
36.41, 36.27, 28.31, 28.18, 27.99 (Adamant. Cs + CH2); MS (EI, 70 eV):
m/z (%) = 477.80 [M+] (20.43%), 303.40 (100%); Anal. Calcd for
C24H23N5O2S2 (477.60): C, 60.36; H, 4.85; N, 14.66; Found: C, 60.48; H,
4.82; N, 14.45%.
4.2. Biological evaluation
The method of all biological evaluation were performed according to
our reported methods [79–83] and represented in supplementary
material.
4.3. Molecular docking simulation
Molecular docking targeting EGFR was performed using Molecular
Operating Environment software 10.2008 (MOE), Chemical Computing
Group Inc., Montreal, Quebec, Canada. X-ray crystallography structure
of EGFRwt co-crystalized with original ligand 4-anilinoquinazoline in­
hibitor (erlotinib) (PDB: 1M17) [78] were downloaded and obtained
from the protein data bank. All water molecules were deleted then the
active site was generated according to standard protocol and according
to our reported methods [16,17]. The structure of the newly designed
and most promising compounds was drawn using ChemDraw14.0 then
exported to MOE. The new structure was potentate 3D and minimized
energy using MMFF94x forcefield. The co-crystalized ligand was
exposed to validation process with RSMD 1.99 Å using Triangle Matcher
placement method and London dG as docking score energy.
17
Bioorganic Chemistry 110 (2021) 104794
CRediT authorship contribution statement
Mohammed M.S. Wassel: Conceptualization, Methodology, Inves­
tigation, Resources, Writing - original draft. Yousry A. Ammar:
Conceptualization, Methodology, Software, Formal analysis, Writing -
original draft, Writing - review & editing, Supervision, Project admin­
istration. Gameel A.M. Elhag Ali: Conceptualization, Methodology,
Investigation, Resources, Writing - original draft, Supervision. Amany
Belal: Methodology (Biology) and participation in the revise of manu­
script. Ahmed B.M. Mehany: Methodology (Biology). Ahmed Ragab:
Conceptualization, Software, Formal analysis, Validation, Methodology,
Investigation, Data curation, Writing - original draft, Writing - review &
editing, Visualization.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgment
Dr. Mohammed M. S. Wassel wants to thank Dr. Ahmed Ragab,
lecturer of Organic Chemistry, Faculty of Science (Boys), Al-Azhar
University, for his real sharing, valuable creative thoughts, honest
advice, helpful supervision, sincere encouragement, and continual help
throughout the development of this work. Besides, all authors thank Dr.
Amany Belal and Dr. Ahmed B. M. Mehany for their efforts in the bio­
logical part (methodology) as well as their participation in revise of the
manuscript.
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bioorg.2021.104794.
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