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In this research work, a series of eighteen novel coumarinyl substituted thiazolidin-2,4-dione analogs (4a-4r) have been designed by molecular hybridization approach, synthesized and their structures were established on the basis of FTIR, 1H NMR, 13C NMR and elemental (CHN) analysis. These title compounds were screened for their cytotoxicity using MTT assay methodology against five different mammalian cancer cell lines viz. hormone dependant breast adenocarcinoma (MCF7), cervical carcinoma (HeLa), colorectal carcinoma (HT29), lung cancer (A549) and prostate adeno carcinoma (PC3). The cytotoxicity screening studies revealed that MCF-7, HeLa and A549 cancer cell lines were sensitive to all the tested compounds. Though the compounds showed varying degrees of cytotoxicity in the tested cell lines, most significant effect was observed for compounds 4i (1.06, 2.4 and 3.06 µM) and 4o (0.95, 3.2 and 2.38 μM) against MCF7, HeLa and A549 cell lines respectively. In conclusion, the anticancer results of these promising leads strongly encouraged us for additional lead optimization with the aim of developing more potential anticancer agents.

Azetidin-2-one, a β -lactam four-membered heterocyclic ring is widely identified for its diverse medicinal properties. Ezetimibe a cholesterol absorption inhibitor and Aztreonam a potent cephalosporinase inhibitor proved the medicinal value of azetidin-2-ones. On the other hand marine bromopyrrole alkaloids are well known for their diverse biological significance. Hence twenty novel conjugates of azetidin-2-ones integrated with 4,5-dibromopyrrole motif were synthesized and screened for antineoplastic activity using MTT assay. Synthesized hybrids displayed good antineoplastic profile particularly towards breast cancer cell line MCF7, where hybrid 5e displayed maximum cytotoxicity (IC50 = 0.5 µM). The selective cytotoxicity displayed by these conjugates towards tested cancer cells with non-toxicity against normal human VERO cells indicated their potential for further antineoplastic drug development.

A new series of imidazo[2,1- b ][1,3,4]thiadiazoles 5 ( a – g ), 6 ( a – g ), 9 ( a – i ) and 12 ( a – h ) were synthesized as transforming growth factor-β (TGF-β) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and their TGF-β -induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. Compound 6d , 2-(5-((2-cyclopropyl-6-(4-fluorophenyl) imidazo [2,1-b][1,3,4]thiadiazol-5-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl) acetic acid, shows prominent ALK5 inhibition (IC 50 = 0.0012 μM) and elective inhibition (91%) against the P38αkinase at10 μM. The binding mode of compound 6d by XP docking studies shows that it fits well into the active site cavity of ALK5 by forming broad and tight interactions. Lipinski's rule and in silico ADME pharmacokinetic parameters are within the acceptable range defined for human use thereby indicating their potential as a drug-like molecules.

Synthesis of novel set of forty semicarbazide/thiosemicarbazide hybrids inspired from marine bromopyrrole alkaloids is reported. Biological screening of these hybrids against a panel of five human cancer cell lines identified a number of hits endowed with interesting cytotoxicity profile. Compounds 5c and 5e (IC50 = 0.03 μm), 5t (IC50 = 0.03 μm), 4s (IC50 = 0.07 μm), and 5n (IC50 = 0.01 μm) displayed maximum cytotoxicity toward hormone-dependent breast cancer cells MCF7, hepatic cancer cells WRL68, colon cancer cells CaCO2 and mouth and oral cancer cells KB403, respectively. The most active hits were further investigated for their potential to inhibit MMP-2 and MMP-12. Compound 5e showed maximum activity (IC50 = 1.8 μm) toward MMP-2. Further, we preformed anti-invasive assay on the most active compounds, where CaCO2 tumor cell migration was significantly decreased (77.9%) by hybrid 5e. The non-toxicity toward human VERO cells (IC50 = 83.1 to 231.8 μm) indicated the selectivity of most active hits (5c, 5e, 5t and 5n) toward cancer cells.

A quantitative structure activity relationship study of 66 molecules was performed using MLR(Multiple Linear Regression) and PCR (Principal component Analysis) of aldose reductase by flavonoids compounds.Various descriptors, topological indices were used to characterize flavonoids molecules.In the developed model MLR is giving vary significant results wheras PCR has revealed some important information. Keywords: Flavonoids, aldose reuctase, QSAR, Multiple Linear Regression, Principle Component Regression

A series of novel synthesized imidazo[2,1-b][1,3,4]thiadiazoles is screened for their in vitro antihyperlipidemic activity.

A new stability-indicating reversed-phase high-performance thin-layer chromatographic (RP-HPTLC) method for densitometric analysis of thiocolchicoside was developed and validated. The chromatograms were developed using aluminum plates pre-coated with silica gel 60 RP-18 F254S as a stationary phase and methanol : water (70 : 30 v/v) as a mobile phase. The compact band for thiocolchicoside was observed at R f value of 0.60 ± 0.02 at an absorption wavelength of 377 nm. The linear regression data for the calibration plots (r (2) = 0.9984) was found with respect to peak area in the concentration range of 100-600 ng per band. The limit of detection (LOD) and limit of quantification (LOQ) were 9.77 ng and 29.63 ng, respectively. The drug was exposed to acidic and alkaline hydrolysis, oxidation, photo degradation, and dry heat conditions. The peaks of degradation products were well-resolved from the peak of the standard drug with significantly different R f values. Statistical analysis proved that the established RP-HPTLC method is reproducible, selective, and accurate for the determination of thiocolchicoside in its formulations. The method can effectively separate the drug from its degradation products, and it can be considered as stability-indicating assay.

Pharmacophore modeling studies were undertaken for a series of quinoline derivatives as VEGFR-2 tyrosine kinase inhibitors. A five-point pharmacophore with two hydrogen bond acceptors (A), one hydrogen bond donor (D), and two aromatic rings (R) as pharmacophore features was developed. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of r 2 = 0.8621 for training set compounds. The model generated showed excellent predictive power, with a correlation coefficient of q 2 = 0.6943 and for a test set of compounds. Furthermore, the structure–activity relationships of quinoline derivatives as VEGFR-2 tyrosine kinase inhibitors were elucidated and the activity differences between them discussed. Docking studies were also carried out wherein active and inactive compounds were docked into the active site of the VEGFR-2 crystal structure to analyze drug-receptor interactions. Further we analyzed all the compounds for Lipinski’s rule of five to evaluate drug likeness and established in silico ADME parameters using QikProp. The results provide insights that will aid the optimization of these classes of VEGFR-2 inhibitors for better activity, and may prove helpful for further lead optimization and virtual screening.

A variety of novel title heterocycles (III) (34 examples) are synthesized and selected derivatives are screened for their cytotoxicity.

In an attempt to find a new class of antimicrobial agents, a series of novel N ′-(5 or 7 substituted-2-oxoindolin-3-ylidene)benzofuran-2-carbohydrazides 3 ( a – p ) were synthesized by reacting benzofuran-2-carbohydrazide 1 with 5 and 7 substituted-isatins 2 ( a – p ). The synthesized compounds were confirmed by melting point, IR, 1 H NMR, 13 C NMR and mass spectroscopy. All the synthesized compounds were screened for antimicrobial activity among the tested series, 3o exhibited excellent antibacterial activity against Escherichia coli and Pseudomonas vulgaris while 3p against Bacillus subtilis , E. coli and P. vulgaris (31.25 μg/mL) when compared with standards. Similarly 3o and 3p showed significant antifungal activity (31.25 μg/mL) when compared to fluconazole against Aspergillus niger .

A benzothiazole moiety is incorporated in the quinazoline nucleus by recyclization of benzoxazinone (I) with substituted aminobenzothiazoles (II).

A series of 6-bromo-2-ethyl-3-(substitutedbenzo[ d ]thiazol-2-yl)quinazolin-4(3 H )-one 3 ( a – j ) were synthesized using appropriate synthetic route and evaluated experimentally by the Maximal Electro Shock (MES) and the PTZ-induced seizure methods. Among the tested compounds, 3-(benzo[ d ]thiazol-2-yl)-6-bromo-2-ethylquinazolin-4(3 H )-one ( 3a ) has shown significant activity against tonic seizure by the MES model and 6-bromo-2-ethyl-3-(6-methoxybenzo[ d ]thiazol-2-yl)quinazolin-4(3 H )-one ( 3h ) against clonic seizure by PTZ-induced seizure model. Not one of the selected compounds demonstrated any sign of neurotoxicity and hepatotoxicity.

Novel derivatives of 2-amino benzothiazoles 4(a-j) have been synthesized and tested for their antitumor activity using National Cancer Institute (NCI) disease oriented antitumor screen protocol against nine panel of cancer cell lines. Among the synthesized compounds, two compounds were granted NSC code and screened at National Cancer Institute (NCI)-USA for anticancer activity at a single high dose (10(-5) M) and five dose in full NCI 60 cell panel. Among the selected compounds, 7-chloro-N-(2,6-dichlorophenyl)benzo[d]thiazol-2-amine (4i) with GI(50) values of 7.18 × 10(-8) M against Non-Small Cell HOP-92 Lung Cancer cell line proved to be the most active members in this study. Virtual screening was carried out through docking the designed compounds into the ATP binding site of epidermal growth factor receptor (EGFR) to predict if these compounds have analogous binding mode to the EGFR inhibitors.

Among all the compounds, synthesized compound (VIb) is found to be the most active candidate with a degree of selectivity toward Leukemic cancer cell line.

A set of thirty one substituted 2-phenoxy-N-phenylacetamide derivatives with HIF-1 inhibitory activities was subjected to 2D and 3D Quantitative Structure Activity Relationship (QSAR) studies using various combinations of descriptors. 2D-QSAR was performed using Multiple Linear Regression (MLR), Principal Component Regression (PCR) and Partial Least Squares Regression (PLS) methods. Among these three methods Multiple Linear Regression (MLR) led to the statistically significant best 2D-QSAR Model-I having correlation coefficient r(2) = 0.9469 and cross validated squared correlation coefficient q(2) = 0.8933 with external predictive ability of pred_r(2) = 0.7128 with the descriptors like SssNHE-index, slogp, T_O_N_1 and T_2_Cl_1. 3D-QSAR study was performed using the simulated annealing variable selection procedures k-nearest neighbor molecular field analysis approach. 3D-QSAR shows interesting results in terms of internal and external predictability. Molecular field analysis was applied for the generation of steric, hydrophobic and electrostatic descriptors based on aligned structures which shows good correlative and predictive capabilities in terms of q(2) = 0.9672 and pred_r(2) = 0.8480. Hence the model proposed in this work provides important structural insight in designing novel derivatives with specific HIF-1 inhibitory activity.

Epidermal growth factor receptor (EGFR) protein tyrosine kinases (PTKs) are known for its role in cancer. Quinazoline have been reported to be the molecules of interest, with potent anticancer activity and they act by binding to ATP site of protein kinases. ATP binding site of protein kinases provides an extensive opportunity to design newer analogs. With this background, we report an attempt to discern the structural and physicochemical requirements for inhibition of EGFR tyrosine kinase. The k-Nearest Neighbor Molecular Field Analysis (kNN-MFA), a three dimensional quantitative structure activity relationship (3D- QSAR) method has been used in the present case to study the correlation between the molecular properties and the tyrosine kinase (EGFR) inhibitory activities on a series of quinazoline derivatives. kNNMFA calculations for both electrostatic and steric field were carried out. The master grid maps derived from the best model has been used to display the contribution of electrostatic potential and steric field. The statistical results showed significant correlation coefficient r(2) (q(2)) of 0.846, r(2) for external test set (pred_r2) 0.8029, coefficient of correlation of predicted data set (pred_r(2)se) of 0.6658, degree of freedom 89 and k nearest neighbor of 2. Therefore, this study not only casts light on binding mechanism between EGFR and its inhibitors, but also provides hints for the design of new EGFR inhibitors with observable structural diversity.

In this paper, an attempt was made to develop a quantitative structure–activity relationship (2D and 3D QSAR) and molecular docking studies on a series of quinazoline derivatives acting as protein tyrosine kinases (EGFR) inhibitors. 2D QSAR was performed using multiple linear regression (MLR), principal component regression (PCR) and partial least squares regression (PLS) methods. Among these three methods, multiple linear regression (MLR) method has come out with a very promising result as compared to other two methods. According to Model-1 by MLR anticancer activity of quinazoline derivatives were influenced by individual (H-donor count, and XlogP) and alignment independent descriptor (T_C_Br_1, T_2_O_1 and T_2_N_7) help in understanding the effect of substituent at different position of quinazolines. The contribution plot of steric and electrostatic field interactions generated by 3D-QSAR shows interesting results in terms of internal and external predictability. Molecular field analysis was applied for the generation of steric and electrostatic descriptors based on aligned structures. Steric and electrostatic field effects are discussed in the light of contribution plot generated. Finally, molecular docking analysis was carried out to better understand the interactions between EGFR target and inhibitors in this series. Hydrophobic and hydrogen bond interactions lead to identification of active binding sites of EGFR protein in the docked complex. The present study is more versatile than the earlier reported methods. Hence the model proposed in this work can be employed to design new derivatives of quinazoline with specific tyrosine kinase (EGFR) inhibitory activity.

A series of 1,3,4-thiadiazole derivatives of 2-(4-formyl-2-methoxyphenoxy) acetic acid ( 6a – s ) were synthesized by cyclization of carboxylic acid group of 2-(2-methoxy-4-(3-oxo-3-substituted phenylprop-1-enyl)phenoxy) acetic acid ( 4a – s ) with thiosemicarbazide in the presence of POCl 3 or PPA. The structures of the compounds were confirmed by IR, 1 H NMR and mass analysis. All the compounds have been evaluated in vitro for their antimicrobial activities against several strains of microbes and show significant activity.