Design, Synthesis, and Molecular Docking Studies of a Conjugated Thiadiazole–Thiourea Scaffold as Antituberculosis Agents

Esra Tatar; Sevgi Karakuş; Şükriye Güniz Küçükgüzel; Sinem Öktem Okullu; Nihan Ünübol; Tanıl Kocagöz; Erik De Clercq; Graciela Andrei; Robert Snoeck; Christophe Pannecouque; Sadık Kalaycı; Fikrettin Şahin; Dharmarajan Sriram; Perumal Yogeeswari; İlkay Küçükgüzel

doi:10.1248/bpb.b15-00698

Regular Articles

Design, Synthesis, and Molecular Docking Studies of a Conjugated Thiadiazole–Thiourea Scaffold as Antituberculosis Agents

Esra Tatar, Sevgi Karakuş, Şükriye Güniz Küçükgüzel, Sinem Öktem Okullu, Nihan Ünübol, Tanıl Kocagöz, Erik De Clercq, Graciela Andrei, Robert Snoeck, Christophe Pannecouque, Sadık Kalaycı, Fikrettin Şahin, Dharmarajan Sriram, Perumal Yogeeswari, İlkay Küçükgüzel

Author information

Esra Tatar
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University
Sevgi Karakuş
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University
Şükriye Güniz Küçükgüzel
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University
Sinem Öktem Okullu
Department of Medical Microbiology, School of Medicine, Acıbadem University
Nihan Ünübol
Department of Medical Microbiology, School of Medicine, Acıbadem University
Tanıl Kocagöz
Department of Medical Microbiology, School of Medicine, Acıbadem University
Erik De Clercq
Rega Institute for Medical Research
Graciela Andrei
Rega Institute for Medical Research
Robert Snoeck
Rega Institute for Medical Research
Christophe Pannecouque
Rega Institute for Medical Research
Sadık Kalaycı
Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University
Fikrettin Şahin
Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University
Dharmarajan Sriram
Medicinal Chemistry and Drug Discovery Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science-Pilani
Perumal Yogeeswari
Medicinal Chemistry and Drug Discovery Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science-Pilani
İlkay Küçükgüzel Corresponding author
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University

Keywords: 1,3,4-thiadiazole, thiourea, antituberculosis activity, cytotoxicity, molecular docking

JOURNAL FREE ACCESS FULL-TEXT HTML

2016 Volume 39 Issue 4 Pages 502-515

DOI https://doi.org/10.1248/bpb.b15-00698

Details

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.

Graphical Abstract Fullsize Image

Corresponding author

Register with J-STAGE for free!