Trupti S. Chitre

Design, synthesis and pharmacological screening of novel antihypertensive agents using hybrid approach.

Eight derivatives of general formula 2-(2-(4-(3-((5-substituted methylene)-4-oxo-2-(phenylimino)thiazolidin-3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate were synthesized and tested for electrocardiographic, antiarrhythmic, vasorelaxing and antihypertensive activity as well as for in-vitro nitric oxide (NO) releasing ability. Compound 8b 2-(2-(4-(3-(5-benzyliden-4-oxo-2-(phenylimino)thiazolidin-3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate, was the most potent in this series. The pharmacological results suggested that the antiarrhythmic effects of these compounds were related to their adrenolytic properties which are believed to be due to the presence of the 5-(substituted)methylen-2-(phenylimino)thiazolidin-4-one moiety with less bulky, electron donating substituent on the phenyl ring at 5th position of the thiazolidin-4-one. In conclusion, most of the synthesized compounds were significantly potent as antiarrhythmic and antihypertensive; this might be due to the presence of different pharmacopores which might act at different locations with different mode of action. Further insights of the same can be obtained by doing investigation at receptor level. The potency of compounds 8a-8h were promising enough to continue further experiments.

Design, synthesis, and evaluation of anti-inflammatory, analgesic, ulcerogenicity, and nitric oxide releasing studies of novel indomethacin analogs as non-ulcerogenic derivatives.

Most non-steroidal anti-inflammatory drugs (NSAIDs) suffer from the deadlier gastrointestinal (GI) toxicities. The free -COOH group is responsible for the GI toxicity associated with all traditional NSAIDs. In the present research work, the main objective was to develop new chemical entities as potential anti-inflammatory agents with no GI toxicities. The results of synthesis and pharmacological screening of a series of hybrid molecules having general formula 2-(5-(5-(substituted phenyl)-2-oxo-ethylthio)-1,3,4-oxadiazole-2-yl)-2-phenyl-1H-indol-1-yl)-2-oxoethyl nitrate are described. These compounds were tested in vivo for their anti-inflammatory, analgesic, and ulcerogenic properties, and subjected to histopathological studies. Compound 7c, 2-(5-(5-(3-hydroxyphenyl)-2-oxo-ethylthio)-1,3,4-oxadiazole-2-yl)-2-phenyl-1H-indol-1-yl)-2-oxoethyl nitrate, was the most potent in this series. The compounds that showed significantly reduced GI ulcerogenicity also showed promising results in histopathological studies, and they were found to cause no mucosal injury. All the synthesized compounds were found to exhibit significant nitric oxide releasing activity in an in vitro method. In conclusion, the designed hybrid molecules were found to be significantly promising.

Design, docking study and ADME prediction of Isatin derivatives as anti-HIV agents

Non-nucleoside reverse transcriptase inhibitors (NNRTI) has a definitive role and most commonly used in treatment of HIV infection. NNRTI act by binding to specific binding site (non-nucleoside binding pocket-NNBP) in reverse transcriptase (RT) enzyme. With the objective of developing efficient NNRTI, we have designed various Isatin analogs for effective treatment of AIDS and were subjected to molecular docking studies on five different crystal structures of RT complexed with five different ligands Nevirapine, Delaviridine, Efavirenz, Etravirine, and Rilpivirine. Combined dock-score of compound N21, N11, N23 was found to be comparable with standards indicated that Isatin analogs have good binding affinity for NNBP. Docking results suggested that these types of compounds could be binding in the NNRTI binding site in a similar mode to a known non-nucleoside inhibitors. ADME properties of Isatin analogs were also analyzed using Qikprop 2.5 tool of Schrodinger software.

Pharmacophore optimization and design of competitive inhibitors of thymidine monophosphate kinase through molecular modeling studies.

A series of N1‐(4‐substituted‐benzyl)‐pyrimidines were subjected to 2D and 3D quantitative structure–activity relationship analyses. Statistically significant models were generated, and the most robust model for 2D quantitative structure–activity relationship was obtained using simulated annealing‐multiple linear regression. The physicochemical descriptors, viz., slogp, estate descriptors like SaaCHE index and SdsCHE index contribute significantly to the biological activity. The pharmacophore requirements for selective inhibition of Mycobacterium tuberculosis thymidine monophosphate kinase were optimized using the information derived from 2D and 3D quantitative structure–activity relationship studies. With the results from the studies, we have designed new chemical entities using the CombiLib Tool of V‐Life Molecular Design Suite. In addition, using structure‐based drug design, the distances between interacting groups of ligands and amino acid residues of the protein Mycobacterium tuberculosis thymidine monophosphate kinase (PDB ID:1W2H) were thoroughly analyzed. Thus, we have successfully replaced the sugar moiety with substituted aromatic ring on N1 of thymidine. Thorough studies on substitution pattern around pyrimidine ring were carried out.

QSAR, docking studies of 1,3-thiazinan-3-yl isonicotinamide derivatives for antitubercular activity

The enzyme - enoyl acyl carrier protein reductase (enoyl ACP reductase) is a validated target for antitubercular activity. Inhibition of this enzyme interferes with mycolic acid synthesis which is crucial for Mycobacterium tuberculosis cell growth. In the present work 2D and 3D quantitative structure activity relationship (QSAR) studies were carried out on a series of thiazinan-Isoniazid pharmacophore to design newer analogues. For 2D QSAR, the best statistical model was generated using SA-MLR method (r2=0.958, q2=0.922) while 3D QSAR model was derived using the SA KNN method (q2=0.8498). These studies could guide the topological, electrostatic, steric, hydrophobic substitutions around the nucleus based on which the NCEs were designed. Furthermore, molecular docking was performed to gauze the binding affinity of the designed analogues for enoyl ACP reductase enzyme. Amongst all the designed analogues the binding energies of SKS 01 and SKS 05 were found to be -5.267kcal/mol and -5.237kcal/mol respectively which was comparable with the binding energy of the standard Isoniazid (-6.254kcal/mol).

Exploring Pyrimidine Pharmacophore as Thymidine Monophosphate Kinase Inhibitors for Antitubercular Activity: A Review

Tuberculosis (TB) has been declared as a health emergency due to emergence of resistant strains of M. tuberculosis, multidrug resistant (MDR), extensively drug resistant (XDR) TB strains and totally drug resistant tuberculosis (TDR-TB) reported recently in some parts of the world. Therefore, the current situation necessitates developing new antitubercular agents acting on novel targets for effectively controlling TB. Thymidine Monophosphate Kinase (TMPKmt) enzyme is one such target, which is being explored. This review focuses on Structure Activity Relationship studies (SARs) and computational studies of various nucleotide and nucleoside derivatives of pyrimidine analogs reported as TMPKmt inhibitors.