Hydrazone-Tethered 5-(Pyridin-4-yl)-4H-1,2,4-triazole-3-thiol Hybrids: Synthesis, Characterisation, in silico ADME Studies, and in vitro Antimycobacterial Evaluation and Cytotoxicity

Ogunyemi O Oderinlo; Audrey Jordaan; Ronnett Seldon; Michelle Isaacs; Heinrich C Hoppe; Digby F Warner; Matshawandile Tukulula; Setshaba D Khanye

doi:10.1002/cmdc.202200572

Hydrazone-Tethered 5-(Pyridin-4-yl)-4H-1,2,4-triazole-3-thiol Hybrids: Synthesis, Characterisation, in silico ADME Studies, and in vitro Antimycobacterial Evaluation and Cytotoxicity

ChemMedChem. 2023 Mar 14;18(6):e202200572. doi: 10.1002/cmdc.202200572. Epub 2023 Jan 30.

Authors

Ogunyemi O Oderinlo^{1

2}, Audrey Jordaan³, Ronnett Seldon⁴, Michelle Isaacs⁵, Heinrich C Hoppe^{5

6}, Digby F Warner^{3

7

8}, Matshawandile Tukulula⁹, Setshaba D Khanye^{1

5

10}

Affiliations

¹ Department of Chemistry, Faculty of Science, Rhodes University, Makhanda, 6140, South Africa.
² Department of Chemistry, Faculty of Science, Federal University, Otuoke, Bayelsa, Nigeria.
³ SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, Department of Pathology, University of Cape Town, Cape Town, Observatory, 7925, South Africa.
⁴ SAMRC Drug Discovery and Development Unit, University of Cape Town, Cape Town, 7700, South Africa.
⁵ Centre for Chemico- and Biomedicinal Research, Rhodes University, Makhanda, 6140, South Africa.
⁶ Department of Biochemistry and Microbiology, Faculty of Science, Rhodes University, Makhanda, 6140, South Africa.
⁷ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, Rondebosch, 7701, South Africa.
⁸ Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), University of Cape Town, Cape Town, Rondebosch, 7701, South Africa.
⁹ School of Chemistry and Physics, University of KwaZulu-NatalWestville Campus, Durban, 4000, South Africa.
¹⁰ Division of Pharmaceutical Chemistry, Faculty of Pharmacy, Rhodes University, Makhanda, 6140, South Africa.

PMID: 36617507
DOI: 10.1002/cmdc.202200572

Abstract

Compounds containing arylpyrrole-, 1,2,4-triazole- and hydrazone structural frameworks have been widely studied and demonstrated to exhibit a wide range of pharmacological properties. Herein, an exploratory series of new 1,2,4-triazole derivatives designed by amalgamation of arylpyrrole and 1,2,4-triazole structural units via a hydrazone linkage is reported. The synthesised compounds were tested in vitro for their potential activity against Mycobacterium tuberculosis (MTB) H₃₇ Rv strain. The most promising compound 13 - the derivative without the benzene ring appended to the pyrrole unit displayed acceptable activity (MIC₉₀ =3.99 μM) against MTB H₃₇ Rv, while other compounds from the series exhibited modest to weak antimycobacterial activity with MIC₉₀ values in the range between 7.0 and >125 μM. Furthermore, in silico results, predicated using the SwissADME web tool, show that the prepared compounds display desirable ADME profile with parameters within acceptable range.

Keywords: 1,2,4-Triazoles.; Arylpyrroles; Hydrazone; Molecular hybridisation; Mycobacterium tuberculosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antitubercular Agents* / chemistry
Antitubercular Agents* / pharmacology
Microbial Sensitivity Tests
Mycobacterium tuberculosis*
Structure-Activity Relationship
Triazoles / chemistry
Triazoles / pharmacology

Substances

Antitubercular Agents
1,2,4-triazole
Triazoles