Ramprasad, J.Nayak, N.Udayakumar, U.2026-02-052015European Journal of Medicinal Chemistry, 2015, 106, , pp. 75-842235234https://doi.org/10.1016/j.ejmech.2015.10.035https://idr.nitk.ac.in/handle/123456789/26184A 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.1 (2 chloro 10h phenothiazin 10 yl) 2 [2 imino 5 (4 tolyl) 1,3,4 thiadiazol 3(2h) yl] ethanone1 (2 chloro 10h phenothiazin 10 yl) 2 [2 imino 5 methyl 1, 3, 4 thiadiazol 3(2h)yl]ethanone1 (2 chloro 10h phenothiazin 10 yl) 2 [2 imino 5 propyl 1,3,4 thiadiazol 3(2h) yl]ethanone1 (2 chloro 10h phenothiazin 10 yl) 2 [5 (3,4 dimethoxyphenyl) 2 imino 1,3,4-thiadiazol 3(2h) yl]ethanone1 (2 chloro 10h phenothiazin 10 yl) 2 [5 (4 fluorophenyl) 2 imino 1, 3, 4 thiadiazol 3(2h) yl]ethanone1 (2 chloro 10h phenothiazin 10 yl) 2 [5(4 chlorophenyl) 2 imino 1,3,4 thiadiazol 3(2h) yl] ethanone1,3,4 thiadiazole derivative2 (2 imino 5 propyl 1,3,4 thiadiazol 3(2h) yl] 1 (10h phenothiazin 10 yl) ethanone2 (2 imino 5 propyl 1,3,4 thiadiazol 3(2h) yl] 1 [2 (trifluoromethyl) 10h phenothiazin 10 yl] ethanone2 amino 5 subsituted 1,3,4 thiadiazole derivative2 chloro 1 (10h phenothiazin 10 yl)ethanone derivative2 [2 imino 5 (4 tolyl) 1,3,4 thiadiazol 3(2h) yl] 1 [2 (trifluoromethyl) 10h phenothiazin 10 yl] ethanone2 [2 imino 5 methyl 1,3,4 thiadiazol 3(2h) yl] 1 (10h phenothiazin 10 yl)ethanone2 [2 imino 5 methyl 1,3,4 thiadiazol 3(2h) yl] 1 [2 (trifluoromethyl) 10h phenothiazin 10 yl] ethanone2 [5 (3,4 dimethoxyphenyl) 2 imino 1,3,4-thiadiazol 3(2h) yl] 1 (10h phenothiazin 10 yl) ethanone2 [5 (3,4 dimethoxyphenyl) 2 imino 1,3,4-thiadiazol 3(2h) yl] 1 [2 (trifluoromethyl) 10h phenothiazin 10 yl]ethanone2 [5 (4 chlorophenyl) 2 imino 1,3,4 thiadiazol 3(2h) yl] 1 (10h phenothiazin 10 yl)ethanone2 [5 (4 chlorophenyl) 2 imino 1,3,4 thiadiazol 3(2h) yl] 1 [2 (trifluoromethyl) 10h phenothiazin 10 yl]ethanone2 [5 (4 fFluorophenyl) 2 imino 1,3,4 thiadiazol 3(2h) yl]1 (10h phenothiazine 10 yl] ethanone2 [5 (4 fluorophenyl) 2 imino 1,3,4 thiadiazol 3(2H) yl] 1 (10h phenothiazin 10 yl) ethanone2 [5 (4 fluorophenyl) 2 imino 1,3,4 thiadiazol 3(2h) yl] 1 [2 (trifluoromethyl) 10h phenothiazin 10 yl] ethanone2[(2 imino 5 para tolyl 1,3,4 thiadiazol 3(2h) yl] 1 (10h phenothiazin 10 yl) ethanoneciprofloxacinethambutolisoniazidphenothiazine derivativestreptomycinthiadiazole derivativetuberculostatic agentunclassified drugunindexed drugphenothiazineanimal cellantibacterial activityArticlecontrolled studycytotoxicitydrug designdrug synthesisin vitro studyminimum inhibitory concentrationmolecular dockingmolecular hybridizationMycobacterium tuberculosisnonhumanstructure activity relationVero cell lineanimalcell survivalchemical structurechemistryChlorocebus aethiopsdose responsedrug effectsEscherichia colimicrobial sensitivity testPseudomonas aeruginosaStaphylococcus aureussynthesisAnimalsAntitubercular AgentsCell SurvivalCercopithecus aethiopsDose-Response Relationship, DrugDrug DesignMicrobial Sensitivity TestsMolecular Docking SimulationMolecular StructurePhenothiazinesStructure-Activity RelationshipThiadiazolesVero Cells