Novel pyrazoles derivatives as an anticancer

lead against A-549, MCF-7, HeLa, HepG-2,

PaCa-2, DLD-1, PC-3, B16F10, K-562,
MDA-MB-231, A2780, and NUGC: 2D-
QSAR. PART 2
ABSTRACT
The term cancer defines as abnormal and uncontrolled proliferation of
cells. The burden of cancer is rapidly rising globally, and several drugs
PLAN are in market already and many newer agents are in different phases of
clinical trials. In this study QSAR models were applied to check the
ABSTRACT desired physicochemical properties of the newer agents to find out
potential cytotoxic entity for different cancers. Quantitative structure-
activity relationship (QSAR) is a computational modeling technique used
INTRODUCTION to correlate the structural and biological activities of a compound. In this
study the compounds 48, 54, 55, 60 and showed high cytotoxic activity
MATERIEL AND METHODS against the PC-3 with pIC50 5.2647; 5.3206; 5.2652 and 5.1415μM. The
compounds 36, 41, 42 and 43 showed high cytotoxic activity against the
B16F10 with pIC50 6.7535; 6.5148; 6.3024 and 6.7368μM.
1. Experimental Data sources Subsequently, compound 1 showed high cytotoxic activity against the K-
2. Molecular descriptors calculation 562 with pIC50 7.313μM. While the compounds 4, 5, 32 and 33 having
3. Data Splits potent cytotoxic activity against the MDA-MB-231 with pIC50 6.3657;
5.8921; 7.0300 and 6.5565μM respectively. The compounds 4, 19, 30 and
4. Model Development and validation 32 showed excellent anticancer activity against A2780 with pIC50
5. Applicability domain 8.5720; 8.5720; 8.1494 and 8.6362μM. Compounds 1, 5, 20 and 33 show
high anticancer activity against ACHNwith pIC50 6,106; 6.4812; 5.8703
and 6.36432μM. Finally, the compounds 32, 33, 47 and 52 showed potent
RESULTS AND DISCUSSION cytotoxic activity against the NUGC with pIC50 43.6232; 34.4487;
34.7843 and 36.0286μM respectively. These QSAR models have
1. QSAR STUDY indicated the importance of pyrazoles derivatives as potential candidates
and this data is quite significant and can be helpful in development of
potential drugs in future.
1.1 Correlation matrix and ACP for each
cell line INTRODUCTION
1.2 PLS Models for each cell line's The term cancer defines as abnormal and
uncontrolled proliferation of cells of specific
1.3 External validation organ and tissue. It is a non-communicable
1.4 Internal validation chronic disease. Burden of cancer is rapidly
rising and around 19 million new cancer cases
1.5 Prediction of anticancer activity of our were reported and roughly 10 million cancer
synthesis series related deaths occurred in just 2020. Prostate
malignancy is the 5thdominant factor of expired
ratio of people and is the 2nd most recurrent
2. Design of new compounds for 12 cancer diagnosed in men [1]. In current era,
there exist many options for management of
cancer cell line prostate cancer diagnosed in men. Hormonal
therapeutics, bone-targeting agents and newly
CONCLUSION added vaccines have shown efficacy in
metastatic prostate cancer that are contrary to
REFERENCES the traditional therapy of hormones. Cell lines
that are derived from cancer cells are very
APPENDIX(Supplementary Data) important tools for understanding the nature of
cancer and to test the therapeutic efficacy of
new chemical agents. In prostate cancer
DU145, PC3 and LNCaP are the most
commonly used cell lines,in our QSAR model
PC3 cell lines were of particular interest and
we checked the therapeutic effectiveness of
pyrazole derivatives against PCa using PC3
lines. Docetaxel is the most commonly used are diagnosed younger individuals below 45
chemotherapeutic agent used for prostate years of age. The best time for the surgery for
cancer. [2]. Skin cancer is quite prevalent treatment of gastric cancer is when a tumor is
especially cutaneous melanoma has shown mostly sensitive to chemotherapy [9]
greater than 50,000 deaths per year and Perioperative chemotherapy and postoperative
responsible for around 75% deaths associated chemotherapy in addition to chemoradiation is
to skin cancer. B16F10 cells have high capacity preferred in current guidelines [10].
to metastasize and we used melanoma cell lines Quantitative structure-activity relationship
(B16F10) in our QSAR model to find out the techniques are major indicator of cellular effect
efficacy of our chemical agents. Leukemia is of the chemical compounds according to
hematological disorder which comprises of mathematical and statistical approach.
heterogenous subgroups including acute Quantitative structure-property relationship
lymphoblastic leukemia, acute myeloid (QSPR) methods demonstrate physical and
leukemia, chronic lymphocytic leukemia, chemical properties allotted for certain
chronic myeloid leukemia. Leukemia ranges molecular features of compounds. QSAR
between 8th to 12th most prevailed cancer methods counts on fundamental principle of
disease worldwide. Without any discrimination chemistry that explains that the cellular activity
based on sociodemographic background, it is of any compound or a ligand is attributed to the
prevailed in all people of the world. Some arrangement of atoms that forms the structure
studies show it has greater possibly in of molecule. In other words, similar cellular
urbanized people. It was also demonstrated that activities are possessed by structurally related
it is mainly present in children comprising of molecules. This structural information can be
29% of 3,707 children cancers. In our study we interpreted by a series of framework known as
used K562 cell line that are myelogenous molecular descriptors. Quantitative structure-
leukemia cells and used widely because of their activity relationship research includes
high and reproducible sensitivity. preference of both inactive and active
Treatmentincludes combination of compounds along with the course of action of
chemotherapies i.e. vincristine, daunorubicin. cellular activity, specification and computation
[4]. The most common gynecological cancer is of molecular descriptors, range of suitable
ovarian cancer with highest rate of mortality. characteristics accompanied by establishment
As per available data in 2017-18 is 5%% of all of mathematical framework and its assessment
cancer-related mortality was imputed to ovarian [11].
cancer in women. A2780 is the cell line used in
our study derived from adenocarcinoma of
ovaries. Usually combined chemotherapy
consists of platinum analog (carboplatin) plus
taxane (docetaxel) is used to treat ovarian
cancer. Kidney cancer constitutes for 3.7% of
all new cases of cancers and accounts for more
than 131,000 deaths pr year worldwide. Kidney
cancers are included in most important cancer
around the world and accounts for heavy
economic burden which is found to be $1.6
billion on metastatic kidney cancer in selected
countries. ACHN cell line is derived from
metastatic renal carcinoma and it is used in our
QSAR model for renal cancer. Renal carcinoma
is not well responsive to chemotherapeutic
agents and it is not considered as standard
therapy but still 5-FU and cisplatin can be used
in certain situations [7]. The last type of cancer
for which we have developed a QSAR model is
gastric cancer (GC) and considered as an
important cause of deaths associated with
cancer globally. Around 0% stomach cancers
Aims of this work:
1. The aim of this work is to reveal the relationships between structural properties of
chemical compounds and biological activities.
2. The discovery of new and more potent anti-cancer agents by using QSAR techniques.
3. To confirm the predictions about cancer by experimental validation.

MATERIALS AND METHODS

1.Experimental Data sources

The biological activity investigated is the inhibition of cancer cell proliferation (anti-
neoplastic activity) on ATCC (American Type Culture Collection)-referenced cancer cell
lines. It is measured by the IC 50, which refers to the lowest effective concentration of the
compound that inhibits cancer cell growth by 50%. The data were collected from the literature
in this stage, the tables (summarized in Appendix) reflect the database provenance for each
cancer cell line, and the values of IC50 are converted to -ve log IC50.

Molecular descriptors calculation

The methods followed to compute the descriptors are described in our previous work.
Data Split
The data set for each cancer line was divided into two sets: the first is the training set for
developing QSAR models, and the second is the test set for testing the prediction quality of
the developed model. In the training set, 75 percent of molecules were separated, whereas 25
percent were separated in the test set using various data division approaches. (Table1). The
number of molecules in the test set and training set for each cancer line is summarized in the
table below.

Table 1: Split of the data bank into test set and training set results for the 13 cancer cell lines

Experimental data Total Numbers Training Set Test set

Cancer Cell line of molecules

PC-3 prostate cancer 30 25 5

B16F10 skin cancer 35 28 7

K-562 chronicmyelogenous leukemia 37 30 7

MDA-MB-231c breast cancer 35 28 7

3
A2780ovarian cancer 27 22 5
ACHN Kidney cancer 31 25 5
NUGC Stomach cancer 24 20 4
Model Development and validation

…………………………………………………………………………

Applicability Domain

………………………………………………………………………

RESULTS AND DISCUSSION

QSAR STUDY

1.1 Correlation matrix and CPA for each cell line

1.1.1 PC-3 Prostate Cancer

The correlation matrix below shows the relationship between the three descriptors chosen for
this cancer lineage and PIC50 (Table 8).

4
Tableau 8 Correlation matrix (Pearson (n)) for the PC-3 cancer cell line, linking the many
variables gathered. The topological descriptor Balaban (which stands for 2D Balaban
averaged distance sum connectivity) has a negative relationship with PIC50 (r=-0.509). The
descriptor ' SlogP VSA4' has a positive correlation (r=-0.572) with PIC50.
PIC50 BalabanJ SlogP_VSA4 Density
PIC50 1
BalabanJ -0,509 1
SlogP_VSA4 0,572 -0,020 1
Density 0,391 0,029 -0,016 1
In bold character we show the variables which are highly correlated.
Figure 7-A The density descriptor is well correlated along the F2 axis (r=0.886), the SlogP VSA 4
descriptor is well correlated along the F1 axis (r=0.651), and the balabanJ descriptor is negatively
correlated along the F1 axis (r=-0.576), according to Figure 7-A, which shows the correlation circle
corresponding to a projection of the variables on a two-dimensional plane.

`A B
Figure 7. CPA of PC-3: A represents a correlation circle of descriptors and anticancer activity
(PIC50g), B represents a biplot of the molecules in the plan of the first two axes F1 and F2, and the
percentages of variance for the two axes F1 and F2 are respectively 46.40 percent and 25.81 percent.
The overall amount of data is predicted to be 72.22 percent.

Analysis of the Biplot (Figure 7-B) shows three groups of molecules.

 The molecules 270, 258, 269, 268, 257, 256, and 254 at the bottom right of the biplot,
which are characterized by the surface of hydrophilic molecules 'SlogP VSA4', have a
favorable influence on anticancer activity, with a correlation coefficient of r=0.573.

5
  The second group, which included molecules 249, 246, 240, 245, 248, 275, 266, 267,
272, and 250, was found to have moderate anticancer activity. This can be explained
by the negative contribution of the descriptor 'BalabanJ,' which indicates the
topological index of connectivity at distance with a correlation coefficient of r=-0.510.
Indeed, anticancer effectiveness against PC-3 prostate cancer was reduced by drugs
with a high topological index of remote connectivity (BalabanJ> 1.40).
 The molecules 251, 252, 254, 256, 258, 261, 268, 269, and 270, which are depicted in
the upper right of the biplot, demonstrated superior anticancer activity because the
descriptor 'density' linked favorably with a correlation coefficient of r=0.391.
1.1.2B16F10 Skin cancer
The correlation matrix depicts the relationship between the six descriptors chosen for this
HepG-2 line (Table 9).
Table 9: A correlation matrix (Pearson (n)) was built for the B16F10 cancer cell line to link
the various factors obtained. The descriptors PEOE VSA+0 and SlogP VSA5 are positively
associated (r = 0.703).
Zagreb is positively linked with SlogP VSA5 (r=0.0616) and PEOE VSA+0 (r = 0.523).
Soother (Stands for 2D VDW another surface area (A**2)) is negatively connected with
SlogP VSA5.
PEOE VSA+0 and Zagreb, respectively, with r = -0.752, -0.715, and -0.768. With r=0.676,
r=0.519, and r=-0.577, SMR VSA7 (stands for 2D Molar refractivity) is associated with
SlogP VSA5, PEOE VSA+0, and soother.

PIC50 SlogP_VSA PEOE_VSA+ zagre Vsa_oth SMR_VSA SMR_VSA

5 0 b er 1 7

PIC50 1
SlogP_VSA5 0,320 1
PEOE_VSA+0 0,550 0,703 1
Zagreb 0,397 0,616 0,523 1
Zagreb -0,626 -0,752 -0,715 - 1
0,768
SMR_VSA1 0,003 -0,027 -0,267 0,467 0,064 1
SMR_VSA7 0,359 0,676 0,519 0,383 -0,577 -0,293 1
In bold character we show the variables which are highly correlated.

Figure 8-A indicates a positive association between the descriptors SplgP VSA5 and PEOE VSA+0
with r=0.783, SlogP VSA5 and zagreb with r=0.616, and SlogP VSA5 and SMR VSA7 with r=0.676
in the biplot analysis.

6
While there is a negative correlation between the descriptors zagreb and Zagreb (r=0.769) and the
descriptors PEOE VSA+0 and Zagreb (r=-0.715), there is a positive correlation between the
descriptors PEOE VSA+0 and Zagreb (r=0.715).

A B

Figure 8. ACP: Represent Correlation Circle of Descriptors and anticancer activity (PIC50g), B:
Represent biplot of the molecules in the plan of the first two axes F1 and F2, the percentages of
variance for the two axes F1 and F2 are correspondingly 55.37 percent and 20.52 percent. 75.90
percent of the total data is estimated.

Figure 8-B shows a biplot graph that separates two groups.

 The first group of molecules (PIC50>5uM) showed better anticancer activity (276,
278, 279, 280, 282, 283, 286, 302, 296, 295, 294 and 293). This group is characterized
by the topological descriptor zagreb (a molecule's chirality index), which contributes
positively to anticancer activity with a correlation coefficient of r=0.397.
 The second group contains the remaining compounds, which have a moderate
cytotoxicity (PIC50<5µM) and are identified by the descriptor 'SMR VSA7'
(approximate accessible van der Waals surface for atoms with atomic contribution to
the molar refraction), which contribute positively to anticancer activity with a
correlation coefficient of r=0.359. The descriptor 'PEOE VSA+0(van der Waals
surface of molecule)' then has a positive correlation coefficient of r=0.555, and the
descriptor 'Zagreb' has a negative correlation value of r=-0.627.

7
1.1.3K-562 Leukemia
The correlation matrix below shows the correlation between the four descriptors chosen for
line K-562 (Table 10).
Table 10: Pearson (n) correlation matrix connecting the various factors found for the K-562
cancer cell line. SMR VSA4 (molar refraction) and BCUT SLOGP 2 have a positive
relationship (r = 0.600). SMR VSA4 has a positive correlation (r = 0.459) with a no (number
of oxygen atoms in a molecule). The number of sulfur atoms in a molecule (a ns) is negatively
associated with the amount of oxygen atoms (a no) (r = -0.543). BCUT SLOGP 2 has a r =
0.468 positive correlation with PIC50. The number of oxygen atoms in a molecule (a n6) is
positively connected with PIC50 (r = 0.467). With a r = 0.919, SMR VSA4 (molar refraction)
is highly linked with PIC50.

PIC50 BCUT_SLOGP_2 a_nO a_nS SMR_VSA4

PIC50 1
BCUT_SLOGP_2 0,468 1
a_nO 0,467 0,095 1
a_nS -0,231 0,384 -0,543 1
SMR_VSA4 0,919 0,600 0,459 0,033 1
In bold character we show the variables which are highly correlated.

A B

8
Figure 9: K-562's CPA: A represents a correlation circle of descriptors and anticancer
activity (PIC50µg), B represents a biplot of the molecules in the plan of the first two axes F1
and F2, and the percentages of variance for the two axes F1 and F2 are respectively 52.13
percent and 32.51 percent. The overall amount of data is expected to be 84.64 percent.
Figure 9-A depicts the correlation circle between descriptors, with a positive correlation
coefficient of r=0.600 between BCUT SLOGP 2 and SMR VSA4, a negative correlation
coefficient of r=-0.543 between descriptors a no and a ns, and a low correlation coefficient of
r=0.459 between descriptors a no and SMR VSA4.
Two groups are identified by the Biplot graph (Figure 9-B).
 Compounds 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, and 358 are part of the
first group, which has stronger anticancer activity (PIC508 M) against the K562 cell
line. Furthermore, with a correlation coefficient of r=0.468, the descriptor 'a no'
(number of oxygen atoms in the molecule a no>2') contributes favorably to the
examined activity. The more oxygen atoms, the higher the value of anticancer activity.
 The second group, which includes compounds 322-347, has a moderate anticancer
activity (PIC504) and the descriptor 'SMR VSA4' (gross approximate surface
assessable for van der Waals forces for atoms with an atomic contribution to the molar
refraction), which strongly contributes to the anticancer activity with a correlation
coefficient of r=0.919.

1.1.4MDA-MB-231Breast cancer
The correlation matrix depicts the relationship between the four descriptors chosen for this MDA-MB-
231 line (Table 11).

Table 11: Pearson (n) correlation matrix for the MDA-MB231 cancer cell line's various
obtained factors. Q PC- (2D partial charge that is total negative) has a r=-0.644 negative
correlation with PEOE VSA+1. PEOE VSA+ is closely associated with Q VSA HYD (2D
Total hydrophobic surface area of van der Waals force), with r=0.701. Q VSA HYD (2D total
hydrophobic surface area of van der Waals force) has a negative correlation (r=0.594) with Q
PC- (2D total negative partial charge). PEOE VSA+1 has a r=0.799 correlation with (PIC50).
Q PC- has a r=-0.794 correlation with (PIC50).

PIC50 PEOE_VSA+1 Q_PC- Q_VSA_HYD

PIC50 1
PEOE_VSA+1 0,799 1
Q_PC- -0,794 -0,644 1
Q_VSA_HYD 0,487 0,701 -0,594 1
In bold character we show the variables which are highly correlated.

9
The correlation circle between the descriptors is shown in Figure 10-A. There is a good
correlation between the descriptors 'PEOE VSA+1' and 'Q VSA HYD' with a correlation
coefficient of r=-0.644, but a negative correlation between the descriptors 'Q PC-' and 'Q VSA
HYD' with a correlation coefficient of r=-0.594.

A B
Figure 10: MDA-MB-231 CPA: A represents the Correlation Circle of Descriptors and
Anticancer Activity (PIC50g), B represents the biplot of the molecules in the plan of the first
two axes F1 and F2, and the percentages of variance for the two axes F1 and F2 are 75.46
percent and 13.79 percent, respectively. The overall amount of data is expected to be 89.25
percent.
The Biplot graph (Figure 10-B) allows us to visualize the individuals on a two-dimensional
map, allowing us to classify the molecules into three categories based on their cytotoxicity.
 The first group, which includes compounds 369, 374, 375, 376, 377, 387, 388, 393,
and 395, exhibited moderate anticancer activity (PIC50 4M) against the MDA-MB-
231 cell line; this group is distinguished by the descriptor 'Q PC-' (the total negative
partial charge in the molecule 'Q PC'), which contributes negatively to anticancer
activity with a correlation coefficient of r=0.7 We divide them into three groups based
on their cytotoxicity.
 Compounds 360, 361 and 362 were shown to have greater anticancer activity (PIC50≥
6µM). This group is distinguished by the descriptor 'Q VSA HYD' (surface area of
total hydrophobic van der waal forces), which contributes positively to anticancer
activity with a correlation coefficient of r=0.487.

10
  The remaining molecules in the third group are 359, 363, 364, 368, 370, 371, 372,
373, 378, 379, 380, 381, 382, 383, 389, 390, 391, 392, 396, 397, and 398, which have
moderate to acceptable anticancer activity (4 µM ≤PIC50≤6 µM). These compounds
are characterized by the descriptor 'PEOE VSA+1,' which contribute remarkably with
a correlation coefficient of r=

1.1.5A2780 ovarian cancer

The correlation matrix depicts the relationship between the three descriptors chosen for cell
line A2780 (Table 12).
Table 12: Pearson (n) correlation matrix relating the various obtained factors for the
A2780cancer cell line. With a r=0.411, SlogP VSA5 is positively linked with (PIC50). TPSA
(mean 2D Topological Polar Surface Area (A**2)) has a r=-0.649 relationship with PIC50.

PIC50 PEOE_VSA-1 SlogP_VSA5 TPSA

PIC50 1
PEOE_VSA-1 -0,402 1
SlogP_VSA5 0,411 -0,340 1
TPSA -0,649 -0,041 0,055 1
In bold character we show the variables which are highly correlated.
A B

The correlation circle of descriptors and PIC50 is depicted in Figure 11-A. A positive
association was evaluated in the descriptors 'TPSA' and 'PIC50' with a correlation coefficient
of r=-0.649, as well as the descriptor 'SlogP VSA5' and the 'PIC50' with r=0.411.
Figure 11. CPA of A2780: A represents the Correlation Circle of Descriptors and anticancer
activity (PIC50g), B represents the biplot of the molecules in the plan of the first two axes F1

11
and F2, and the percentages of variance for the two axes F1 and F2 are respectively 48.24
percent and 31.25 percent. The overall amount of data is expected to be 79.49 percent.
We used the study of the Biplot graph (Figure 11-B) to better understand the relationship
between the descriptors and the anticancer activity of the examined compounds.
This allows us to define two groups of molecules based on their cytotoxicity.
 The first group, which is represented by molecules 401, 403, 406, 419, 427, 428, and
429 in the top left of the biplot, showed moderate anticancer activity against cell line
A2780 (5.50MPIC506.35M). This group is characterized by the descriptor 'TPSA' (the
topological polar surface), which contributes negatively to anticancer activity with a
correlation coefficient of r=-0.650.
 The second group, which is represented by molecules 399, 400, 404, 407, 408, 409,
410, 411, 412, 413, 414, 415, 416, 417, 418, 420, 421, 423, 424, 425, and 426 on the
lower left of Biplot (Figure 11-B), showed better anticancer activity when compared to
the A2780 cell line (6.50µM≤PIC50≤7.00µM) and is Then, with a correlation
coefficient of 0.411, the descriptor 'SLOGP VSA5' (the summation of the estimated
accessible van der Waals surface).
1.1.6ACHN kidney cancer
The correlation matrix created below shows the correlation between the four descriptors used
for this lineage (Table 13).
Table 13: For the ACHN cancer cell line, a correlation matrix (Pearson (n)) was created to
correlate the various variables gathered. (diameter) r=0.540 is positively connected with opr
nrot (denotes 2D Oprea Rotatable Bond Count). PEOE VSA PNEG (denotes 2D Total polar
-ve surface area of Van der Waals force) is inversely linked with Q VSA PNEG (r=-0.484).
PIC50 Diameter PEOE_VSA_PNE Q_VSA_PNE opr_nrot
G G
PIC50 1
diameter -0,419 1
PEOE_VSA_PNE -0,249 0,309 1
G
Q_VSA_PNEG 0,338 0,128 -0,484 1
opr_nrot 0,105 0,540 0,039 -0,193 1

12
In bold character we show the variables which are highly correlated.

A B
The PIC50 and the variables evaluated are correlated, as shown by the correlation circle
(Figure 12-A). The descriptors 'oprt nrot' and 'diameter' have an excellent collinearity
coefficient of 0.540, followed by a negative correlation of r=-0.484 between the descriptors
'PEOE VSA PNEG' and 'Q VAS PNEG,' and a weak correlation between the other
descriptors.
Figure 12: ACHN's CPA: A represents a correlation circle of descriptors and anticancer
activity (PIC50g), B represents a biplot of the molecules in the plan of the first two axes F1
and F2, and the percentages of variance for the two axes F1 and F2 are respectively 39.18
percent and 27.12 percent. The overall amount of data is predicted to be 66.30 percent.
We were able to differentiate three groups based on their descriptors using the Biplot analysis
(Figure 12-B).
 The first group, which included molecules 466, 452, 470, 465, 467, 468, 454, and 469,
was found in the upper left of the biplot and showed moderate anticancer activity
against the ACHN cell line. This group is defined by the descriptor 'Q VSA PNEG,'
which contributes positively to the increase in anticancer activity studied with a
correlation coefficient of r=0.338.
 The second group included molecules 434, 435, 446, 459, 460, 461, 451, 464, 472,
473, and 474, which were found in the bottom right corner of the biplot (Figure 12-B)
and shown high anti-neoplastic activity (PIC505M). The descriptor 'PEOE VSA
PNEG' (total -ve surface area of Van der Waal forces) has a correlation coefficient of
-0.250, which defines this group.

13
  The third set of molecules on the upper right of the biplot, 441, 440, 439, 438, 448,
436, 447, 444, 445, 458, and 475, showed moderate anticancer activity
(4.40µM≤PIC50≤5.50µM). Two descriptions are combined in this group. With a
correlation coefficient of -0.419, one based on the physicochemical descriptor
'diameter' demonstrated a negative contribution to ACHN anticancer activity. The
additional descriptor, 'opr-nrot,' indicates that the number of single bonds in rotation
contributes positively, with a r=0.106 correlation coefficient.1.1.7NUGC Stomach
cancer
The correlation matrix below shows the relationship between the three descriptors chosen for
this NUGC lineage and PIC50 (Table 14).
Table 14: Pearson (n) correlation matrix connecting the NUGC cancer cell line's numerous
obtained factors. balabanJ (desinge 2D Balaban averaged distance sum connectivity) is
inversely connected with b single (denotes the number of single bonds (including implicit
hydrogens) with a r=-0.603. PEOE VSA+1 is positively linked with b single (r=0.469)

PIC50 a_nS BalabanJ PEOE_VSA+1 B_singl

e
PIC50 1
a_nS 0,294 1
balabanJ 0,168 -0,299 1

14
 PEOE_VSA+1 -0,412 -0,129 0,037 1
b_single -0,281 -0,295 -0,603 0,469 1
In bold character we show the variables which are highly correlated.
A B
The correlation between the variables studied and anticancer activity is depicted in Figure 13-
A; most variables have a good collinearity of r> 0.5.
Figure 13: NUGC CPA: A represents the Correlation Circle of Descriptors and anticancer
activity (PIC50g), B represents the biplot of the molecules in the plan of the first two axes F1
and F2, with percentages of variance of 40.04 percent and 28.02 percent for the two axes F1
and F2, respectively. The overall amount of data is expected to be 69.06 percent.
We may divide the molecules into three groups based on the study of the Biplot graph shown
in Figure 13-B.

 The first group, which includes molecules 485, 494, 497, 486, 478, and 500 in
the bottom left of the biplot (Figure 13-B), has better anticancer activity
(PIC50≥7.00µM) against the NUGC cell line and is distinguished by the
descriptor 'a ns' (which indicates the number of sulfur atoms in the molecule)
which contributes positively to anticancer activity with a correlation coefficient
of r=0.294.
 In the bottom right of the biplot, molecules 477, 479, 480, 482, 483, 488, 487,
489, 484, 498, 499, and 486 are found; these compounds have moderate

anticancer activity (5.48µM≤PIC50≤5.97µM), which can be explained by the

negative contribution of the descriptor 'b single,' which indicates the number of
single bonds (also implicit hydrogens). Aromatic bonds do not include single
bonds with a correlation coefficient of r=0.21.
15
  The third group consists of molecules 476, 481, 484, 492, 493, 495, and 496,
which are displayed on the top left of the biplot and have significant anticancer
activity (6.45µM≤PIC50≤6.97µM) against the NUGC cell line, and are
characterized by the descriptor 'BlabanJ,' which contributes positively to
anticancer activity with a correlation coefficient of r=0.168.
1.2PLS Models for each cell lines
Table 15 equations Model corresponding to each cancer cell lines.

Cancer cell line QSAR equation of model's

PIC50 =3.04136 -0.81740 * balabanJ +0.01517 * SlogP_VSA4+3.32414 *
PC-3 density
PIC50 = 7.16690 -0.01083 * SlogP_VSA5 +0.00750 *
B16F10 PEOE_VSA+00.02026 * zagreb-0.04075 * vsa_other +0.02723 *
SMR_VSA1+0.00853 * SMR_VSA7
PIC50 =5.25700-1.47700 * BCUT_SLOGP_2-0.17497 * a_nO -1.69613 *
K-562 a_nS +0.08339 * SMR_VSA4
PIC50 =3.52539+0.01852 * PEOE_VSA+1-0.60365 * Q_PC--0.00942 *
MDA-MB-231 Q_VSA_HYD
PIC50 =11.48171 -0.00701 * PEOE_VSA-1 +0.01031 * SlogP_VSA5-
A2780 0.05911 * TPSA
PIC50 =6.64342-0.27307 * diameter+0.01999 * PEOE_VSA_PNEG
ACHN +0.01918 * Q_VSA_PNEG +0.20834 * opr_nrot
PIC50 =-0.72647+0.61538 * a_nS +3.70474 * balabanJ -0.06358 *
NUGC PEOE_VSA +1+0.15136 * b_single

Table 16 value of statistical parameters for the thirteen cancer cell lines

Correlatio Cross Q2 R2
n Cross valiadted internal external
Cancer Cell
coefficient RMSE validated RMSE validation validation
Lines
R2 of R2
model
PC-3 0.83200 0.10710 0.76061 0.12826 0.76061 0.669
B16F10 0.82751 0.19496 0.71697 0.25319 0.71697 0.776
K-562 0.98478 0.24926 0.97920 0.29148 0.97920 0.878
MDA-MB-231 0.81342 0.18571 0.76541 0.20896 0.76541 0.798
A2780 0.84065 0.14372 0.73024 0.18770 0.73024 0.647
ACHN 0.87813 0.10311 0.81326 0.12809 0.81326 0.751
NUGC 0.92013 0.19987 0.86062 0.26587 0.86062 0.8078

We expand below more details for each cancer cell line. ==> paraphraser

16
1.1.1Model PLS PC-3
From the equation we notice that the descriptors balabanJ and SlogP_VSA4 could contribute
to the improvement of the anticancer activity.
1.1.2Model PLS B16F10
According to this equation, the descriptors Slog VSA5; zagreb, and vsa other have a negative
impact on anticancer activity, implying that the van der waals surface can help to reduce
anticancer activity in the B16F10 cell line. The descriptors PEOE VSA+0; SMR VSA1; and
SMR VSA7 then showed a positive coefficient, indicating that molar refractivity and the
overall positive van der Waals surface may play a role in improving the studied biological
activity.
1.1.3Model PLS K-562
We can see from the equation that the number of sulfur atoms has a negative coefficient,
which suggests that the number of atoms can help to boost anticancer activity against the K-
562 cell line.
The number of oxygen atoms had a negative coefficient, indicating that the number of oxygen
atoms may play a role in improving the biological activity under consideration.
1.1.4Model PLS MDA-MB-231
The descriptor (Q PC-), which indicates the total negative partial charge, contributes to the
increase in biological activity, as shown in the equation.
In the version, the descriptor (Q VSA HYD) has a -ve coefficient, implying that an increased
amount of partial charge at the surface enhances the anticancer impact.
1.1.5Model PLS A2780
According to the QSAR model equation for this cell line, the descriptors (TPSA) (topological
polar surface area) (PEOE VSA-1) (sum of negative Van Der Waals surface) (PEOE VSA-1)
(PEOE VSA-1) (PEOE VSA-1) (PEOE VSA-1) (PEOE VSA-1) (PEOE VSA-1) (PEOE
VSA-1) (PEOE VSA-1) (This suggests that the pyrazole structure's Van Der Waals surface
charge enhances the cytotoxic activity.
1.1.6Model PLS ACHN
The descriptors diameter (Diameter), partial negative charge (PEOE VSA PNEG), negative
polar area (Q VSA PNEG), and number of rotational bonds (opr nrot) are found to contribute
to the enhancement of antineoplastic activity against the ACHN cancer cell line. This
indicates that the diameter and partial charge of molecular structures have a positive impact
on cytotoxicity.
1.1Prediction of anticancer activity of the new synthesis series
PIC50Cell PIC50 predicted of value in µM of best potential inhibitors for each cell line line
PC-3
M48=5,2647 M55=5,3206 M60=5,2652 M54=5,1415

17
prostate cancer
B16F10
M36=6,7535 M41=6,5148 M42=6,3024 M43=6,7368
Skin cancer
K-562
M1=7,3133
Leukemia
MDA-MB-231
M4=6,3657 M5=5,8921 M32=7,0300 M33=6,5565
Breast cancer
A2780
M4=8,5720 M19=8,5720 M30=8,1494 M32=8,6362
ovarian cancer
M33=6,3643
Kidney cancer M1=6,1061 M5=6,4812 M20=5,8703
2
NUG M32=43,623 M52=36,028
M33=34,4487 M47=34,7843
Stomach cancer 2 6

1.1.1Antiproliferative effects against the PC-3 prostate cancer cell line

We discovered that compounds 48, 54, 55, and 60 (Figure 25) have the highest cytotoxic
activity against PC-3 using the QSAR model.

18
Figure 25 Structure of novel series of pyrazole triazole thiol showing the best PIC50
valuesagainst the PC-3 prostate cancer cell line.
Conjugates 48, 55 and 60 bearing the methyl and Ph-group on the bromo group and pyrazole
ringat benzene ring manifest cytotoxicity against the PC-3 cell line with cytotoxicity values of
PIC50=5.264µM, PIC50=5.320µM and PIC50=5.265µM respectively, and are approximately
similar to those obtained in the literature[74, 75].On the other hand, the conjugate 54 carrying
on the pyrazole ring the phenyl group as well as the electron-withdrawing group
dichlor(2,4Cl) on the benzene ring showed a moderate cytotoxic effect with a cytotoxicity
value PIC50=5.141µM. This suggests that the optimal order of increasing substitutions activity
on the benzene ring is Br>(-N-CH3)2>OCH3>>Phenyl>2,4-Cl>CH3 (Figure 26).

Figure 26 Structure-activity relationship study (SAR) of pyrazole triazole thiol derivative as

potent anticancer agents.

1.1.2Antiproliferative effects against the B16F10 skin cancer cell line

Based on the QSAR prediction results obtained for this line, we detected four
conjugates with the highest cytotoxic activity.

19
Figure 27 Structure of novel series of pyrazole triazole thiol showing the best PIC50 values
against the B16F10 skin cancer cell line.
The pyrazole carbohydrazide conjugates 36, 41, 42 and 43 (Figure 27) shows average to
acceptable antiproliferative effect in opposition toB16F10 line of cell with cytotoxicity values
of PIC50=6.753μM, PIC50=6.514μM, PIC50= 6.302 μM and PIC50=6.736μM. This is explained
by the presence of dimethyl on the pyrazole A ring as well as Br, OH and OCH3groups on the
benzene B ring. Similarly, compounds substituted by dimethyl on the same pyrazole A ring
and substituted by N(CH3)2, NO2, Clone the benzene B ring and furan exhibited a reduced
effect of cytotoxicity against the B16F10 cell line. Hence, the ideal elevated order of the
activity of ring substitutions on ring B is Br>OH>OCH3>Furan>NO2>(-N-
CH3)2>2,4Cl>CH3(Figure 28).

Figure 28 Structure-activity relationship study (SAR) of pyrazole triazole thiol derivative as

potent anticancer agents.

1.1.3Antiproliferative effect against LeukemiaK-562

In the continued QSAR-based investigation of our synthesized compounds, we include
the K-562Leukemia cell line. Analysis of the prediction results shows that only compound 1
(Figure 29) is the most potent against K-562with a PIC50 =7.313 µM.

20
Figure 29Structure of pyrazole triazole thiol showing the best PIC50 values against LeukemiaK-562.
This high cytotoxicity can probably be explained by the presence of a methyl group on the
pyrazole ring and a hydrazide group linked to the carbonyl function. The other conjugates
showed a moderate to weak effect against this line.
1.1.4Antiproliferative effect against the MDA-MB-231 cell line of breast cancer
For the line of MDA-MB-231, the results of QSAR prediction show that the conjugate4, 5, 32
and 33 (Figure 30) show the highest cytotoxic activity.

Figure 30 Structure of novel series of pyrazole acetohydrazide showing the best PIC50 values
against the MDA-MB-231breast cancer cell line.
Conjugate 4 and 5 belong to the pyrazole carbohydrazide family showed moderate anticancer
potential against the cell line of MDA-MB-231 with cytotoxicity values: PIC50=6.365 μM and
PIC50=5.892μM this can be explained by the presence of methyl group (CH3) on the pyrazole
ring A as well as the benzene ring B substituted by the dimethylamino(N(CH3)2)
electrondonor group, this group contributes to the enhancement of the activity of this
compound. On the other hand, compound 5 substituted by an electron withdrawing group

21
Nitro (NO2) on the benzene ring contributes decrease the bioactivity. Similarly, compound 32
substituted with dimethyl (CH3)2 on the same pyrazole ring A and keeping the same
dimethylamino(N(CH3)2) group bearing on the benzene ring B exhibited an increased
cytotoxic effect PIC50=7.030μM. This due to the presence of two methyl groups on the
pyrazole ring. Next, pyrazole acetohydrazide compound 33 showed significant
PIC50=6.556μM cytotoxic activity against cell line that has been studied. Our QSAR model
predicted the cytotoxic values that are higher than those obtained in literature [76, 77].
Therefore, on B ring the activity substitution of optimal ascending order is NCH 3)2>OCH3>2-
Cl 2,4-Cl>Furan>4-Cl>F NO2.
1.1.5Antiproliferative effect against the A2780 ovarian cancercell line
Our QSAR study also identified cancer cell line A2780 to explore other conjugates
that may be a potential agent against this cell line. In this regard, the information extracted
from prediction results analysis, indicates that compounds 4, 19, 30 and 32 (Figure 31)
present the highest cytotoxic activity.

Figure 31 Structure of novel series of pyrazole acetohydrazideshowing the best PIC50 values
against the A2780 ovarian cancercell line.
The prediction results show that compound 4 has the highest anticancer potential against this
cell line with a PIC50=8.572μM. This antiproliferative activity of this compound is explained
by the presence of methyl (CH3) bearing on the pyrazole ring A as well as the benzene ring B
substituted by the dimethylamino electron-donor group (N(CH3)2). This group improves the
activity of this conjugate. On the other hand, the conjugate substituted by the nitro group on
the benzene ring, showed low anticancer activity compared to compound 4. Similarly,
compound 19 substituted by phenyl on the same pyrazole ring A and keeping the same
dimethylamino(N(CH3)2) group bearing on the benzene ring B exhibited a PIC50=8 cytotoxic

22
effect.572 μM increased against the A2780 cell line. This can be explained by the presence of
phenyl on the pyrazole ring which increases the anticancer activity of this compound. Next,
compounds 30 and 32 belonging to the pyrazole acetohydrazide family showed significant
PIC50= 8.149μM and PIC50=8.636μM cytotoxicity against the cell line that has been studied
isA2780. The presence of two methyl groups contributes to a slight increase in activity.
Therefore, on the B-ring the substitution activity of optimal increasing orderis
NCH3)2>NO2>phenyl>OCH3>2-Cl,4-Cl>.

1.1.6Antiproliferative effect against the ACHN kidney cancer lineage

To unravel the cytotoxic effect of new derivative of our synthesized carbohydrazide
pyrazole series, our QSAR study also included the cancer cell line (ACHN). The high PIC 50
values of the conjugates1, 5 and 33 (Figure 32) indicate that they can be considered as a
potential agent against kidney cancer.

Figure 32 Structure of novel series of pyrazole carbohydrazide and acetohydrazide showing

the best PIC50 values agaisnt the ACHN kidney cancer cell line.
The QSAR model notes that conjugate 1 belonging to the pyrazole carbohydrazide family
exhibited high anticancer potential against the ACHN cell line with a cytotoxicity value of,
PIC50=6.106μM. This antiproliferative activity of this compound is explained by the presence
of methyl (CH3) bearing on the pyrazole A ring as well as the hydrazine group linked to the
ketone function. This indicates that this group improves the activity of this conjugate against
the studied cell line. Then, the conjugate 5 substituted by the same methyl group linked to the
pyrazole ring, and the benzene ring substituted by the Nitro (NO2) electron-withdrawing
group showed a slight increase in the anticancer activity (PIC 50=6.481μM) compared to
compound 1. On the other hand, the conjugates substituted by the Cl, Br, OCH3, CH3 and F

23
groups bearing on the benzene ring, show a decrease in their activities. Similarly, compound
20 substituted in this case by phenyl on the pyrazole ring A and benzene ring B substituted by
the Nitro (NO2) group showed a moderate cytotoxic effect (PIC50=5.870μM) against the
ACHN cell line. This is probably due to the presence of phenyl group that is present on the
ring of pyrazole. This phenyl group decreases the activity of anticancer of this compound.
Then, compound 33 substituted with dimethyl on the same pyrazole ring A and benzene ring
B substituted with the same
Nitro group (NO2) showed a high cytotoxic effect compared to compound 20
(PIC50=6.364μM) against the ACHN cell line, this is probably explained by the presence of
two methyl groups on the pyrazole ring which increases the anticancer activity of this
compound 33. Therefore, on ring Bthe substitutions activity of optimal increasing order is
NO2> Furan>OH>OCH3>2-Cl>Phenyl>N-CH3)2>2,4-Cl>.

1.1.7Antiproliferative effect against the NUGC gastric cancer cellline

We ended our study with the last cell line NUGC, the information obtained from QSAR
model analysis, indicate that compounds 32, 33, 47 and 52 (Figure 33) present the highest
cytotoxic activity.

Figure 33.Structure of novel series of pyrazole triazole thiol and acetohydrazide showing the
best PIC50 values against the NUGC gastric cancer cell line.

24
Conjugate 32 from thepyrazole acetohydrazide family bearing a dimethyl (CH3)2 substitution
on the pyrazole A ring and the electron-donating group (N(CH3)2) on the benzene B ring,
against the NUGC cell line, showed a promising cytotoxic effect with PIC 50=43.623.
Similarly, the conjugate 33 carrying the same dimethyl (CH3)2 electron donor groups onthe
pyrazole ring A as well as the benzene ring B substituted by an electron-withdrawing group
(NO2) showed a slight decrease compared to compound 32 in cytotoxicity against the gastric
cancer cell line with PIC50 = 34.448. It suggests the presence of withdrawing the electron
group decreases the anti-cancer activity. Moreover, compound 47 belonging to pyrazole
triazole thiol family increase the cytotoxicity compared to compound 33 against NUGC cell
line with the value of PIC50=34.784µM, Since the pyrazole ring substituted with methyl group
as well as benzene ring substituted with dimethyl amino(N(CH3)2 suggests a slight increase in
the anticancer activity against NUGC cell line. Finally, the last compound 52 showed a high
cytotoxic activity (PIC50=36.028µM) compared to compound 47. This increased activity is
probably explained by the occurrence of phenyl group carried on the ring of pyrazole as well
as, the benzene ring which keeps the same previous group (compound 47).
Therefore, Therefore, on ring B the substitutions activity of optimal increasing order is
NO2>N-CH3)2>Phenyl>OH>OCH3>Furan>diphenyl>Br>F>4-Cl>2-Br>5-OH>2,4-Cl>2-Cl>.

2. Design and prediction of pIC50 of new pyrazoles derivatives

2.1Prostate cancer PC-3

Based on the t-test results to evaluate the contribution of each descriptor on the
PIC50anticancer activity of pyrazole carbohydrazide derivatives. The t-test values for our
descriptors shown in the model are 145.5845168; 35.79896876 and 0.664387517 for density,
balabanJ and SlogP_VSA4, respectively.
The compound that served as Template for the substitution is compound 55.

25
pIC =3.04136 -0.81740 * balabanJ +0.01517 * SlogP_ VSA4+3.32414 * density50

Therefore, to increase the value of the activity, we will (Table 24):

Decrease the values of descriptors balabanJ (denotes the topological connectivity index) of
new compounds (balabanJ<1.2993), by the introduction of benzene rings substituted by Br,
CH(Br)2, COBr, CO2CH3, morpholine. This means that a substitution by the groups
containing the substituted benzene ring with electron-withdrawing entities can increase the
studied activity.
Increase the values of descriptors density (denotes the molecular density: weight divided by
vdw_vol (amu/Å 3)), for which we add in the group R a ring substituted by an electron
withdrawing group.
The SlogP_VSA4 descriptor values of new compounds must be greater than 8.6991, for this
descriptor to contribute to the increase in activity, adding large substituents such as benzene
carries electron-withdrawing groups, this results in an increase in activity for a group
containing CH(Br)2, COBr.

26
Table 24Values of descriptors for the new pyrazole carbohydrazide derivatives and their
predicted anticancer activity PIC50 (Prostate cancer PC-3) calculated according to PC-3
mathematical model.

27
2.2Skin cancer B16F10
The anticancer activity is decreased by the descriptors SlogP VSA5, vsa Other, and zagreb,
while it is increased by the descriptors PEOE VSA+0, SMR VSA1, and SMR VSA7. For
SlogP VSA5, PEOE VSA+0; zagreb; vsa other; SMR VSA1 and SMR VSA7, the t-test values
are 0.338999522; 0.234764212; 0.634176392; 1.275552219; 0.8523506 and 0.267005164,
respectively.

pIC =7.16690 -0.01083*SlogP_ VSA5 +0.00750*PEOE_ VSA+0-0.02026*zagreb 50

-0.04075*vsa_ other+0.02723*SMR_ VSA1+0.00853*SMR_ VSA7
The compound that served as Template for the substitution is compound 36.
28
In addition, to raise the PIC50 value, we shall (Table 25):
By including Br, CH(CH3)2, OH, Dimethyl, 3-hydroxy-3methyl, 3-hydroxypropyl substituted
benzene rings, increase the values of descriptors SlogP VSA5 (denotes the van der Waals
Sum area (SlogP VSA5>19.781). This indicates that substituting groups containing the
benzene ring with electron-withdrawing/donor moieties can result in increased activity.
Increase the values of the zagreb descriptors (The sum of di2 on all heavy atoms I for which
the benzene ring is substituted by a branched alkyl containing OH, Br, in the group R.
Decrease the vsa_other descriptor values (means other van der waals surface) of new
compounds must be less than 33.2490, for it to contribute to the increase in activity, by adding
substituents containing a branched alkyl, a branched bromoalkane or a secondary or primary
alcohol on the benzene ring, these leading to an increase in anti-cancer activity
The other descriptors PEOE_VSA+0; SMR_VSA1 and SMR_VSA7 contribute positively on
anticancer activity, as indicated in the model, to make these descriptors more significant,
PEOE_VSA+0>67.6947; SMR_VSA1>60.4878 and SMR_VSA7>129.8205.

Table 25. Values of descriptors for new pyrazole carbohydrazide derivatives and their
predicted anticancer activity PIC50 (B16F10 skin cancer) calculated according to B16F10
mathematical model.

29
 111.258 291.864
41.6416 286.8487 210 19.6490 9,3311
2 2

15

2.3Leukemia K-562

30
In the model equation, the descriptors BCUT_SlogP_2, a_nO and a_nS contribute to the
decrease in anticancer activity against Leukemia, while the descriptor SMR_VSA4
contributes to its increase. The t-test values for our descriptors shown in the model are
37.8029547; 4.478255236; 43.41145941and 2.134318478 for BCUT_SlogP_2; a_nO; a_nS
and SMR_VSA4, respectively.
The compound that served as Template for the substitution is compound 1.

pIC =3.04136 -0.81740 * balabanJ +0.01517 * SlogP_ VSA4 50

+3.32414 * density
Therefore, to increase the value of the PIC50, we will (Table 26):
The increase of BCUT_Slogp-2 descriptor values (BCUT descriptors using atomic
contribution to logP instead of partial charge, BCUT_SlogP-2> 0.3397), by incorporation of
nitrogenous groups containing primary amines, aromatic amines, amides, or alkyl imidamides
can lead to higher activity values.
Decrease the values of descriptors a_nO of new compounds, for which we add in the group R
of entities containing the amide or ketone function, provided that the total number of oxygen
atom introduced does not exceed 2 (a_nO≤2), so that it contributes positively.
Decrease the values of descriptors a_nS of new compounds which must be lower than 1
(a_nS<1). Indeed, the absence of sulfur atom incorporated in the group to be substituted
presents an asset for this descriptor to contribute positively to the increase of the PIC50.
The descriptor SMR_VSA4 (stands for Sum of the surfacearea of van der Waals to molar
refractivity) on the anticancer activity, contributed positively. As shown in model (9), to make
this descriptor more significant, SMR_VSA4>32.7747 is required.

31
Table 26Values of the descriptors for new pyrazole carbohydrazide derivatives and their
predicted anticancer activity PIC50 (K-562Leukemia) calculated according to K-562
mathematical model.

BCUT_SlogP
N° a_nO a_nS SMR_VSA4 PIC50
_2
0.55531985

1 0 65.794373 9,7484

12

9,749
0.55486625 1 0 65.794373
0

13

2.4Breast cancer MDA-MB-231

32
The t-test values for our descriptors are 20.55850184; 0.630735449; and 0.320816843 for Q
PC-; PEOE VSA+1; and Q VSA HYD, respectively, to compare the influence of each
descriptor on the PIC50 anticancer activity of pyrazole carbohydrazide derivatives.
As a result, we can create new compounds by making appropriate replacements that improve
the values of the descriptors Q PC- and Q VSA HYD, resulting in increased activity over the
base molecule that served as Template 32.

PIC50 =3.52539+0.01852 * PEOE_ VSA+1-0.60365 * Q_ PC-

-0.00942 * Q_ VSA_ HYD
Furthermore, to increase the value of the activity, we will (Table 27):
Increase the values of descriptors PEOE_VSA+1 (denotes van der waals sum of area when
partial charge is in the range (0.05-0.10), PEOE_VSA+1> 161.0262), by the incorporation of
nitrogenous species containing partial charges such as tertiary amines, nitro/Cyano or alkyl
imidamides
Decrease the values of descriptors Q_PC- (denotes the total negative partial charge) of new
compounds, for which we add in the benzene ring the nitro and methoxy group, as well as
replacing the two methyls bound by the pyrazole ring by nitrogenous groups bearing the
partial charges as imidamide, N(CH3)2, NO2, OH, CN, NH2 and CONH(CH 3)2 provided that
the values of descriptors Q_PC-≤-2.9590), so that this descriptor contributes positively.
Decrease the values of descriptors Q_VSA_HYD (stands for total of surface area of
hydrophobic van der Waals) of new compounds which must be less than 161.1534
(Q_VSA_HYD<161.1534). Indeed, the values of these descriptors decrease with the increase
of the partial charge in the molecule.

33
Table 27Valuesof descriptors for the new pyrazole carbohydrazide derivatives and their predicted
anticancer activity PIC50 (Breast cancer MDA-MB-231) calculated according to MDA-MB-231
mathematical model.

-
248.67508 105.47758 9,9750
4.7010002

15

34
2.5Ovarian Cancer A2780

In the model equation for this line, the descriptor SlogP_VSA5 increases anticancer
activity against ovarian cancer A2780, while the descriptors PEOE_VSA-1- and TPSA
contribute negatively on the activity. The t-test values for our descriptors are 2.232199341;
0.389341486 and 0.264721999 for TPSA; SlogP_VSA5 and PEOE_VSA-1, respectively.
Hence, we can design new compounds by adding appropriate substitutions that can improve
the descriptor values and thus increase the PIC50, the compound that served as Template for
substitution is compound 32.

pIC50=11.48171-0.00701*PEOE_ VSA-1+0.01031*SlogP_ VSA5

-0.05911*TPSA50
Furthermore, to increase the value of anti-cancer activity, we will (Table 28):
Keeping the descriptor values PEOE_VSA-1 (denotes the van der waals sum area) zero
(PEOE_VSA-1=0.000), replacing the first methyl group (CH 3) bound to the pyrazole ring by
incorporating the tertiary amine-containing nitrogen species methoxy (OCH3), Br, F, aromatic
tertiary amines and branched alkyls as well as the other methyl group bound to the pyrazole
by dimethylamino N(CH3)2 can lead to higher activity values.
Increase the descriptor values SlogP_VSA5 (denotes the van der waals sum area) of new
compounds, for which we add in the pyrazole ring a benzene ring substituted by nitrogenous
electron-donor and electron-attractant species provided that the descriptor values
SlogP_VSA5>82.4574, to improve the meaning of this descriptor.
Increase the TPSA descriptor values (designates the topological polar surface of a molecule)
of new compounds to be higher than 62.5200 (TPSA> 62.5200). Indeed, the values of this
descriptor increase with the electron-donor groups linked to the benzene ring in the molecule.

35
Table 28Values of the descriptors for the new pyrazole carbohydrazide derivatives and their
predicted anticancer activity PIC50 (Ovarian cancer A2780) calculated according to A2780
mathematical model.

0 254.67343 60.41 10,5365

14

2.6 Kidney cancer ACHN

36
Based on the t-test to compare the relevance of each descriptor on PIC50, the t-test values for
diameter, PEOE VSA PNEG, Q VSA PNEG, and opr_nrot in the model are 9.930449469;
0.726955304; 0.697498886 and 7.576481643, respectively.
As a result, we may create additional compounds by making appropriate replacements to
increase the diameter descriptor's value; the compound utilized as a template is compound 5.

pIC50=6.64342-0.27307*diameter+0.01999*PEOE_ VSA_ PNEG 50

+0.01918*Q_ VSA_ PNEG+0.20834*opr_ nrot
To boost the activity's value, we will include (Table 29):
Replacement of the methyl group (CH3) bound to the pyrazole ring by incorporating
nitrogenous species containing primary amines, methoxy (OCH3), NO2, nitroethyl,
Nitrobenzene, and imidamide can lead to higher activity values by increasing the diameter
descriptor (denotes the largest value of the distance matrix) that must be greater than 13
(diameter>13,000).
To enhance the values of the descriptor PEOE_VSA_PNEG (which represents the total area
of Negative Polar Van der Waals) of novel compounds, the pyrazole ring is added.
Table 29 Values of descriptors and anticancer activity PIC50 (Kidney cancer ACHN)
computed using the ACHN mathematical model for novel pyrazole carbohydrazide
derivatives.

37
 115.36006 143.62318 8 9,5478
14
12

CONCLUSION
Cancer is a non-communicable, chronic disease that is rapidly becoming a worldwide health
threat. According to recent evidence, noncommunicable diseases such as cancer are quickly
displacing communicable diseases. Despite the fact that much scientific study has been done
on cancer in recent decades, there are currently a number of innovative medications on the
market and several more in the development phase. Before entering clinical trials, many
methods and approaches are utilized to find chemical compounds and verify their affinity
activity against various targets. QSAR is a strategy for identifying and designing newer
medicines as well as predicting their physicochemical and biological properties. This tool can
help improve the drug's kinetic profile and lower toxicity. We constructed QSAR models
against six different forms of neoplasias in this study, including prostate cancer, ovarian
cancer, skin cancer (melanoma), renal cell carcinoma, leukemias, and stomach malignancies.
The major drugs employed in this investigation are novel Pyrazole derivatives. With pIC50
values of 5.2647, 5.3206, 5.2652, and 5.1415 M, the compounds 48, 54, 55, and 60
demonstrated remarkable cytotoxic action against prostate cancer (PC-3). With pIC50 values
of 6.7535, 6.5148, 6.3024, and 6.7368 M, the compounds 36, 41, 42, and 43 demonstrated
high cytotoxic action against skin cancer (B16F10). Compound 1 then shown strong cytotoxic
action against chronic myelogenous leukemia (K-562), with a pIC50 of 7.313μM Compounds
4, 5, 32, and 33 have significant cytotoxic action against MDA-MB-231, with pIC50 values of
6.3657, 5.8921, 7.0300, and 6.5565μM , respectively.The compounds 4, 19, 30 and 32
showed excellent anticancer activity against ovarian cancer (A2780) with pIC50 8.5720;
8.5720; 8.1494 and 8.6362 μM. Compounds 1, 5, 20 and 33 show high anticancer activity
against Renal cancer (ACHN) with pIC50 6,106; 6.4812; 5.8703 and 6.3643μM.
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