ABSTRACT
The synthesis of a series of benzimidazole-N-benzylpropan-1-amines and adenine-N-benzylpropan-1-amines is described. Subsequent evaluation against two strains of the anaerobic bacterium Clostridium difficile was performed with three amine derivatives displaying MIC values of 16 µg/mL. Molecular docking studies of the described amines determined that the amines interact within two active site pockets of C. difficile methionyl tRNA synthetase with methoxy substituents in the benzyl ring and an adenine biaryl moiety resulting in optimal binding interactions.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Clostridioides difficile/drug effects , Methionine-tRNA Ligase/drug effects , Propane/analogs & derivatives , Anti-Bacterial Agents/chemistry , Drug Design , Microbial Sensitivity Tests , Models, Molecular , Propane/pharmacologyABSTRACT
A series of novel 5-(substituted phenyl)-3-[(substituted phenylamino)methyl]-3H-[1,3,4]oxadiazole-2- thione derivatives were prepared and their in vitro cytotoxicity was evaluated against a panel of three cancer cell lines, namely, hepatocarcinoma HepG2, breast adenocarcinoma MCF-7, and leukemia HL-60 cells, using the widely accepted MTT assay. In general, the synthesized compounds displayed weak to moderate cytotoxic activity against the three tested cell lines. Compound 5a, which has trimethoxy substituents on both phenyl rings, exhibited the highest cytotoxic effect against all cell lines tested with IC50 values of 12.01, 7.52 and 9.7 µM against HepG2, MCF-7 and HL-60 cells, respectively. Mechanistic studies revealed that the test compounds showed a good inhibitory effect on cellular tubulin of hepatocellular carcinoma. Compound 5h was the most potent tubulin inhibitor in HepG2 cells, with 81.1 % inhibition of the original control tubulin. Moreover, the mechanism of tubulin polymerization inhibition was confirmed by immunofluorescence assay, flow cytometry, and docking study.
Subject(s)
Antineoplastic Agents/pharmacology , Oxadiazoles/pharmacology , Polymerization/drug effects , Thiones/pharmacology , Tubulin Modulators/pharmacology , Tubulin/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HL-60 Cells , Hep G2 Cells , Humans , MCF-7 Cells , Molecular Docking Simulation , Molecular Structure , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Structure-Activity Relationship , Thiones/chemical synthesis , Thiones/chemistry , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry , Tumor Cells, CulturedABSTRACT
Two series of 1,2,4-triazoles and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles derived from three selected arylpropionic acids namely, ibuprofen, flurbiprofen and naproxen, were synthesized and evaluated for anti-inflammatory activity and ulcerogenic potential. All the tested compounds exhibited anti-inflammatory activity comparable to that of hydrocortisone. Compared to ibuprofen, however, all the tested compounds displayed more potent anti-inflammatory activity. Compounds tested for ulcerogenicity showed no or minimal ulcerogenic effect compared to indomethacin.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Propionates/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/toxicity , Flurbiprofen/chemistry , Ibuprofen/chemistry , Male , Naproxen/chemistry , Propionates/pharmacology , Propionates/toxicity , Rats , Stomach Ulcer/chemically induced , Structure-Activity Relationship , Thiadiazoles/chemical synthesis , Thiadiazoles/pharmacology , Thiadiazoles/toxicity , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Thiazoles/toxicityABSTRACT
A new series of 2-arylquinoline-4-carboxylic acid hydrazide-hydrazones was synthesized using an appropriate synthetic route. All the target compounds were evaluated for their in vitro antimicrobial activity against Staphylococcus aureus as an example for Gram-positive bacteria, Escherichia coli as an example for Gram-negative bacteria, and Candida albicans as a representative of fungi. The minimum inhibitory concentration (MIC) was determined for test compounds as well as for reference standards. Among the compounds tested, compounds having nitro substituents at the arylidene moiety showed the most potent antifungal as well as antibacterial activities against E. coli. Compound 23 displayed an antifungal activity comparable to that of nystatin. However, none of the compounds demonstrated any antibacterial activity against S. aureus. Hydrophobicity of the target compounds correlated weakly with their antibacterial and antifungal activities. The most potent compounds namely, 7, 18, 19, 22, and 23 were assessed for hemolytic toxicity and found to be non-hemolytic up to a concentration of 100mug/mL. In addition, the most potent compound (23) was evaluated for in vitro cytotoxic activity against various cancer cell lines. This compound was found to display no cytotoxic activity but rather it induces the proliferation rate of Hep-G2 cells.
