Srinivasa Rao Avula

Discovery of coumarin–monastrol hybrid as potential antibreast tumor-specific agent

Development of new, targeted antibreast cancer drug which can treat both the hormone receptor (positive and negative) breast cancers is a very challenging task. The concept of molecular hybridization led us to discover a novel class of coumarin-monastrol hybrid, as a novel breast cancer agent which selectively induce apoptosis in both primary and metastatic breast cancer cell lines.

Coumarin chalcone fibrates: a new structural class of lipid lowering agents.

In our continuing search for safe and efficacious antidyslipidemic agents, structurally interesting coumarin-chalcone fibrates were synthesized and evaluated in triton WR-1339 induced hyperlipidemic rats. The most active compound 41 decreased the total cholesterol (TC), phospholipids (PL) and triglycerides (TG), of hyperlipidemic rats by 26, 24, and 25% respectively. In addition, the compound 41 significantly reversed the levels of VLDL, LDL HDL and also increased the LPL activity. Altogether, our data suggests that these novel hybrids would be a potential new class of therapeutic agents against dyslipidemia.

Synthesis and in vitro evaluation of new chloroquine-chalcone hybrids against chloroquine-resistant strain of Plasmodium falciparum.

The control of malaria has been complicated with increasing resistance of malarial parasite against existing antimalarials. Herein, we report the synthesis of a new series of chloroquine-chalcone based hybrids (8-22) and their antimalarial efficacy against both chloroquine-susceptible (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. Most of the compounds showed enhanced antimalarial activity as compared to chloroquine in chloroquine-resistant (K1) strain of Plasmodium falciparum. Furthermore, to unfold the mechanism of action of these synthesized hybrid molecules, we carried out hemin dependent studies, in which three compounds were found to be active.

Molecular iodine catalysed one-pot synthesis of chromeno[4,3-b]quinolin-6-ones under microwave irradiation

We demonstrate a facile one pot approach for the regioselective synthesis of chromeno[4,3-b]quinolin-6-one derivatives in excellent yields under microwave (MW) irradiation. This transformation presumably proceeds via a three-component tandem annulation of 4-hydroxycoumarin with aromatic aldehydes and aromatic amines, involving a Povarov type reaction.

Identification of quinoline-chalcone hybrids as potential antiulcer agents

Antiulcer activity of novel quinoline-chalcone hybrids (13-37) was investigated. Among them, eight compounds (14, 16, 17, 23, 29, 31, 32 and 35) were found to be active in various ulcer models in Sprague-Dawley (SD) rats. To understand the mechanism of action of these hybrids, the effects of the compounds on antisecretory and cytoprotective activities were studied. All these active hybrids improved the depleted levels of mucin and consequently inhibited the formation of erosions in a pyloric ligated ulcer model. In addition, they also significantly increased the gastric PGE2 content in an aspirin induced ulcer model. The additional experiments including the in vitro metabolic stability and in vivo pharmacokinetics led to the identification of compound 17 as an orally active and safe candidate that is worthy of further investigation to be developed as an antiulcer agent.

Designing, synthesis of selective and high-affinity chalcone-benzothiazole hybrids as Brugia malayi thymidylate kinase inhibitors: In vitro validation and docking studies

In our continuing search for safe and efficacious antifilarials, a series of novel chalcone-benzothiazole hybrids have been synthesized and evaluated for their Brugia malayi thymidylate kinase (BmTMK) enzyme inhibition activity. Their selectivity towards BmTMK was studied and compared to the human TMK (HsTMK) by an in silico method. Out of seventeen derivatives, compounds 34 and 42 showed higher interactions with the BmTMK active site. MolDock docking model revealed the interactions of these two derivatives and the results corroborated well with their in vitro antifilarial activities. Our studies suggest that these hybrids are selective towards the BmTMK enzyme and may serve as potential therapeutic agents against filariasis.

Synthesis and evaluation of anti-thrombotic activity of benzocoumarin amide derivatives☆

A series of novel benzocoumarin amide derivatives have been synthesized and evaluated for their anti-thrombotic activity. Amongst these, compounds 5, 7 and 8 exhibited promising anti-thrombotic profile in an established model of mouse thrombosis. Hence, comprehensive profiling on platelet aggregation and coagulation parameters was carried out to assess its potential as a lead candidate. In vitro treatment of these compounds in mice plasma resulted into significant reduction in ADP (p<0.01) and collagen (p<0.001) induced platelet aggregation. Moreover, Compounds 5, 7 and 8 also significantly increased thrombin time (p<0.05). Thus, in the present study, these benzocoumarin amide derivatives exhibited anti-thrombotic profile via both anti-platelet as well as anti-coagulant action.

Coumarin–benzimidazole hybrids as a potent antimicrobial agent: synthesis and biological elevation

Molecular hybridization approach is an emerging tool in drug discovery for designing new pharmacophores with biological activity. A novel, new series of coumarin–benzimidazole hybrids were designed, synthesized and evaluated for their broad spectrum antimicrobial activity. Among all the synthesized molecules, compound (E)-3-(2-1H-benzo[d]imidazol-1-yl)-1-((4-chlorobenzyl)oxy)imino)ethyl)-2H-chromen-2-one showed the most promising broad spectrum antibacterial activity against Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis and Proteus vulgaris. In addition, it has showed no cytotoxicity and hemolysis at 10 times the MIC concentration. SAR studies indicate that position of the chlorine atom in the hybrid critically determines the antibacterial activity.