Design of new phenothiazine-thiadiazole hybrids via molecular hybridization approach for the development of potent antitubercular agents
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Date
2015
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Elsevier Masson SAS 62 rue Camille Desmoulins Issy les Moulineaux Cedex 92442
Abstract
A new library of phenothiazine and 1,3,4-thiadiazole hybrid derivatives (5a-u) was designed based on the molecular hybridization approach and the molecules were synthesized in excellent yields using a facile single-step chloro-amine coupling reaction between 2-chloro-1-(10H-phenothiazin-10-yl)ethanones and 2-amino-5-subsituted-1,3,4-thiadiazoles. The compounds were evaluated for their in vitro inhibition activity against Mycobacterium tuberculosis H37Rv (MTB). Compounds 5g and 5n were emerged as the most active compounds of the series with MIC of 0.8 ?g/mL (?1.9 ?M). Also, compounds 5a, 5b, 5c, 5e, 5l and 5m (MIC = 1.6 ?g/mL), and compounds 5j, 5k and 5o (MIC = 3.125 ?g/mL) showed significant inhibition activity. The structure-activity relationship demonstrated that an alkyl (methyl/npropyl) or substituted (4-methyl/4-Cl/4-F) phenyl groups on the 1,3,4-thiadiazole ring enhance the inhibition activity of the compounds. The cytotoxicity study revealed that none of the active molecules are toxic to a normal Vero cell line thus proving the lack of general cellular toxicity. Further, the active molecules were subjected to molecular docking studies with target enzymes InhA and CYP121. © 2015 Elsevier Masson SAS. All rights reserved.
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1 (2 chloro 10h phenothiazin 10 yl) 2 [2 imino 5 (4 tolyl) 1,3,4 thiadiazol 3(2h) yl] ethanone, 1 (2 chloro 10h phenothiazin 10 yl) 2 [2 imino 5 methyl 1, 3, 4 thiadiazol 3(2h)yl]ethanone, 1 (2 chloro 10h phenothiazin 10 yl) 2 [2 imino 5 propyl 1,3,4 thiadiazol 3(2h) yl]ethanone, 1 (2 chloro 10h phenothiazin 10 yl) 2 [5 (3,4 dimethoxyphenyl) 2 imino 1,3,4-thiadiazol 3(2h) yl]ethanone, 1 (2 chloro 10h phenothiazin 10 yl) 2 [5 (4 fluorophenyl) 2 imino 1, 3, 4 thiadiazol 3(2h) yl]ethanone, 1 (2 chloro 10h phenothiazin 10 yl) 2 [5(4 chlorophenyl) 2 imino 1,3,4 thiadiazol 3(2h) yl] ethanone, 1,3,4 thiadiazole derivative, 2 (2 imino 5 propyl 1,3,4 thiadiazol 3(2h) yl] 1 (10h phenothiazin 10 yl) ethanone, 2 (2 imino 5 propyl 1,3,4 thiadiazol 3(2h) yl] 1 [2 (trifluoromethyl) 10h phenothiazin 10 yl] ethanone, 2 amino 5 subsituted 1,3,4 thiadiazole derivative, 2 chloro 1 (10h phenothiazin 10 yl)ethanone derivative, 2 [2 imino 5 (4 tolyl) 1,3,4 thiadiazol 3(2h) yl] 1 [2 (trifluoromethyl) 10h phenothiazin 10 yl] ethanone, 2 [2 imino 5 methyl 1,3,4 thiadiazol 3(2h) yl] 1 (10h phenothiazin 10 yl)ethanone, 2 [2 imino 5 methyl 1,3,4 thiadiazol 3(2h) yl] 1 [2 (trifluoromethyl) 10h phenothiazin 10 yl] ethanone, 2 [5 (3,4 dimethoxyphenyl) 2 imino 1,3,4-thiadiazol 3(2h) yl] 1 (10h phenothiazin 10 yl) ethanone, 2 [5 (3,4 dimethoxyphenyl) 2 imino 1,3,4-thiadiazol 3(2h) yl] 1 [2 (trifluoromethyl) 10h phenothiazin 10 yl]ethanone, 2 [5 (4 chlorophenyl) 2 imino 1,3,4 thiadiazol 3(2h) yl] 1 (10h phenothiazin 10 yl)ethanone, 2 [5 (4 chlorophenyl) 2 imino 1,3,4 thiadiazol 3(2h) yl] 1 [2 (trifluoromethyl) 10h phenothiazin 10 yl]ethanone, 2 [5 (4 fFluorophenyl) 2 imino 1,3,4 thiadiazol 3(2h) yl]1 (10h phenothiazine 10 yl] ethanone, 2 [5 (4 fluorophenyl) 2 imino 1,3,4 thiadiazol 3(2H) yl] 1 (10h phenothiazin 10 yl) ethanone, 2 [5 (4 fluorophenyl) 2 imino 1,3,4 thiadiazol 3(2h) yl] 1 [2 (trifluoromethyl) 10h phenothiazin 10 yl] ethanone, 2[(2 imino 5 para tolyl 1,3,4 thiadiazol 3(2h) yl] 1 (10h phenothiazin 10 yl) ethanone, ciprofloxacin, ethambutol, isoniazid, phenothiazine derivative, streptomycin, thiadiazole derivative, tuberculostatic agent, unclassified drug, unindexed drug, phenothiazine, animal cell, antibacterial activity, Article, controlled study, cytotoxicity, drug design, drug synthesis, in vitro study, minimum inhibitory concentration, molecular docking, molecular hybridization, Mycobacterium tuberculosis, nonhuman, structure activity relation, Vero cell line, animal, cell survival, chemical structure, chemistry, Chlorocebus aethiops, dose response, drug effects, Escherichia coli, microbial sensitivity test, Pseudomonas aeruginosa, Staphylococcus aureus, synthesis, Animals, Antitubercular Agents, Cell Survival, Cercopithecus aethiops, Dose-Response Relationship, Drug, Drug Design, Microbial Sensitivity Tests, Molecular Docking Simulation, Molecular Structure, Phenothiazines, Structure-Activity Relationship, Thiadiazoles, Vero Cells
Citation
European Journal of Medicinal Chemistry, 2015, 106, , pp. 75-84