Kailash G. Bothara

Design, Synthesis and Evaluation of Antiinflammatory, Analgesic and Ulcerogenicity studies of Novel S-Substituted phenacyl-1,3,4-oxadiazole-2-thiol and Schiff bases of Diclofenac acid as Nonulcerogenic Derivatives

Diclofenac sodium is being used for its anti-inflammatory actions since 28 years, but as all the NSAIDs are suffering from the deadlier GI toxicities, diclofenac sodium is also not an exception to these toxicities. The free -COOH group is thought to be responsible for the GI toxicity associated with all traditional NSAIDs. In the present research work, the main motto was to develop new chemical entities as potential anti-inflammatory agents with no GI toxicities. In this paper, the results of synthesis and pharmacological screening of a series of S-substituted phenacyl 1,3,4-oxadiazoles and Schiff bases derived from 2-[(2,6-dichloroanilino) phenyl] acetic acid (diclofenac acid) are described. The 1,3,4-oxadiazoles and diclofenac moieties are important because of their versatile biological actions. In the present studies, the oxadiazole system has been functionalized onto the diclofenac acid moiety and 18 compounds in this series were synthesized. The structures of new compounds are characterized by TLC, FTIR, 1H NMR and Mass spectral data. These compounds were tested in vivo for their anti-inflammatory activity. The compounds, which showed significant activity (comparable to the standard drug diclofenac sodium), were screened for their analgesic activity and to check their ability to induce ulcers by ulcerogenicity and histopathology studies. Eight new compounds, out of 18, were found to have significant anti-inflammatory activity in the carrageenan induced rat paw oedema model, with significant analgesic activity in the acetic acid induced writhing model with no ulcerogenicity. The compounds, which showed negligible ulcerogenic action, also showed promising results in histopathology studies, that is, they were found to be causing no mucosal injury.

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 pharmacological screening of novel nitric oxide donors containing 1,5-diarylpyrazolin-3-one as nontoxic NSAIDs.

Various substituted 1,5-diarylpyrazol-3-one derivatives were synthesized and screened for analgesic, anti-inflammatory activities, ulcerogenic potential and for their ability to release nitric oxide. Most compounds exhibited significant analgesic and anti-inflammatory activities. It was interesting to note that out of ten compounds, 7j (59.64%) was found to have anti-inflammatory activity greater than the standard drug Indomethacin (57.89%), whereas compound 7b (57.89%) was found to be equipotent to that of standard, Indomethacin. The pharmacological studies suggested that the presence of 4-nitro and 2-methoxy on phenyl ring at C(5) of pyrazole has a significant anti-inflammatory activity and 4-chloro substitution on same phenyl ring was found to have decreased activity. However only a phenyl substituted derivative was found to have most potent activity. Compound 7j containing plane phenyl at C(5) of pyrazole was found to have significant analgesic activity (56.86%) in acetic acid induced writhing model. Compounds 7d and 7i having 4-chloro substituted phenyl ring showed least analgesic activity (10.78%) and (6.86%) respectively. The compounds also showed significantly reduced GI-ulcerogenicity and gastroprotective results in histopathological studies i.e. they were found to be causing no mucosal injury. All the synthesized compounds were found to exhibit significant nitric oxide releasing activity, in both in vitro and in vivo models. Molecular docking studies served to be an important tool for the study of binding of compounds with that of a COX-2 enzyme. The results of the docking studies were found to endorse the result of experimental work. Thus, the rationale used to design the NCEs was found to produce the promising results as anticipated. Therefore it can be said that the strategy employed can serve as an important tool in future for the design and development of novel therapeutic agents of various categories too.

Design of potential reverse transcriptase inhibitor containing Isatin nucleus using molecular modeling studies

Two Dimensional (2D) and Three Dimensional (3D) Quantitative Structure-Activity Relationship (QSAR) studies were performed for correlating the chemical composition of Isatin analogues and their anti-HIV activity using Multiple Linear Regression (MLR) Analysis and k Nearest Neighbor Molecular Field Analysis (kNN MFA), respectively. New Chemical Entities (NCEs) were designed using results of QSAR studies. Binding affinities of designed NCEs were studied on Reverse Transcriptase enzyme using docking studies and their ADME properties were also predicted. Finally most promising compounds were selected from molecular modeling studies. Five compounds containing Isatin nucleus were synthesized and tested for their anti-HIV activity by performing Reverse Transcriptase Assay. Three compounds showed significant Reverse Transcriptase inhibiting activity compared to standard Navirapine. Structure-Activity Relationships were also discussed bases on obtained molecular modeling and experimental data.

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.

Synthesis and pharmacological screening of some novel anti-hypertensive agents possessing 5-Benzylidene-2-(phenylimino)-thiazolidin-4-one ring

In the present study, fourteen derivatives comprising of 5-benzylidene-2-(phenylimino)-thiazolidin-4-one moiety were synthesized. The structures of synthesized compounds were established by elemental analysis, IR, (1)H NMR, (13)C NMR and mass spectral data and tested for electrocardiographic, antiarrhythmic and antihypertensive activities. Compound 11 was found to be most potent in this series. The pharmacological results suggested that, the antiarrhythmic effects of these compounds were related to their Ca(++) ion channel antagonistic properties, which are believed to be due to the presence of 5-benzilidine-2-(phenylimino)-thiazolidin-4-one moiety. The antihypertensive effect of β-blocker side chain is enhanced by the presence of less bulky aliphatic and heterocyclic tertiary amines.

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.

Synthesis and Pharmacological Evaluation of Novel 1-(2-(Benzoyl-Substituted-2-phenyl-1H-Indol-5-Carbony) Hydrazinyloxy) Vinyl Nitrate Derivatives as Potent Non-Ulcerogenic, Analgesic and Anti-Inflammatory Agents

Six derivatives of 1-(2-(benzoyl-(substituted)-2-phenyl-1H-indole-5-carbony) hydrazinyloxy) vinyl nitrate were synthesized and tested in vivo for anti-inflammatory, analgesic, and ulcerogenic properties. Synthesized compounds shown significant anti-inflammatory activity comparable to that of Diclofenac sodium in the carrageenan-induced rat paw edema test and all of the compounds were found to be equipotent to Diclofenac sodium in the acetic acid induced writhing analgesic model. Out of six derivatives two derivatives found to produce no ulceration in stomach specimen of rats; nitric oxide seems to contribute to their excellent safety profile which supports several endogenous GIT defense mechanisms, including increase in mucus, bicarbonate secretions, increase in mucosal blood flow, and inhibition of the activation of pro-inflammatory cells by which NO-Indomethacin protects GI mucosa.