ABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/pharmacology , Benzimidazoles/pharmacology , Coumarins/pharmacology , Drug Design , Drug Resistance, Multiple, Bacterial , Models, Molecular , Animals , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Infective Agents/adverse effects , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/chemistry , Bacillus subtilis/drug effects , Bacillus subtilis/growth & development , Benzimidazoles/adverse effects , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Cell Line , Cell Survival/drug effects , Connective Tissue Cells/cytology , Connective Tissue Cells/drug effects , Coumarins/adverse effects , Coumarins/chemical synthesis , Coumarins/chemistry , Hemolysis/drug effects , Humans , Hydrocarbons, Chlorinated/adverse effects , Hydrocarbons, Chlorinated/chemical synthesis , Hydrocarbons, Chlorinated/chemistry , Hydrocarbons, Chlorinated/pharmacology , Mice , Microbial Sensitivity Tests , Molecular Structure , Proteus vulgaris/drug effects , Proteus vulgaris/growth & development , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/growth & development , Staphylococcus aureus/drug effects , Staphylococcus aureus/growth & development , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of novel indole-chalcone fibrates were synthesized and their hypolipidemic activity was evaluated in triton WR-1339 induced hyperlipidemic rat model. Preliminary studies indicated that the hybrids 19, 24 and 29 exhibited potent in vitro antioxidant and significant in vivo antidyslipidemic effects. Our results suggest that these new hybrid architectures may serve as promising leads for the development of next generation lipid lowering agents.
Subject(s)
Antioxidants/pharmacology , Chalcone/pharmacology , Drug Design , Hyperlipidemias/drug therapy , Hypolipidemic Agents/pharmacology , Indoles/pharmacology , Animals , Antioxidants/chemical synthesis , Antioxidants/chemistry , Chalcone/chemistry , Disease Models, Animal , Hyperlipidemias/chemically induced , Hypolipidemic Agents/chemical synthesis , Hypolipidemic Agents/chemistry , Indoles/chemistry , Lipoproteins/blood , Lipoproteins, HDL/blood , Lipoproteins, HDL/metabolism , Lipoproteins, LDL/blood , Lipoproteins, LDL/metabolism , Male , Molecular Structure , Polyethylene Glycols/administration & dosage , RatsABSTRACT
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.
Subject(s)
Chalcones/pharmacology , Coumarins/pharmacology , Dyslipidemias/drug therapy , Animals , Chalcones/chemistry , Coumarins/chemistry , Dyslipidemias/chemically induced , Male , Molecular Structure , Polyethylene Glycols , Rats , Rats, Inbred StrainsABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Coumarins/pharmacology , Drug Discovery , Pyrimidines/pharmacology , Thiones/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Breast Neoplasms/pathology , Cell Cycle/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Coumarins/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Humans , MCF-7 Cells , Molecular Structure , Pyrimidines/chemistry , Structure-Activity Relationship , Thiones/chemistry , Tumor Cells, CulturedABSTRACT
A novel series of amide based fibrates were synthesized and evaluated for antidyslipidemic activity in triton induced hyperlipidemic rats. Interestingly, the compound 13 produced striking reduction in serum levels of total cholesterol (TC), phospholipids (PL) and triglycerides (TG). In addition, it exhibited improved lipoprotein lipase activity and found to possess moderate radical scavenging potential. The results of the above studies shows that the compounds synthesized on fibrate based pharmacophores might result in identification of new lead for dyslipidemia.
Subject(s)
Amides/chemical synthesis , Antioxidants/chemical synthesis , Fibric Acids/chemical synthesis , Hyperlipidemias/drug therapy , Hypolipidemic Agents/chemical synthesis , Lipoprotein Lipase/blood , Amides/pharmacology , Animals , Antioxidants/pharmacology , Enzyme Activation/drug effects , Fibric Acids/pharmacology , Free Radicals/antagonists & inhibitors , Hyperlipidemias/blood , Hyperlipidemias/chemically induced , Hyperlipidemias/enzymology , Hypolipidemic Agents/pharmacology , Lipid Peroxidation/drug effects , Male , Polyethylene Glycols , Rats , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Chalcone/chemistry , Chalcone/pharmacology , Chloroquine/chemistry , Chloroquine/pharmacology , Plasmodium falciparum/drug effects , Animals , Antimalarials/chemical synthesis , Cell Survival/drug effects , Chalcone/chemical synthesis , Chlorocebus aethiops , Chloroquine/chemical synthesis , Drug Resistance , Hemin/metabolism , Humans , Malaria, Falciparum/drug therapy , Vero CellsABSTRACT
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.
