Chapter 1

LITERATURE REVIEW
LITERATURE REVIEW
It has been nearly 40 years since the quantitative structure-activity relationship
(QSAR) paradigm first found its way into the practice of agro chemistry,
pharmaceutical chemistry, toxicology, and eventually most facets of chemistry. Its
attributed to the strength of its initial postulate that activity was a function of
structure. It is described by electronic attributes, hydrophobicity, and steric
properties.

Further rapid and extensive development in methodologies and

computational techniques that have ensued to describe and refine the many
variables and approaches. The overall goals of QSAR retain their original essence
and remain focused on the predictive ability of the approach and its receptiveness
to mechanistic interpretation.
It is well recognized that QSAR is one of the best tools for in silico (using siliconbased computer technologies to perform simulations, modeling and experiments)
drug design. There is a dedicated quest for robust QSAR models. Origin of QSAR
is from the field of toxicology (1).It was noted by Cros in 1863 that toxicity of
substances is governed by their properties, which in turn are determined by their
chemical structure. This showed interrelationship exists between structure,
properties, and toxicity (2).
74

Structure Activity Relationships (SAR) studies have been published since 1868,
when Crum-Brown & Fraser stipulated the idea that the physiological action of a
substance in a certain biological system is a function of its chemical constitution
.Meyer and Overton suggested that the narcotic (depressant) action of a group of

(3)

organic compounds paralleled their olive oil/water partition coefficients leading to

QSAR concepts in field of drugs discovery (4).
Use of various physical properties as a descriptor for QSAR study begins with
different type of constants and their equation. so, In 1937 Louis P. Hammett had
first introduced the concept of Hammett constant They determine the effect of a
substituent in the Meta or Para position of the benzene ring upon the rate or upon
the equilibrium of a reaction in which the reacting group is in a side chain attached
to the ring (5).
After the introduction of Hammett constant a new constant has derived by
Hantzch and Fujita (6) in 1964. They first introduced the new substituent constant of
derived from partition coefficient. The partition coefficient between 1-octanol
and water has been determined for 203 mono- and disubstituted benzenes. After
that a new researcher Taft

(7)

devised a way for separating polar, steric, and

resonance effects, introducing the first steric parameter E S.The contributions of

Hammett and Taft led to the development of the QSAR paradigm by Hansch and

75

Fujita, which combined the hydrophobic constants with Hammetts electronic

constants to yield the Hansch Equation (8).
In1970 Adamson and coworkers were the first to apply Fragment Descriptor using
multiple linear regression analysis (MLR). They find correlation with some
biological activities, physiochemical properties and reactivity (9).
After the establishment and development of different constants and physiochemical
descriptors, researchers find different QSAR methologies as well as approaches.
Further development in QSAR a CoMFA (comparative molecular field analysis)
method of 3D QSAR was introduced in 1988 by Cramer

(10)

in which related the

shape-dependent steric and electrostatic fields for molecules to their biological

activity and also Introduced a new method of data analysis: PLS (Partial Least
Squares) and cross-validation, to develop models for activity predictions.
Many QSAR studies has been reported for pyridine derivatives in this sequence
Yutaka Kawashima et al. in 1993 published a QSAR study using fuzzy adaptive
least square method for antihypertensive 1, 4 dihydro pyridine having 2 nitro-oxy
alkyl moieties at the 3, 5 positions (11).
With the further development of different QSAR methologies A CoMSIA method
of 3D QSAR analysis was introduced by Klebe

(12)

in 1994 , in which using a

common probe atom, similarity indices are calculated at regularly spaced grid
points for the pre aligned molecules. Later on, Chris L. Waller & Steven D. Wyrick
76

(13)

in 1994 used lipophilic and dipole moment characteristics of the molecules as

physical descriptor variables in the regression equation for QSAR study.

In 1994 Chung and Woo et al. introduced the new antagonist known as Platelet
activating factor (PAF) for heterocyclic lipids. Their study shows that PAF is a very
powerful antagonist (14).
Ki hwan kim et al. developed a new lateral validation equation. This new QSAR
equation laterally correlates to other various QSAR equations that support the new
equation. This method was originally utilized in the classical QSAR field of
physical organic chemistry and has recently been extended to the field of biological
sciences. The possibility of supporting a new 3D-QSAR by lateral validation is
investigated in this study using one of the most often used 3D-QSAR
methodologies, Comparative Molecular Field Analysis (CoMFA) (15).
Kaiser et al. in 1996 represent a brief review on microbial metabolism of pyridine.
they also discussed the metabolism activity of quinoline ,acridine and their
derivatives under aerobic and anaerobic conditions, with emphasis on metabolic
pathways (16). In 1996 Kearsley et al. describe alternative forms of the atom pair and
topological torsion descriptors that use physiochemical atom types. These types are
based on binding property class, atomic log P contribution, and partial atomic
charges (17).

77

1996 afterward in 1997 Pourmorad, Shaifee et al. gave the synthesis and calcium
channel antagonist activity of 4- imidazolyl -1,4 dihydropyridine .they concluded
the symmetrical esters showed that increasing the length of methylene chain of
ester more than 3 units decrease calcium channel antagonist activity (18).
Quantitative structure activity relationship study is based on structure/ activity as
well as required large or small datasets. So, in 1997 A new Genetic Algorithm
(GA) strategies for variable selection of QSAR study had been reported by
Hasegawa, Miyashita et al. In these study they use GA based PLS analysis and
found high internal predictivity for small set of datasets. The GAPLS (GA-based
PLS) program is written in FORTRAN language and is running on VAX
workstation (19).
After the development of 3D QSAR a new method 4D QSAR introduced by
Christian D. P. Klein and A. J. Hopfinger in 1998

these 4D-QSAR methods are

employed on a set with anti-arrhythmic activity. In their 4d QSAR study molecules

are built using CHEM-2 LAB, Semi-empirical calculations carried by MOPAC
6.0(22) package, molecular simulation dynamic package MOLSIM 3.0(23) were
used for conformation and energy optimization.

Molecular dynamics simulation

provided the set of conformation of datasets, which were analyzed using Partial
least regression in combination with the genetic function approximation algorithm
to construct QSAR model (20).
78

In 1999 R. Katritzky et al.gave overview on the development of QSPR/QSAR

equations using various descriptor mining techniques and multilinear regression
analysis in the framework of program CODESSA (Comprehensive Descriptors for
Structural and Statistical Analysis). The CODESSA software accepts various
standard structures formats as input: MDL .mol file; Hyperchem .hin file;
SYBYL .mol file; MOPAC/AMPAC regular .out file. In their paper the QSAR and
QSPR models derived for eighteen molecular activities and properties (21).
In the field of receptor based docking Burden and Winkler in 1999 introduced the
concept of a virtual receptor, and this is illustrated by the results of screening a
database of 40, 000 molecules. This concept gave a new QSAR model applied to
structure activity mapping and combinatorial chemistry (22). Soon after on , in 1999
An-Hu Li et al. synthesized 3,5-Diacyl-2,4-Dialkylpyridine Derivatives and
performed QSAR analysis using COMFA approach and partial least square
regression studying receptor docking for selective A3 Adenosine Receptor
Antagonists activity (23). Further development carried by Ju rgen Schleifer in 1999
and investigated a 3D pseudo receptor modeling approach for stereo selectivity
characterization of 1, 4 dihydropyridine binding site at L-type calcium channel in
the resting state (24).
In the year of 1999 authors was applied only one approach at a time but by Tatiana
Netzeva et al. in 2000 showed the importance of the lipophilicity in case of
79

valporic acid for anticonvulsant activity using 2D and 3D QSAR approaches.for

2D qsar analysis Log P and pKa values were obtained with ACD/Labs computer
program. Molecular modeling, conformational analysis, quantum mechanics,
mechanical optimization and electronic descriptor calculation as well as steric and
electrostatic field generation for 3D QSAR and statistical evaluation of the models
were performed with the Chem-X computer program (25).Yoshida and topless et al.
observed quantitative structure-bioavailability relationship of 232 structurally
diverse drugs to evaluate the feasibility of constructing a predictive model. They
developed different models for the human oral bioavailability of prospective new
medicinal agents in 2000 (26).
In 2001 researchers applied principal component analysis neural network algorithm
with Hologram Quantitative Structure Activity Relationship (HQSAR) on a set of
1, 4 dihydro pyridine by Viswanadhan and Weinstein. They define that the HQSAR
more straight forward and easier as compared to multiple linear regression (27).After
that, Yashri and Hart-sough et al. in 2001 gave new combined method for the
development of a novel variable selection and neural network model building
technique called ARQeDES. The method was successfully applied to both artificial
and real biological data sets (28). Many more developments were reported

for the

synthesis of pyridine derivatives in these sequences in 2001 by Stephanie and Rao

80

et al. gave the synthesis and Evaluation of a New Class of Nifedipine Analogs with
T-Type Calcium Channel Blocking Activity (29).
Kharkar Prashant et al. in 2002 for developing Three-Dimensional Quantitative
Structure-Activity Relationship of 1, 4-Dihydropyridines as Antitubercular Agents
.In 2002 Victor E. Kuzmin et al. used 4D QSAR approach for the molecular

(30)

structure of macro cyclic pyridinophanes for anticancer and antiviral activity. This
novel 4D QSAR approach is based on simplex representation of molecular
structure with PLS regression for developing QSAR models (31).In 2002 by Zefirov,
Palyulin et al. gave a new Fragmental approach, this was employed through
fragmental descriptors for QSPR/QSAR .They are applicable for modeling of a
wide range of properties and biological activities very often providing good
predictive models and interpretable results

(32)

.Later on, in 2002 Xing and Glen

gave a novel methods for predicting logP, pKa, and logD values using data sets
(592 molecules for logP and 1029 for pKa) containing a wide range of molecular
structures. logP (based on polarizability and atom charge) and pKa (based on a
novel tree structured fingerprint) (33).Sheridan in 2002 enhance the use of biological
activity for large data sets , in these order he written a method that extracts one-toone replacements of chemical groups in pairs of drug-like molecules with the same
biological activity .they also counts the frequency of the replacements in a large
collection of such molecules (34).
81

Many achievements could be gained by researchers in QSAR methods and

descriptors in the previous year after that in 2003 Zamponi and Nat ale et al.
performed a unique structure activity relationship for 4- isoxazolyl -1,4
dihydropyridines .they performed this experiment through patch clamp analysis
.The continued progress of descriptors could be forwarded by Oliferenko, Rogers

(35)

Zefirov et al. in 2003 through the derivation of new HB descriptors for hydrogen
bonding and fluid phase equilibria. These descriptors also functions in ligand
docking and in Absorption, Distribution, Metabolism, Excretion (ADME)
evaluations (36).In 2003 Golbraikh and Tropsha et al. has reported that topological
chirality descriptors can be successfully used to generate 2D QSAR models for
data sets containing stereo isomers. In these QSAR study descriptors obtained
using Molconn-Z program, predictive ability of a model obtained using MATLAB,
RS configurations for chiral atoms were assigned using a SYBYL Programming
Language (SPL) script (37).In 2003 Hansch and Hoek-man et al. explained

the

importance of electronic effects in their role in the QSAR of chemical-biological

interactions. They also discussed the polarizability effects in ligand-substrate
interactions in terms of molecular polarizability (MR) and NVE (number of
valence electrons) using additive values for valence electrons (38).Arakawa et al. In
2003 investigated and proposed a novel molecular alignment method with the
Hopfield neural network (HNN). They successfully obtained a robust 3D QSAR
82

model for 12 pairs of enzyme inhibitors (39). In 2003 Alberto and Goobi describes
Directed Sphere Exclusion (DISE), a modification of the Sphere Exclusion
algorithm, which retains all positive properties of the Sphere Exclusion algorithm
but generates a more even distribution of the selected compounds in the chemical
space (40).In 2003 Herve et al. describe a Probe feature selection method that can
be applied directly to models that are linear with respect to their parameters, and
indirectly to others. It is independent of the target machine. This method is very
useful for those who cannot expert in statics (41). Bleck-mann and Miler et al. in
2003 investigated the relation between the structure of epothilones (a new class of
anti-tumor agents) and their potential to influence the tubulin-microtubule
equilibrium (42).
Du and Chou et al. in 2004 reported a 2D QSAR study to Liver alcohol
Dehydrogenase (LADH) of molecular family and pyrazole derivatives. They used
quantum chemical and structure-based technique heuristic molecular lipophilicity
potential (HMLP) in the liver alcohol dehydrogenase (LADH) for pyrazole
derivatives

.For the further development of QSAR a new descriptor could be

(43)

proposed by Stanton et al. in 2004 developed a new series of 25 whole-molecule

molecular structure descriptors. The new descriptors are termed Hydrophobic
Surface Area, or HSA descriptors. This descriptor designed to capture information
regarding the structural features responsible for hydrophobic and hydrophilic
83

intermolecular interactions (44). In progress of descriptors the Marius Olaha et al. in

their paper, An automated PLS search for biologically relevant QSAR descriptors
studied two major categories of descriptors: the 2D descriptors, and the 1D
descriptors, based on chemical substructures in 2004 (45).many statistical methods
could be mentioned by different authors in these sequence , In 2004 Heloisa de
Mello et al. used multiple regression and non linear parabolic relationship for
QSAR study on antileishmanial Pyrazolo pyridine Derivatives (46). Later on, In 2004
Abbas shaffei et al. diagnosed anticonvulsant activity as well as synthesized some
1, 4 dihydropyridine derivatives having nitro-imidazol moiety. They analyzed
anticonvulsant activity on mice.

They observed that new synthesized

dihydropyridine derivatives are more potent than reference drug (47).

In 2005 Matheus P. Freitas and Jose A. Martins established a simple quantitative
structureactivity relationship (QSAR) method of analysis used to predict
biological activity for co generic series of compounds. This method is based on the
application of bilinear or multilinear partial least squares regression to a data set,
which is a binary matrix representing the various substituents of a framework (48).
Abilash Thakur in 2005 reported a QSAR study on benzenesulfonamide
dissociation constant pKa made using the physicochemical parameter surface
tension (ST). The regression analysis has shown that even in mono-parametric
regression this physicochemical parameter gave significant results (49). Later on, In
84

2005 Gieleciak, Polanski et al. compare the results of Comparative molecular

field analysis (CoMFA) and Comparative Molecular Surface Analysis (CoMSA), a
3D QSAR method. They show that a sector CoMSA formalism enables an analysis
of the biological activity that is more directly related to the molecular shape and
individual molecular functionalities than the traditional uniform and directionless
CoMFA field

.Fabrizio Manetti et al. In 2005 synthesized pyrazolo [3, 4 b]

(50)

pyridines and developed a new 3D QSAR approach using partial least component
analysis for potent and selective inhibitors of A1 adenosine receptors method (51).
Dervarics et al. in 2006 introduced a newly devised chirality -sensitive flexibility
(CSF) descriptor, which is based on the distance between a pharmacophore point
and a plane defined by three pharmacophore points. These descriptors are used for
3+3D QSAR (52).In 2005 Gramatica et al. they compare different molecular
descriptors in the development of new statistically validated QSAR models to
predict the aquatic toxicity of chemicals in Pimephales promelas (Fathead
Minnow).they applied multiple linear regression based on theoretical descriptor.
For QSAR modeling, descriptors were selected by the Genetic Algorithm-Variable
Subset Selection procedure. They verified the effectiveness of Genetic Algorithms
as a fast and efficient procedure to select (not by chance)significant variables to
manage complex systems (53).Hammeteja et al. In 2005 evaluated three different
factor selection procedures including Eigen value ranking, correlation ranking, and
85

genetic algorithm .PC-ANN modeling method is applied to predict the

carcinogenic activity of 735 drugs using 1350 theoretically derived descriptors.
They found that both genetic algorithm and correlation ranking resulted in more
generalized models. They concluded that the correlation ranking procedure is much
simpler than GA (54).A study by P Jain et al. in 2005 subjected a series of DHFR
analogs of 2,4-diaminopyrido[2,3-d] pyrimidines and 2,4-diaminopyrrolo [2,3-d]
pyrimidines to quantitative structure-activity relationship analysis. The results
showed that the electronic properties, energy of lowest non occupied molecular
orbital (LUMO) and Z-component of dipole moment (DPL 3) of the molecule could
be explored to design the potent DHFR inhibitors (55)
Huabei Zhang et al. reported

two three-dimensional QSAR techniques and one

two-dimensional QSAR technique were used to correlate the molecular structure

with the biological activity of 64 analogues of 3-pyridyl ethers.(56)
In 2006 Shuxing Zhang et al. developed a novel automated lazy learning
quantitative structure-activity relationship (ALL-QSAR) modeling approach based
on the lazy learning theory. ALL-QSAR modeling approach gave for
anticonvulsant activity of chemically diverse functionalized amino acid (FAA)
structures. Various approaches used in their study are k-Nearest Neighbors (KNN),
Simulated Annealing-Partial Least Squares (SA-PLS), Support Vector Machines
(SVM), and the Automated Lazy Learning QSAR (ALL-QSAR) (57).
86

Nazneen Khan et al. in 2006 investigated the relationship between the various
physiochemical parameters and antibacterial activity of N-alkyl derivatives of
imidazole that may be helpful in development of potent antibacterial agent using
both 2D and 3D QSAR approaches. Stepwise Multi Linear Regression (MLR) was
used to obtain QSAR equation from calculated descriptors (58).In 2006 Tingjun Houa
et al. gave a brief review on many physiochemical descriptors .among all these
descriptors authors discussed about one of descriptor known as Abraham
descriptor. They concluded that Abraham Descriptor is the simplest way of
calculating the hydrogen bonding capacity is to count the number of hydrogen
bond donor and acceptor atoms or to count the number of lone pairs of electrons on
certain kinds of atoms

.Zhang et al. in 2006 developed two quantitative pKa

(59)

prediction models for aliphatic carboxylic acids and alcohols using MLR with
empirical atomic inductive descriptors. They demonstrated that pKa has captured
the substitutents inductive effect on the acidic center. Therefore it can also be used
for QSAR/QSPR studies of reactivity in organic compounds (60).Later on, In 2006
Abraham and Ibrahim et al. had investigated gas to olive oil partition coefficient
through linear free energy equation for 218 compounds. The linear free energy
Equation shows that olive oil is not very polar as a solvent but is reasonably basic,
although with a weaker hydrogen bond base than ethyl acetate or acetone, and has
no hydrogen bond acidity (61).
87

In 2007 Gupta et al. developed a QSAR equation using De novo, Hansch approach
and Fujita-ban analysis for estrogen analogues

.Urmila J. Joshi et al. in 2007

(62)

reported the development of a QSAR equation relating the ligand binding activity
of various literature reported aryl piperazines acting as agonists at the 5-HT 1A
receptor to their 2D descriptors. Significant equation was generated using MOE
2004.03 and validated subsequently using leave one out and test set prediction
methods. The equation revealed the importance of combination of electronic and
lipophilic parameters in explaining the observed variance

.Yangjeh et al. in 2007

(63)

developed two new descriptor for non-linear computational neural network.

Descriptor has been developed for prediction of acidity constant. These descriptors
are used for substituted acetic acids in water (64).Authors used Quantitative Structure
Activity relationship (QSAR) for descriptor generation. In 2007 Pattan and Desai
et al. synthesized some new derivatives of 1, 4 dihyro pyridine. They evaluate their
antihypertensive activity through tail-cuff method over rat. Conformation of newly
synthesized compounds was obtained by the results of IR, 1NMR, MASS
spectroscopy

.In 2007 B. Hemmateenejad et al. studied the effects of the

(65)

structural features of some 4, 5-dichloroimidazolyl-1, 4-dihydro pyridine on their

calcium channel antagonist activity, using molecular modeling and quantitative
structure

activity-relationship

analysis.

Semi-empirical

quantum

chemical

calculation was used to find the optimum 3-D geometry of the molecules. For
88

molecular modeling chemical structures of the molecules were constructed using

HYPERCHEM software (Version 7, Hypercube Inc.), all constructed structure
were transform to GUASSIAN 98 program for semi empirical (AM1) calculation.
A large number of descriptors were calculated using HYPERCHEM, GUASSIAN
98 and DRAGON software

(66)

.In 2007 R. Sabet et al. studied antimicrobial and

antifungal activity of some 3-hydroxypyridine-4-one and 3-hydroxypyran-4-one

derivatives against a variety of microorganisms. QSAR equation was developed
using Multiple Linear Regression

(67)

.In 2007,Piyush Trivedi et al. Reported the

effects of the structural features of some 4, 5-dichloroimidazolyl-1, 4dihydropyridine on their calcium channel antagonist activity, using molecular
modeling and Quantitative Structure Activity-Relationship analysis. They used
both symmetrical and asymmetrical dihydropyridine derivatives (68).
In 2008 A.S.Narute et al. performed Quantitative structure activity relationship
study on a series of (substituted 1,2 dihydro)4-thoazolidinones and 2-azetidinones
bearing benzo -thiophene nucleus with anti-tubercular activity.QSAR study has
been carried out using a combination of various physiochemical descriptors

.In

(69)

2008 further studies were conducted by the same author comparing QSAR models
obtained through different chemometric methods, including factor analysis-based
multiple linear regression (FA-MLR), principal component regression (PCR) and
partial least squares combined with genetic algorithm for variable selection (GA89

PLS) to establish connections between structural parameters and antimicrobial

activity against S. aureus and C. albicans (70). In 2008 a concept came about related
to Fragment Descriptors by Alexendar vaskien . It is occupy a special place and
represent selected sub graphs of a 2D molecular graph

.In 2008 Michielan et al.

(71)

described the application of Molecular Electrostatic Potential auto correlated

vectors (autoMEPs). These autoMEPs are used for generating both linear (Partial
Least-Square, PLS) and nonlinear (Response Surface Analysis, RSA) 3D-QSAR
models to predict the binding affinity of human adenosine A3 receptor antagonists.
Moreover, he was also reported a novel GPCR modeling approach, called LigandBased Homology Modeling (LBHM) (72). Sciabola et al. in 2008 used free Wilson
QSAR analysis for predicting kinase inhibitors selectivity (73).More than century ago
Hantzch developed the preparation method of 1 ,4 dihydro pyridine later than In
2008 S. Sandhu et al. discussed a detailed review on the recent advance on 1,4
dihyro pyridine through Hantzch reaction . Their present review present production
procedure, major reaction of current interest, oxidation and reduction of Hantzch
1,4 dihyro pyridine, besides indication of some existing gaps and areas to be
developed (74).
Further QSAR study conducted on the inhibition of Bacillus subtilis and
Salmonella enteritidis by 1, 2, 4-triazoles. For these QSAR study Dimova and
jenjic et al. were using several physicochemical descriptors in 2009 (75). Polishchuk
90

and Muratov et al. in 2009 developed a random forest statistical approach for
Tetrahymena pyriformis through various 2D descriptors .They explained that the
Principle Linear Regression (PLS), K-Nearest Neighbor (KNN), Random Forest
(RF) is insignificantly gave better results rather than any separate model

. In

(76)

2009 B.B. Subhudhi et al. synthesized 3, 5 Diethoxycarbonyl-1, 4 dihydro-2, 6

dimethyl- 4-(substituted)- pyridine by Hantzch method and evaluate their antiulcer
activity. They accomplished that antiulcer activity of 1, 4 dihyro pyridine enhanced
significantly on conjuction with sulfanilamide (77).In 2009,Yas and Joshi et al. Some
new derivatives of cynopyridine and cynopyrane has been synthesized .they
evaluate their antimicrobial and antitubercular activity towards mycobacterium
tuberculosis and other microorganism (78).The medicinal chemistry approach which
led to the discovery of a novel pyridine-3-carboxamide series of CB2 receptor
agonists was described by Mitchell et al. in 2009 (79).
Mahesh Kumar et al. in 2010 a 2-D QSAR model has been developed for
correlating activity of 1, 4- dihydropyridines as calcium channel blockers with
physicochemical properties (80).In 2010 Su et al. developed a QSAR model based on
4D-fingerprints and MOE descriptors for prediction of hERG blockage. These
models are applicable to both virtual screening and limited chemical modification.
These studies based on interpretation of the models (81).In 2010 Riadh Hammami
and Ismail Fliss gave a detailed review about the progress in the development of
91

computational methods, tools and databases used for organizing and extracting
biological meaning from antimicrobial research. They also mentioned that the
QSAR modeling is one of the most broadly used chemo informatics approach. This
is widely used as a tool for antimicrobial drug discovery (82).
In 2011 Mukesh Sharma et al. A 2D QSAR studies were conducted with a series
of angiotensin 2 antagonist .The physiochemical and alignment independent
descriptors were found to have an important role governing the change in
antihypertensive activity

.In 2011 Sabet et al. showed the importance of

(83)

topological, geometrical and quantum chemical descriptor through QSAR using

Feature analysis- Multiple Linear Regression (FA-MLR), Genetic AlgorithmPrincipal Component Analysis (GAPLS), and Principal Component Regression
Analysis (PCRA) (84).Noolvi and Bhardwaj et al. in 2011developed various QSAR
models using MLR, PLS and PCR. They showed that the MLR is the best method
among PLS and PCR. For model validation authors used sphere exclusion method
successfully

(85)

.In 2010 Michielan and Stefano Moro focused on the development

of QSAR models by machine learning methods as an attractive and helpful strategy

in drug discovery. They combined several types of molecular descriptors with
powerful nonlinear techniques. These molecular descriptors properly describe the
relationship existing between the structural features and the desired property (86).

92

In 2011 G.Swarnlatha et al. presented a detail review on 1, 4 dihyro pyridine .

Their review concludes that 1,4-DHP as a Multifunctional potent lead Molecule,
which has various feasible positions for substitution and exhibit several
pharmacological activities such as calcium channel antagonist activity
antihypertensive activity (88),antianginal activity (89),antioxidant activity

(87)

1,4 dihyro

(90)

pyridine apart from CVS activities also exhibit other pharmacological activities
such as antitubercular activity (91),antibacterial activity (92),anti-inflammatory activity
, anticonvulsant activity

(93)

(94)

,analgesic activity (95) and soon. Sadek and Elz et al. in

2011 a new derivatives of m- nifedipine have been successfully synthesized by

substituting an ester moiety with an amide (5-phenylcarbamoyl) moiety, use
modified Hantzsch reaction. They concluded that these new compounds have
increased metabolic stability and consequently longer duration of actions as
compared to nifidipine

.Again, in 2011 Prakash, Aneja et al. Synthesized some

(96)

new derivatives of 1, 4 dihyro-4 pyrazolyl pyridines and 4-pyrazolypyridines and

also evaluate their antimicrobial activity using agar diffusion method

(97)

.In 2011

Al-Said and Ghorab et al. observed the anti-breast cancer activity of some novel
1,2-dihydropyridine, thiophene and thiazole derivatives
activity, some new

(98).

Again for anticancer

1,4 dihydropyridine derivatives has been synthesized by

Surendra Kumar et al. in 2011 and their activity screened against HepG2(liver),
Hepa (cervical) ,MCF-7 breast cancer cells
93

.Ramin miri et al. in 2011

(99)

performed an investigation about the intrinsic cytotoxicity of some derivatives

of DHP containing nitroimidazole moiety on their C4 position on four different
cancer cell lines (Raji, K562, Fen and HeLa). The result showed that these
compounds had moderate-good cytotoxic activity. They also developed QSAR
model and shows the importance of N atom in cytotoxicity Ca2+ channels (100).
In 2012, Datar and Auti et al. Applied a 2D QSAR approach on a series of novel
1, 4-dihydropyridines as antihypertensive agent and developed different models
based on multiple linear regressions (MLR), to find out correlation between the
physicochemical parameters and the biological activity (101).
In 2013 Das and Grovac et al. reported the some properties of Zagber eccentricity
indices. They concluded that hydrogen depleted tool derived from topological
indices is used to predict the structure property correlation of organic compounds
.

(102)

94

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