title: Design of new phenothiazine-thiadiazole hybrids via molecular hybridization approach for the development of potent antitubercular agents.
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 5 g and 5 n were emerged as the most active compounds of the series with MIC of 0.8 μg/mL (∼ 1.9 μM). Also, compounds 5a, 5b, 5c, 5e, 5l and 5m (MIC = 1.6 μg/mL), and compounds 5j, 5k and 5o (MIC = 3.125 μg/mL) showed significant inhibition activity. The structure-activity relationship demonstrated that an alkyl (methyl/n-propyl) 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.
authors.affiliation: Organic Chemistry Laboratory, Department of Chemistry, National Institute of Technology Karnataka, Surathkal, Srinivasanagar, Mangalore 575025, India.
authors.forename: Jurupula
authors.initials: J
authors.lastname: Ramprasad
authors.affiliation: Organic Chemistry Laboratory, Department of Chemistry, National Institute of Technology Karnataka, Surathkal, Srinivasanagar, Mangalore 575025, India.
authors.forename: Nagabhushana
authors.initials: N
authors.lastname: Nayak
authors.affiliation: Organic Chemistry Laboratory, Department of Chemistry, National Institute of Technology Karnataka, Surathkal, Srinivasanagar, Mangalore 575025, India. Electronic address: udayaravi80@gmail.com.
authors.forename: Udayakumar
authors.initials: U
authors.lastname: Dalimba
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004926:Escherichia coli / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010640:Phenothiazines / Q000737:chemistry / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology*; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D010640:Phenothiazines; D013830:Thiadiazoles; C031637:phenothiazine
keywords: 1,3,4-Thiadiazole; Antimycobacterial activity; Cytotoxicity; Molecular docking; Mycobacterium tuberculosis; Phenothiazine