title: Design, Synthesis, and Molecular Docking Studies of a Conjugated Thiadiazole-Thiourea Scaffold as Antituberculosis Agents.
abstract: In view of the emergence and frequency of multidrug-resistant and extensively drug-resistant tuberculosis and consequences of acquired resistance to clinically used drugs, we undertook the design and synthesis of novel prototypes that possess the advantage of the two pharmacophores of thiourea and 1,3,4-thiadiazole in a single molecular backbone. Three compounds from our series were distinguished from the others by their promising activity profiles against Mycobacterium tuberculosis strain H37Rv. Compounds 11 and 19 were the most active representatives with minimum inhibitory concentration (MIC) values of 10.96 and 11.48 µM, respectively. Compound 15 was shown to inhibit M. tuberculosis strain H37Rv with an MIC value of 17.81 µM. Cytotoxicity results in the Vero cell line showed that these three derivatives had selectivity indices between 1.8 and 8.7. In order to rationalize the biological results of our compounds, molecular docking studies with the enoyl acyl carrier protein reductase (InhA) of M. tuberculosis were performed and compounds 11, 15, and 19 were found to have good docking scores in the range of -7.12 to -7.83 kcal/mol.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University.
authors.forename: Esra
authors.initials: E
authors.lastname: Tatar
authors.forename: Sevgi
authors.initials: S
authors.lastname: Karakuş
authors.forename: Şükriye Güniz
authors.initials: ŞG
authors.lastname: Küçükgüzel
authors.forename: Sinem
authors.initials: S
authors.lastname: Öktem Okullu
authors.forename: Nihan
authors.initials: N
authors.lastname: Ünübol
authors.forename: Tanıl
authors.initials: T
authors.lastname: Kocagöz
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.forename: Sadık
authors.initials: S
authors.lastname: Kalaycı
authors.forename: Fikrettin
authors.initials: F
authors.lastname: Şahin
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.forename: İlkay
authors.initials: İ
authors.lastname: Küçükgüzel
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects / Q000254:growth & development; D002176:Candida albicans / Q000187:drug effects / Q000254:growth & development; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D015195:Drug Design; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D013830:Thiadiazoles / Q000737:chemistry* / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D014709:Vero Cells
chemical_list: D000890:Anti-Infective Agents; D013830:Thiadiazoles; D013890:Thiourea