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Isoniazid‐phytochemical conjugation: A new approach for potent and less

toxic anti‐TB drug development

Article  in  Chemical Biology & Drug Design · April 2020

DOI: 10.1111/cbdd.13685

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Received: 17 January 2020 
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  Accepted: 14 March 2020

DOI: 10.1111/cbdd.13685

REVIEW ARTICLE

Isoniazid–phytochemical conjugation: A new approach for potent

and less toxic anti-TB drug development

Shasank S. Swain1,2   | Sudhir K. Paidesetty3   | Rabindra N. Padhy2   |

Tahziba Hussain1

1
Division of Microbiology and NCDs,
ICMR-Regional Medical Research Centre,
Abstract
Bhubaneswar, India Mycobacterium tuberculosis (Mtb) causes one of the most grievous pandemic in-
2
Central Research Laboratory, Institute fectious diseases, tuberculosis (TB), with long-term morbidity and high mortality.
of Medical Sciences and SUM Hospital,
The emergence of drug-resistant Mtb strains, and the co-infection with human im-
Siksha ‘O’ Anusandhan Deemed to be
University, Bhubaneswar, India munodeficiency virus, challenges the current WHO-TB stewardship programs. The
3
Department of Pharmaceutical Chemistry, first-line anti-TB drugs, isoniazid (INH) and rifampicin (RIF), have become exten-
School of Pharmaceutical Sciences, Siksha sively obsolete in TB control from chromosomal mutations during the last decades.
‘O’ Anusandhan Deemed to be University,
Bhubaneswar, India
However, based on clinical trial statistics, the production of well-tolerated anti-TB
drug(s) is miserably low. Alternately, semi-synthesis or structural modifications of
Correspondence first-line obsolete antitubercular drugs remain as the versatile approach for getting
Shasank S. Swain, Division of
Microbiology and NCDs, ICMR- some potential medicines. The use of any suitable phytochemicals with INH in a
Regional Medical Research Centre, hybrid formulation could be an ideal approach for the development of potent anti-TB
Chandrasekharpur, Bhubaneswar, Odisha
drug(s). The primary objective of this review was to highlight and analyze avail-
751023, India.
Email: swain.shasanksekhar86@gmail.com able INH–phytochemical hybrid research works. The utilization of phytochemicals
through chemical conjugation is a new trend toward the development of safer/non-
Funding information
toxic anti-TB drugs.
ICMR-Young Scientist Scheme,
Grant/Award Number: 3128113 and
R.12014/14/2017-HR KEYWORDS
co-infection with human immunodeficiency virus, first-line anti-TB drugs, INH–phytochemical hybrid,
Mycobacterium tuberculosis

1  |   IN TRO D U C T IO N failure of first-line, second-line (ethambutol, moxifloxacin,

Mycobacterium tuberculosis (Mtb) is a slow-growing rather
staggering pathogen, and nearly about one-third of the world
population suffers from this infection (WHO, 2016, 2018).
According to the World Health Organization (WHO) global
tuberculosis (TB) statistical record, each year, approximately
8–10  million new Mtb cases were recorded (WHO, 2016,
2018). Notably, African and Asian countries were suffer-
ing more than the Western Pacific regions; unfortunately,
6–7 million new Mtb cases were recorded from African and
Asian countries (WHO, 2018). Furthermore, 60% of new Mtb
cases were recorded from China, India, Indonesia, Nigeria,
Pakistan, and South Africa in 2015 (WHO, 2016). The
kanamycin, capreomycin, ethionamide, para amino-salicylic
acid, cycloserine, etc.,) drugs and ineffectiveness of “di-
rectly observed treatment short” (DOTS) drugs are the lead-
ing causes for the emergence of multidrug-resistant (MDR),
extensively drug-resistant (XDR), extremely drug-resistant
(XXDR), and totally drug-resistant (TDR) Mtb stains, world-
wide (Caminero, Sotgiu, Zumla, & Migliori, 2010; Zhang &
Yew, 2015). Besides, the increased rate of TB-HIV (human
immunodeficiency virus) and other comorbidity incidences
are the major obstacles for TB control; particularly, 0.4 mil-
lion of mortality were recorded from TB-HIV co-infection
in 2015–16 (Al-Humadi, Al-Saigh, & Al-Humadi, 2017;
Sandhu, 2011; WHO, 2018).

Chem Biol Drug Des. 2020;00:1–17. wileyonlinelibrary.com/journal/cbdd © 2020 John Wiley & Sons A/S.     1 |
 |
2       SWAIN et al.
In 1944 after the discovery of streptomycin, TB treatment
had been revolutionized, and accordingly, several classes of
anti-TB drugs were introduced, which were active for a short
period (Koul, Arnoult, Lounis, Guillemont, & Andries, 2011;
Zhang, Post-Martens, & Denkin, 2006). In the early stage,
50%–70% of TB cases could be controlled with an ongoing
combined drug regimen, but the current therapies are not
competent enough in front of newly emerged MDR-TB strains
(WHO, 2018). Alarmingly, 9.5% of MDR-TB cases approxi-
mately improved to XDR-TB cases in 117 countries, creating
fear of undue decimations (WHO, 2018). Comparatively, an-
ti-TB drugs have become ineffective rapidly than drugs used
against other infectious diseases. Consequently, the expensive
and time-consuming treatment adds fuel to the fire of public
health morbidity rate from MDR-TB (Zhang et al., 2006).
Thus, the development of an alternative potent anti-TB drug
is essential to combat against MDR-Mtb.
The nitrogen heterocyclic ring of INH remains charac-
teristically potent in TB control since 1967. From the struc-
ture–activity relationship (SAR), the active pharmacophore
of INH is able to disturb lipid metabolism, and syntheses of
proteins and nucleic acids in Mtb (Pal et al., 2018). However,
in the long-term use, abuse and consequent point mutation
in drug-targeted Mtb enzymes are possible reasons for INH
resistance (Zhang & Yew, 2015). Today, INH being the front-
line anti-TB drug and cannot be ordinarily replaced due to
the unavailability of any well-tolerated medicines for anti-TB
therapy. The syntheses of novel INH derivatives have been
continuing by several academic and industrial researchers
from the last decades. Strategically, the development of novel
INH hybrids using isolated phytochemicals, in place of any
synthetic moiety, could be taken as an ingenious method
in the current anti-TB drug discovery. Indeed, the sophisti-
cated genetic machinery of Mtb is unable to overcome the
hybrid strength of phytochemical–INH drug combination.
Additionally, a hybrid molecule may act in multiple drug ac-
tions with balance pharmacokinetics and toxicity profiles.
This present review focuses and highlights the events of
INH–phytochemical conjugations as a newly adopted trend
for reactivation of the primary INH through phytochemicals
as well as utilization of more phytochemicals toward the de-
velopment of well-tolerated safe anti-TB agents.
2  |   M E C H A N IS M O F A N T I-TB
DRU G RE S I STA NC E TA RG E T ING
CE L L WA L L SY N T H E SIS
Control of this acid-fast bacilli is a challenge with ongoing
empiric therapies. The Mtb cell wall consists of three co-
valently attached macromolecules, namely peptidoglycan,
arabinogalactan, and mycolic acid, known as “mycolyl-ara-
binogalactan-peptidoglycan” or mAGP complex. The role
of mycolic acid was well known, and several anti-TB drugs
were developed targeting cell wall-associated enzymes. For
example, katG is a significant obstacle for INH, ethambu-
tol, ethionamide, and delamanid drugs targeting Mtb cell
wall synthesis inhibition. From previous records, a mutation
in the S315T position on katG is the most pervasive muta-
tion for INH resistance up to 90% cases (Ando et al., 2011).
Recently, several newer molecular studies found that inhA,
kasA, ahpC, niA, ndh, and FadE24 were involved for INH re-
sistance (Gygli, Borrell, Trauner, & Gagneux, 2017; Hameed
et al., 2018; Palomino & Martin, 2014; Xu, Jia, Huang, Sun,
& Zhang, 2015). Similarly, mutations in embB and embC
cause resistance targeting arabinosyl transferases associated
with mycobacterial cell wall synthesis (Palomino & Martin,
2014). Particularly, chromosomal mutations in embB with
decaprenyl-phosphoryl-5-phosphoribose (DPPR) synthase-
associated gene, ubiA, were associated with ethionamide
resistance (Pourakbari, Mamishi, Mohammadzadeh, &
Mahmoudi, 2016). The cell wall targeting anti-TB drug, cy-
closerine, clofazimine, amoxicillin, meropenem, imipenem,
thioacetazone, and delamanid, is resistant due to mutations,
individually (see Table 1).
Indeed, several unique lipids are present in the Mtb cell
envelope act as a permeability barrier for the anti-TB drug.
As a result, the lipid barrier plays a vital role in Mtb drug
resistance from recent research findings (Cholo, Mothiba,
Fourie, & Anderson, 2017; Lyonnet et al., 2014). The struc-
turally distinct mycobacterial lipids derived from malonyl co-
enzyme A (CoA) and assembled with acyl-CoA carboxylases
(ACC) subunits, AccA1 to AccA3, AccD1 to AccD6, AccE5.
Strategically, these ACC subunits are essential factors for the
synthesis of Mtb fatty acids, mycolates, and lipid association
with biotin, also known as vitamin B7 and a crucial cofactor
in the post-translational process (Gler et al., 2012). Thus, any
enzymes in the biotin-ACC biosynthesis pathway could be a
new target for the development of newer anti-TB drugs.
3  |   PHY TOCHEMI CAL S I N AN T I - T B
DRUG DEVELOPMENT
Throughout the history of drug discovery, natural products
played a significant role by proving newer lead chemicals
and pharmacophores to mainstream medicine. A significant
number of active secondary phytochemicals having potent
anti-TB activity at some lower minimum inhibitory concen-
tration (MIC) were recorded (Xu et al., 2004). For example,
phytochemicals, namely, calanolide A was active against Mtb
within MIC value, 0.0031–0.016  mg/ml, dihydro-β-agaro-
furan sesquiterpenes with 0.0062  mg/ml, ethyl-p-methox-
ycinnamate within 0.242–0.485  μg/ml, mono-O-methyl
curcumin isoxazole within 0.195–3.125  μg/ml, myricetin
with 0.250 mg/ml, plumbagin within 0.0015–0.0033 mg/ml,
T A B L E 1   Genetic factors involved in drug resistance of first-line and second-line anti-tuberculosis (TB) drugs targeting cell wall and mycolic acid inhibition

Minimum
SWAIN et al.

inhibitory
Chemical class Inhibition target (associated concentration Genetic
Drug (year) (activity type) action) (mg/L) factor Associated function Drug resistance Reference
a
Isoniazid   Isonicotinic acid Enoyl-(acyl carrier protein) 0.02–0.2 katG Intracellular survival Modification Forbes, Kuck, and Peets
(1952) (bactericidal) reductase including, inhA Mycolic acid biosynthesis overexpression of (1962); Timmins and
catalase–peroxidase, NADH- drug target due to Deretic (2006)
kasA Fatty acid biosynthesis
dependent enoyl ACP, mutations
3-Oxoacy ACP, β-Ketoacyl AhpC Defense from oxidative stress and altered efflux
ACP; inhibition of cell wall niA Associated with efflux pump pump activity
synthesis) and pro-drug
FadE24 Degradation lipid and fatty acid
conversion
ndh Electron transference from NADH to the respiratory
chain
FabG1 Fatty acid biosynthesis pathway
Ethambutola  Ethylenediamine Arabinosyl transferase 1–5 emb A, B Associated with biosynthesis of the mycobacterial cell Change and Grumbach et al. (1956);
(1961) (bacteriostatic) (inhibition of arabinogalactan and C wall overexpression of Timmins and Deretic
synthesis) embR embCAB operon synthesis regulator drug target; and (2006)
altered efflux pump
rmLD dTDP-L-rhamnose biosynthesis
activity
iniA Associated with efflux pump
Ethionamidea  Isoconitic acid Inhibition of mycolic acid 2.5–25 ethA Activates the pro-drug ethionamide Alteration and Cáceres et al. (1997);
(1956) derivative synthesis by binding ethR Regulates transcriptional repressor protein EthR overexpression Thee, Garcia-Prats,
(bacteriostatic) to the ACP reductase drug target due to Donald, Hesseling, and
KasA Involved in fatty acid biosynthesis
InhA (disrupts cell wall mutation Schaaf (2016)
biosynthesis) inhA Mycolic acid biosynthesis
inhA pro. Regulation of expression of inhA
Cycloserine Serine derivative Inhibition of peptide-glycan 25–30 alr Associated with d-alanine required for cell wall Overexpression of Chen, Plekar, Gordon,
(1955) (bacteriostatic) synthesis by blocking biosynthesis resistance gene and Cole (2012); Upton
d-alanine racemase enzyme ddl Involved in cell wall formation et al. (2015)
(inhibition of cell wall
Ald Associated with cell wall synthesis
synthesis)
cycA Transport across the cytoplasmic membrane
Delamanid Nitroimidazole Impeding the synthesis of   fgd1 Catalyzes oxidation of glucose-6-phosphate to Mutations on Dookie, Rambaran,
(2014) (bactericidal) mycolic acid 6-phosphogluconolactone reductive activating Padayatchi, Mahomed,
fbiC Participates in a portion of the F420 biosynthetic gene and Naidoo (2018)
pathway Tiwari et al. (2018)

fbiA Required for coenzyme F420 production from FO

fbiB Required for coenzyme F420 production from FO
ddn Converts bicyclic nitroimidazole drug candidate pa-824
to 3 metabolites
  

a
|

First-line anti-drugs, and rest of all are second-line anti-TB drugs.

   3
 |
4       SWAIN et al.
quercetin-3-O-β-d-glucoside with 0.250 mg/ml, and 7-meth-
yljuglone with 0.57  µg/ml, have been identified (Mathew
et al., 2010; Xu et al., 2004; Zhang et al., 2006). The potent
naphthoquinone class of phytochemical, the plumbagin iso-
lated from Plumbago rosea as well as other aromatic plants,
was reported as an active agent against co-infected Mtb-HIV
with MIC value >0.003 mg/ml (Sen & Chakraborty, 2016;
Velderrain-Rodríguez et al., 2018). Thus, the present sce-
nario has encouraged pursuing some novel approaches of
integrated anti-TB drug discovery by using the knowledge
of traditional Indian medicine, Ayurveda, and traditional
Chinese medicine (Atanasov et al., 2015; Bernardini, Tiezzi,
Laghezza, & Ovidi, 2018; Sen & Chakraborty, 2016).
Advanced cost-effective isolation techniques and instru-
mental facility combination with several newer medicinal
chemistry approach should help to locate several new classes
of active anti-TB candidates targeting some pertinent patho-
genic target enzymes (Bernardini et al., 2018; Brown &
Wright, 2016; Lage et al., 2018). Mainly, infections are one of
the productive therapeutic areas for natural products or phy-
tochemicals than any other therapeutic area. Unfortunately,
isolated phytochemicals could not be used directly due to
some unknown pharmacological chemical constraints or lack
of drug-likeness properties (Hughes et al., 2008; Yao, Liu,
Xu, Zhu, & Xu, 2017).
4  |   IN H – P HY TO CHE MICA L
H Y B R ID IN A N T I-T B D RU G
DE V ELO P M E N T
Today, the development of a newer anti-TB drug is a chal-
lenge for any pharmaceutical company in the face of the
higher rejection rate of anti-TB agents in clinical trials.
However, except delamanid, bedaquiline, and pretomanid,
no newer anti-TB drugs have been approved during the last
two decades (Dias, Urban, & Roessner, 2012; Lage et al.,
2018). However, individual phytochemicals hardly satisfy
the demands of drug ability and pharmacokinetics as spe-
cific to any ailment (Chen, Li, Yao, & Xu, 2015; Hu et al.,
2017). Indeed, modern combinatorial chemistry with ad-
vanced instrumentations provides a new hope to improve
success rates of more unique chemical entities in drug dis-
covery (Bernardini et al., 2018; García, Bocanegra-García,
Palma-Nicolás, & Rivera, 2012; Gupta, Kumar, Bisht, &
Kaushik, 2017). Thus, chemical conjugation of a natural
bioactive constituent with an existing anti-TB drug could
be an ideal approach in the development of hybrid anti-TB
chemical moiety followed by protocols of medicinal chem-
istry (Carvalho, Silva, Souza, Lourenço, & Vicente, 2008;
Dandawate et al., 2014; Hussein, Aboul-Fadl, & Hussein,
2005; Quan, Nagalingam, Payne, & Triccas, 2017). Based
on the principle of SAR, the hybridization of two or more
pharmacophore moieties produces more active functional
groups toward control growth and cell divisions of Mtb.
Additionally, a significant amount of results on phyto-
chemical conjugation were recorded (Hu et al., 2017; Rizvi,
Khan, Jabeen, Siddiqui, & Choudhary, 2019). For example,
developed INH–gallic acid hybrid products had better phar-
macokinetic profiles in comparison with the parent INH
with lower hepatotoxicity (Sen, Asokkumar, Mamaheswari,
Sivashanmugam, & Subhadradevi, 2013; Ullah et al., 2015;
Bhilare, Dhaneshwar & Mahadik, 2018). The conjugated
product, “INH with natural organic constitute pyrrole” or
LL-3858, is now in the initial stages of phase II clinical trial,
and a few more hybrid molecules are in the preclinical stage
as a new treatment option in against TB (Hu et al., 2017; Xu
et al., 2017a). Thus, the chemical conjugation could be con-
sidered as a suitable approach with a new trend in current
anti-TB drug development using active phytochemicals with
an existing obsolete drug in improving mainstream medicine.
5  |   REPORTED INH–
PHY TOCHEM ICAL CONJUGATED
PRODUCTS
5.1  |  Isoniazid conjugated with aldehyde
class of phytochemicals
Mainly, the aldehyde class of phytochemicals containing the
functional group, carbonyl center, or carbon double-bonded
to oxygen (−CHO) is significantly used in cosmetic and phar-
maceutical industries (Fatima et al., 2018; Velika & Kron,
2002). The smallest aldehyde, benzaldehyde isolated from
several aromatic plants, consists of a benzene ring with a for-
myl substituent side chain. Several benzaldehyde derivatives
were synthesized and reported with various health emulating
activities (Hearn et al., 2009; Novotná et al., 2017; Figure 1).
A series of INH–benzaldehyde hybrid chemicals through
the Schiff base approach were synthesized for structural mod-
ification of INH to improve the anti-TB activity (Hearn et al.,
2009). In the SAR point of view, the INH–benzaldehyde hy-
brid provides lipophilic alterations in hydrazine moiety and
the ability to block the N-arylaminoacetyl transferases of
Mtb by the chemical deactivating process of N2-acetylation
(Orme, 2001). The INH–benzaldehyde conjugate displayed
productive anti-TB activity with MIC value <1 μg/ml against
H37Rv strain, along with acceptable cytotoxicity profile,
assessed with cultured Vero cells, in vitro (Manjashetty,
Yogeeswari, & Sriram, 2011; Orme, 2001; Figure 1).
Manjashetty and co-workers synthesized 29 conjugates
using INH and various benzaldehyde derivatives (Hearn &
Cynamon, 2004; Ramani et al., 2012). Several conjugates
had potent anti-TB activity with MIC value <0.17  μΜ
against H37Rv strain and 0.69  μΜ against MDR strain,
SWAIN et al.
F I G U R E 1   Reported research work on isoniazid (INH) conjugated with aldehyde class of phytochemicals
respectively. Additionally, Ramani and co-workers had
been proposed 32 newer INH–benzaldehyde derivatives
from which, N-(2-(4-(benzyloxy)phenyl)-4-oxo-1,3-thi-
azinan-3-yl) isonicotinamide was reported as three times
more potent than parent INH with the MIC value, 0.12 µM,
with a balanced pharmacokinetics profile (Chokpaiboon
et al., 2018; Figure 1).
Salicylaldehyde too isolated from several medicinal plants
and even its synthetic derivatives having potent antibacterial,
antifungal, and antimycobacterial activities were reported
(Ferraresi-Curotto, Echeverría, Piro, Pis-Diez, & Gonzàlez-
Baró, 2017; Oliveira et al., 2007; Petrlíková, Waisser,
Heinisch, & Stolaříková, 2011). The pipeline anti-TB drugs,
SALIZIDE, a hybrid form of INH and salicylaldehyde, and
VERAZIDE, a hybridized form of the veratraldehyde-INH,
were more active than parent INH against MDR-TB (Sousa,
Freire, Silvestre, & Silva, 2019; Figure  1). Thus, conjuga-
tion of aldehydes could be a prudent approach in preparing
  
|
   5
hybrids to enhance the activity and reducing the toxicity of
the parent INH.
5.2  |  Isoniazid conjugated with terpene and
terpenoid class of phytochemicals
The natural triterpenes—as scaffolds with a suitable chemi-
cal skeleton with “five- or four-ring carboxyl and hydroxyl
groups”—isolated from bark and flowers of several aro-
matic/medicinal plants with diverse therapeutic benefits
(Ali-Seyed, Jantan, Vijayaraghavan, & Bukhari, 2016;
Cichewicz & Kouzi, 2004; Huang et al., 2018; Ladda &
Magdum, 2018). After the addition of an oxygen atom
in the terpene helped the formation of pentacyclic trit-
erpenoid, betulinic acid and its derivatives proved as po-
tent anti-TB agents within the MIC range 50–100  µg/ml
(Fadipe, Mongalo, Opoku, Dikhoba, & Makhafola, 2017;
 |
6       SWAIN et al.

Kazakova et al., 2011; Figure 2). However, the conjugated
form of INH–betulinic acid and other derivatives were ef-
fective within 12.5–100  µg/ml against MDR-TB (Dehaen,
Mashentseva, & Seitembetov, 2011). The betulinic acid
derivative, 28-oxoallobetulone, was also reported as a pro-
ductive anti-TB agent after conjugation with INH (Bhat &
Al-Omar, 2013; Figure 2).
Isoniazid with three monoterpenes, citral, camphor,
and carvone, was synthesized with the Schiff base reaction
method to obtain hydrazide–phytochemical hybrids, active
against several mycobacterium species. The combination of
INH with camphor was the most active anti-TB agent with
the MIC value, 2.8–12 µg/ml, in vitro, than the parent INH
(Bhat & Al-Omar, 2013). Similarly, the natural diterpenoid,

F I G U R E 2   Reported research work on isoniazid (INH) conjugated with terpenes and terpenoid class of phytochemicals
SWAIN et al.   
|
   7

F I G U R E 3   Reported research work on isoniazid (INH) conjugated with phenolic acid and other organic classes of phytochemicals
 |
8       SWAIN et al.
isosteviol from Stevia rebaudiana. had potential anti-TB ac-
tivity against Mtb-H37Rv strain with the MIC value, 50 μg/
ml (Kataev et al., 2011). Synthesized INH and steviol deriv-
atives were compelling anti-TB agents within 10–20  μg/ml
against Mtb-H37Rv in vitro, whereas the reference antibiotic
pyrazinamide had the MIC value, 20 μg/ml (Andreeva et al.,
2011). Additionally, the INH derivative, adipic acid dihy-
drazide conjugated with isosteviol, had the anti-TB activity
with the MIC values, 1.7 and 3.1 μg/ml. Thus, using a natu-
ral triterpenoid and INH in the synthesis of a hybrid anti-TB
product had given impetus to utilize the reported triterpenoid
further in anti-TB drug development.
5.3  |  Isoniazid conjugated with phenolic
acid or other organic classes of phytochemicals
Phenol is another class of phytochemical consist-
ing of a phenyl group (C6H5) attached with a hydroxyl
group (−OH). The phenolic phyto-acid, gallic acid,
and its derivatives are well-known hepatoprotectives
and radical scavenging activities. Gallic acid, syringic
acid, and dodecyl gallate also exhibited several health
benefits as reducing plasma alanine aminotransferase,
γ-glutamyltransferase, aspartate aminotransferase, lipid
peroxidation, necrosis, and fibrosis in the liver, in vivo
(Sen et al., 2013; Ullah et al., 2015). Recently, several
amide pro-drugs were proposed through conjugation of
gallic acid, syringic acid, and vanillic acid with INH,
using Schotten–Baumann reaction (Saharan & Mahajan,
2017; Figure  3). In this synthesis procedure, phenolic
acids were mixed with tetrahydrofuran and thionyl chlo-
ride and then stirred for 4 hr at room temperature to get the
amide product. Evaluations of anti-TB activity of these
synthesized conjugated products were safer hepatoprotec-
tive pro-drugs by an in vitro kinetics study in comparison
with INH (Saharan & Mahajan, 2017).
From another literature, a series (C1–C9) of gallic acid
formazans were designed and the molecular docking study
was carried out against the target enzyme, InhA of Mtb
(Mandewale et al., 2018; Figure  3). Based on the molecu-
lar docking scores, C3, C5, and C9 were the most effective
hybrids. The documented MIC value is as follows: C3 with
1.34  μM, C5 with 1.9  μM, and C9 with 0.96  μM, respec-
tively, against M. tuberculosis H37Rv strain in comparison
with the standard drug, linezolid, with MIC value, 3.70 μM.
From the inhA enzyme inhibition assay, compounds C3, C5,
and C9 were the most promising inhibitors with IC50 values,
5.22 ± 0.36, 5.79 ± 0.22, and 3.42 ± 0.48 μM, respectively.
Negligible cytotoxicity also confirmed in cultured RAW
264.7 cell line with corresponding IC50 values, 0.35 ± 0.02,
0.56 ± 0.04, and 0.62 ± 0.02 (Mandewale et al., 2018; Pontiki
& Peperidou, 2018). Thus, from the above literature, it could
be concluded that conjugation of phyto-phenol gallic acid
with INH would be a prudent approach when viewed from
drug effectivity and reduction of hepatotoxicity.
The cinnamic acid mainly isolated from the bark of
Cinnamomum verum and several pharmaceutical proper-
ties such as antibacterial, antifungal, antioxidant, and anti-
mycobacterial and anticancer activity were reported (Chen
et al., 2011; De et al., 2011; Guzman, 2014; Korošec et al.,
2014; Sova, 2012; Zhu, Shang, Li, & Zhen, 2016). Several
synergistic formulations of trans-cinnamic acid with existing
anti-TB drugs, INH, EMB, RIF, and other known antimicro-
bial drugs, were too effective against drug-susceptible and
MDR-TB strains (Rastogi, Goh, Horgen, & Barrow, 1998;
Yoya et al., 2009). The development of unique hybrid rather
than a physical mixture of cinnamic acid with INH through
the formation of thioesters and amides exhibited potential ac-
tivity against Mtb with the MIC value, 0.1  μg/ml, in vitro
(Reddy, Nadadhur, Daneluzzi, Dimova, & Gangadharam,
1995). Additionally, RIF–cinnamic acid hybrid had ex-
cellent in vivo anti-TB activity compared with parent drug
RIF against isolated drug-susceptible and MDR-TB strains
F I G U R E 4   Reported research work
on isoniazid conjugated with indole class of
phytochemicals
SWAIN et al.
(Barrera-Tomas, Tomas-Chota, Sheen-Cortavarría, Dimova,
& Gangadharam, 2017).
A series (20a-f) of INH–cinnamic acid hybrids had been
designed and synthesized, being integrated with an R-group
is a lipophilicity control factor, and the hybrids exhibited
anti-TB activity within MIC value, 0.3–2.3  μM, against
Mtb-H37Rv strain (Barrera-Tomas et al., 2017). Based on
the SAR analysis, the modification by a short chain was bet-
ter than the longer ones in the R-group site (Me- > Et- >
i-pentenyl-), and mainly, the attachment of electron-donat-
ing groups was better than the electron-withdrawing groups
(Me- > CF3− or Et- > CF3CH2−); De et al., 2011. Among all
INH–cinnamic acid hybrids, the hybrid 20a was potent with
MIC value, 0.3 μM, and two times more potent than parent
INH with the MIC value, 0.6 μM, against Mtb-H37Rv strain.
According to the toxicity profile, 20e was the most safer
conjugate with IC50 value of 256 μM and 20a had IC50 value
of 168  μM in the THP-1-cultured cell lines, respectively.
Furthermore, these two hybrids, 20a and 20e, were studied
against INH-resistant strains, one was inhA-mutated, and the
other was katG-mutated. The MIC values, 16 and 27 μM
against inhA-mutant Mtb strain and 18 and 68 μM against
katG-mutant Mtb strain for the compound number 20a and
20e, while the MIC value of existing INH, 18 and 29 μM
were recorded (Barrera-Tomas et al., 2017). Thus, the above
results indicated that the hybrid obtained after conjugation
of the cinnamic acid enhanced the activity against both sen-
sitive and resistant Mtb strains. Similarly, the naturally oc-
curring furandione class of secondary metabolite usnic acid
exhibited anti-TB activity with a MIC value, 16.0 μg/ml. The
synthesized acyl-hydrazone after chemical hybridization of
INH with usnic showed more active against Mtb-H37Rv and
MDR-Mtb strains with MIC values, 2 and 64 μg/ml, respec-
tively by the tetrazolium microplate assay method (Xu et al.,
2019).
F I G U R E 5   Reported research
work on isoniazid (INH) conjugated with
naphthoquinone class of phytochemicals
  
|
   9
5.4  |  Isoniazid conjugated with indole
class of phytochemicals
Isatin or 2, 3-dioxoindole is an indole derivative isolated
from several medicinal plants with several biological ac-
tivities (Lian, Sun, & Zhu, 2016; Pandeya, Smitha, Jyoti,
& Sridhar, 2005; Yan, Lv, Wen, Zho, & Xu, 2018). In
pharmacophore point of view, isatin alone offers an ideal
hydrophobic aromatic ring for the development of anti-TB
chemical hybrid moiety, and even it was effective against
Mtb (Eldehna, Fares, Abdel-Aziz, & Abdel-Aziz, 2015;
Feng et al., 2012). A series of synthesized isatin–INH hy-
brids using the Mannich base reaction exhibited anti-TB
activity within MIC value, 3.5–4.5  μg/ml, against bovine
Mtb with increased lipophilicity, but with lesser activity
than the parent INH with the MIC value, 1.5 μg/ml (Quan
et al., 2017; Figure 4). Substitution of the C-5 position in
isatin–hydrazide (20a) by hydrogen, chlorine, and bromine,
individually, is evident that Cl− substituted hybrid had in-
creased the anti-TB activity with the MIC value, 12.50 μg/
ml, than the parent substituted isatin moiety with the MIC
value, 25  μg/ml (Aboul-Fadl, Mohammed, & Hassan,
2003). However, the Br- replaced isatin hybrid caused an
increase in the activity with a lower MIC value, 6.25 μg/ml.
Additionally, the order H− < Cl− < Br− corresponds to the
lipophilicity profiles of each conjugate.
A series of 1-alkylisatin–INH hybrids had been pro-
posed to improve the activity of INH. From which, hybrids
bearing a 1-unsubstituted 1-propyl, 1-propynyl, and 1-ben-
zyl group exhibited most against Mtb with the MIC value,
10 μmol/L (Singh et al., 2018; Figure 4). In another study,
isatin was conjugated with several synthetic moieties such
as ferrocene, quinolones, azetidinone, diarylquinoline, tet-
rahydro pyrimidine, and thiolactone, individually, and pro-
duced unique and potent hybrid pharmacophores against
 |
10       SWAIN et al.
several diseases (Hans et al., 2011; Nair et al., 2016; Raj
et al., 2014; Xu et al., 2017a & 2017b).
5.5  |  Isoniazid conjugated with
naphthoquinone class of phytochemicals
The natural 5-hydroxy 1, 4-naphthoquinone, or plumbagin
isolated from Plumbaginacea sp., had several potential
biological activities including antimycobacterial potency
(KAT et al., 2013; Mathew et al., 2010; Nazeem et al., 2009;
Padhye, Dandawate, Yusufi, Ahmad, & Sarkar, 2012). A
novel concept with INH–plumbagin hybrid product coated
with cyclodextrins for improving the aqueous solubility and
thermal stability was reported. Indeed, the hybrid product
showed productive activity against Mtb with the MIC values,
0.5 and 2.0 μg/ml, at a high and low iron condition due to the
advance cyclodextrins formulation for the target drug deliv-
ery (Carvalho et al., 2008; Figure 5).
A series of synthesized INH conjugates bearing plum-
bagin derivatives such as acetyl plumbagin, benzoate plum-
bagin, butyrate plumbagin, cinnamate plumbagin, crotonate
plumbagin, iodobenzoate plumbagin, levulinoate plumbagin,
and propionate plumbagin targeting menaquinone biosyn-
thesis pathway of M. smegmatis and M. tuberculosis H37Rv
were reported (Nayak, Bajpai, & Razdan, 2014; Figure  5).
The butyrate plumbagin product was the most effective hybrid
against M. smegmatis with the MIC value, 15.5 µM. On the
other hand, the crotonate plumbagin product was with higher
activity against Mtb-H37Rv with the MIC value, 15.6  µM
(Rogers, Gammon, & Naidoo, 2013). Moreover, several
plumbagin conjugated products other than INH also reported
having potent enzyme inhibition activities. (Gammon et al.,
2010; Nayak, Ramprasad, & Dalimba, 2015).
F I G U R E 6   Reported research work
on isoniazid conjugated with glycoside and
steroid class of phytochemicals
F I G U R E 7   Reported research work
on isoniazid conjugated with fatty acids
SWAIN et al.
Nayak et al. proposed a series (5a-r) of INH–pyrazole
analogs or isonicotinic hydrazide-based pyrazole derivatives
from which 5j, 5k, 5l, and 4b had a productive anti-TB activ-
ity with the MIC value >4.9 µM and were non-toxic to VERO
cell lines with a selectivity index >160, in vitro (Figure 5).
Mainly, the product, 5l with a MIC value, 1.7 µM, was most
effective than INH and integration of this compound was too
elaborated in molecular docking study against the InhA en-
zyme of Mtb (Zaro et al., 2016).
5.6  |  Isoniazid conjugated with
glycoside and steroid class of phytochemicals
Recently, natural glycosides and steroids were reported hav-
ing potential inhibition activity against Mtb (Barnes et al.,
2003; León-Rivera et al., 2008). For example, glycoside-
based natural chemical constituent, 11-hydroxyhexadecane
carboxylic acid isolated from the Ipomoea tyrianthina and
imberbic acid isolated from Combretum imberbe, exhibited
anti-TB activity with MIC values, 25 and 12.5  mg/ml, re-
spectively (Katerere, Gray, Nash, & Waigh, 2003; Pastorino,
Cornara, Soares, Rodrigues, & Oliveira, 2018; Figure 6). The
tri-terpene glycoside, glycyrrhizic acid from Glycyrrhiza
glabra, was reported having several biological activities such
as antioxidant, antitumor, antidiabetic, hepatoprotective in-
cluding antibacterial and mycobacterial activities (Gupta
et al., 2008; Shah et al., 2018; Sharipova et al., 2011) and
could be used in hybrid drug development against Mtb.
Glycosides from Stevia rebaudiana, stevioside, and stevi-
olbioside had moderate anti-TB activity, in vitro with the MIC
values, 7.5 and 5 μg/ml, respectively (Merlani, Kemertelidze,
Papadopoulos, & Men'shova, 2004). However, after conjuga-
tion of steviolbioside with INH as a conjugate by acid chlo-
ride reaction was comparatively more active within the MIC
range, 5–10 μg/ml (Favrot & Ronning, 2012; Figure 6). The
5-α-ketosteroid tigogenin derivatives wildly isolated from the
Georgian plant, Jucca gloriosa, were conjugated with INH
and synthesized tigogenic derivatives, bearing INH on both
sides had a significant anti-TB activity with the MIC value,
0.04 μg/ml (D'OcaCda et al., 2010).
5.7  |  Isoniazid conjugated with fatty
acid and peptides
Mainly, INH and pyrazinamide target to alternation or inhi-
bition of cell wall synthesis through katG, inhA, and enoyl-
acyl carrier protein (ACP) reductase enzymes, and those are
essential for the production of fatty acid synthase (FAS) for
the synthesis of mycolic acid during pathogen survivability.
Thus, FAS is crucial for cell survival and it is a target in
  
|
   11
use for anti-TB drug development (Helaly, Pesic, Fiedler,
& Süssmuth, 2011). Various naturally saturated and unsatu-
rated fatty acid entities and derivatives such as fatty acid
amides, fatty N-acylamino acids, and fatty N-acyl trihalo-
methylated pyrazoline had reported having several biologi-
cal, anti-TB, and industrial activities (Yuan et al., 2008).
Mainly, fatty acid contains alkyl chains and plays a vital
role in drug permeability as an individual or in the form of
conjugation. Similarly, INH conjugated with several natu-
ral chemical constituents such as elaiomycin (a long alkyl
chain isolated from Streptomyces sp. BK190), micromolide
(a natural product isolated from the plant, Micromelum hir-
sutum) and sarmentine (a pyrrolidine alkaloid isolated from
the roots of Piper sarmentosum) were recorded having
potent anti-TB activity. (Mohamad, Ibrahim, & Sadikun,
2004; Rodrigues et al., 2013). Thus, natural fatty acids in-
crease the logP value of permeability on the lipid-rich my-
cobacterial cell wall of Mtb, due to the presence of long
alkyl chains in fatty acids (Kumarasingam et al., 2018;
Figure 7).
In this context, a series of INH–fatty acid derivative hy-
brids were synthesized and reported anti-TB activity within
MIC range, 3.2–100 µg/ml, against H37Rv-, INH-resistant,
and RIF-resistant strains of Mtb (Nasiruddin, Neyaz, & Das,
2017). The physiological property of fatty acids supports in-
creased permeability and susceptibility of INH against Mtb.
The adopted synthesis procedure was too easy using oxalyl
chloride in dichloromethane (CH2Cl2) solution with an ap-
propriate quantity of fatty acid and INH with an aliquot of
dimethyl aminopyridine (DMAP) for the synthesis. Thus,
the conjugation of fatty acid with INH could be an alter-
native and substituted option for anti-TB drug development
modules.
In contrast to advanced drug delivery point of view, sev-
eral carriers and coating such as nanoemulsions, nanocarrier,
and cyclodextrins, were proposed in anti-TB drug develop-
ment modules to enhance target drug delivery, higher li-
pophilicity, and reduce the side-effects (Carvalho et al.,
2008; Clemens et al., 2012; Horváti, Mező, Szabó, Hudecz,
& Bősze, 2009; Schaaf, Thee, van der Laan, Hesseling, &
Garcia-Prats 2016; Wallis et al., 2016). For example, pep-
tide base of INH carriers had been reported for target release
or drug delivery with the T-cell epitope of immune-dom-
inant 16-kDa protein and tuftsin-derived peptides with a
hetero-bifunctional reagent against Mtb. Moreover, the pep-
tide-conjugated form of INH enhances the activity than the
parent INH (Horvati, Mező, Szabo, Hudecz, & Bősze, 2009;
Schaaf, Thee, van der Laan, Hesseling, & Garcia-Prats
2016). Thus, from the above scientific research analyses, it
can be concluded that hybrids with phytochemicals could be
used for the development of potent and value-added INH for
the control of pandemic MDR-Mtb.
 |
12       SWAIN et al.
6  |   EX P ERT OP IN ION O N
PH Y TO CH EMICA L CO N JU GAT ION
I N A N TI-T B D RU G D E V E LOP MENT
Despite active researchers in academia and pharmaceutical
industries for the development of the potent anti-TB drug in
support of the “WHO's Stop TB program,” no newer novel
anti-TB drug was reported, till date (Barbieri et al., 2017;
Koul et al., 2011; Lauzardo & Peloquin, 2012; Tandon &
Yadav, 2017). Indeed, several new anti-TB drugs from natu-
ral products were well demonstrated (Cowan, 1999; Finn,
2012; Wright, 2014). Three anti-TB drugs, SQ609, PBTZ169
and BTZ043 are in different stages of clinical trials bearing
the pharmacophore of piperine, an alkaloid class of phyto-
chemical targeting inhibition of Mtb cell wall synthesis (Xu
et al., 2004). Similarly, the other two phytochemical deriva-
tives, TBI-166 and TBI-223 with the phenazine moiety, are
in phase I and preclinical stages of anti-TB drug development
pipeline by Institute of Materia Medica and TB Alliance, re-
spectively. Thus, a plant-based lead-drug molecule could be
the right candidate, lent from the traditional ethnic, tribal
documentation and non-documented literature (Finn, 2012;
Sen & Chakraborty, 2016; Xu et al., 2004).
In the present scenario, the newly designed anti-TB drug
should be able to enhance the activity, concomitantly de-
crease the toxicity from the ongoing ancillary drugs, shorten
the duration of treatment, avoid significant antagonism in
drug–drug interactions and preferably would operate via
some new cellular target. Several obsolete antibiotics/drugs
have been improved structurally with the introduction of a
synthetic chemical entity. Indeed, the chemical conjugation
of some natural phyto-constituents rather than any synthetic
moiety using principles of medicinal chemistry is a newer
trend in anti-TB drug development (Rizvi et al., 2019; Swain,
Paidesetty, & Padhy, 2017a, 2017b; Xu et al., 2019). In
our laboratory, an initial focus on the development of such
chemical hybrids had landed at success in the formulation of
new agents with the primary ensconced antibacterial drug,
sulfamethoxazole against the superbug, methicillin-resistant
Staphylococcus aureus; and secondly, dapsone–phytochem-
ical conjugates against the dreadful dapsone-resistant M.
leprae were reported (Kumar, Sharma, Srinivasan, Singh, &
Kaur, 2011; Swain et al., 2018, 2019).
However, INH cannot be replaced for its conformational
strictness in target-binding, and the previously followed
chemical conjugation method was adopted to improve activ-
ity against Mtb (Dandawate et al., 2014; Hearn et al., 2009;
Hu et al., 2017; Swain et al., 2018). Thus N-heterocyclic nu-
cleus, being an essential chemical scaffold, could serve as
an ideal balance in physicochemical and pharmacokinetic
properties in the hybrid form of an active phytochemical and
INH (Rizvi et al., 2019; Xu et al., 2019). Furthermore, INH
leads to sideroblastic anemia from deficiency of pyridox-
ine, the vitamin B6 due to a similarity of the two molecules.
Approximately 20% of people who take INH with the daily
dose of >6 mg/kg suffer from a long-term hepatic problem
with peripheral neuropathy. After incorporation of the lipo-
philic moiety, the “phytochemical–INH nucleus” could in-
crease the permeation of the drug into the bacterial cell wall
during pathogen control.
Thus, chemical conjugation with any active phytochem-
icals with a mainstream drug is a new trend and hopefully
fulfills the deficiency of effective anti-TB medicines soon.
7  |  CONCLUDING REM ARK S
The development of a well-tolerated drug molecule is a
dire necessity for the control of endemic tuberculosis in-
fections. INH is the front-line anti-TB drug use in mon-
otherapy and combination therapy for decades, targeting
inhibition of synthesis of mycolic acid of Mtb. However,
the development of point mutation in recognizing the tar-
geted enzyme by INH creates a vacuum in anti-TB therapy.
Indeed, the absence of any suitable anti-TB drug(s) since
the last two decades, modification/hybridization/derivati-
zation of INH with any phytochemical, would be an ideal
approach than modification through a synthetic chemical.
Additionally, the genetic machinery system of Mtb cannot
overcome the complex characteristics of a phytochemical
with INH in a single chemical moiety. The inherent toxicity
of INH could be corrected after conjugation with a suitable
phytochemical. The defined events of conjugation favored
the improvement in lipophilicity to accelerate diffusion
over the lipid-rich mycobacterial cell wall, consequently
enhancing the anti-TB activity. Additionally, phytochemi-
cal hybridization with INH toward potent anti-TB drug de-
velopment remains an ideal time-kill approach apart from
random searching of a leading anti-TB drug candidate.
ACKNOWLEDGMENTS
This work is supported by the “ICMR-Young Scientist
Scheme” awarded to Shasank S. Swain (FTS No. 3128113/
No. R.12014/14/2017-HR) from Department of Health
Research, Govt. of India, New Delhi. We would like to thank
the Director, ICMR-RMRC, BBSR, for support.
CONFLICTS OF INTEREST
The authors declare that they have no conflict of interests.
DATA AVAILABILIT Y STATEMENT
All data are openly available in public repository sources,
cited adequately, and full information is available in the ref-
erence section of this review article.
SWAIN et al.
ORCID
Shasank S. Swain  https://orcid.org/0000-0001-5089-8304
Rabindra N. Padhy  https://orcid.org/0000-0002-2522-9843
Tahziba Hussain  https://orcid.org/0000-0002-9430-5010
Sudhir K. Paidesetty  https://orcid.org/0000-0003-1210-2293
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How to cite this article: Swain SS, Paidesetty SK,
Padhy RN, Hussain T. Isoniazid–phytochemical
conjugation: A new approach for potent and less toxic
anti-TB drug development. Chem Biol Drug Des.
2020;00:1–17. https://doi.org/10.1111/cbdd.13685