Quinolone-isoniazid hybrids: synthesis and preliminary in vitro cytotoxicity and anti-tuberculosis evaluation

Richard M Beteck; Ronnett Seldon; Audrey Jordaan; Digby F Warner; Heinrich C Hoppe; Dustin Laming; Lesetja J Legoabe; Setshaba D Khanye

doi:10.1039/c8md00480c

Quinolone-isoniazid hybrids: synthesis and preliminary in vitro cytotoxicity and anti-tuberculosis evaluation

Medchemcomm. 2019 Jan 11;10(2):326-331. doi: 10.1039/c8md00480c. eCollection 2019 Feb 1.

Authors

Richard M Beteck¹, Ronnett Seldon², Audrey Jordaan³, Digby F Warner^{3

4

5}, Heinrich C Hoppe^{6

7}, Dustin Laming⁷, Lesetja J Legoabe⁸, Setshaba D Khanye^{1

7

9}

Affiliations

¹ Faculty of Science , Department of Chemistry , Rhodes University , Grahamstown 6140 , South Africa . Email: s.khanye@ru.ac.za.
² Drug Discovery and Development Centre (H3-D) , Department of Chemistry , University of Cape Town , Rondebosch 7701 , South Africa.
³ SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit , Department of Pathology , University of Cape Town , Observatory , 7925 , South Africa.
⁴ Institute of Infectious Diseases and Molecular Medicine , University of Cape Town , Observatory , 7952 , South Africa.
⁵ Wellcome Centre for Clinical Infectious Diseases Research in Africa , University of Cape Town , Observatory , 7925 , South Africa.
⁶ Faculty of Science , Department of Biochemistry and Microbiology , Rhodes University , Grahamstown 6140 , South Africa.
⁷ Centre for Chemico- and Biomedicinal Research , Rhodes University , Grahamstown 6140 , South Africa.
⁸ Centre of Excellence for Pharmaceutical Science , North-West University , Potchefstroom 2520 , South Africa.
⁹ Faculty of Pharmacy , Rhodes University , Grahamstown 6140 , South Africa.

Abstract

Herein, we propose novel quinolones incorporating an INH moiety as potential drug templates against TB. The quinolone-based compounds bearing an INH moiety attached via a hydrazide-hydrazone bond were synthesised and evaluated against Mycobacterium tuberculosis H37Rv (MTB). The compounds were also evaluated for cytotoxicity against HeLa cell lines. These compounds showed significant activity (MIC₉₀) against MTB in the range of 0.2-8 μM without any cytotoxic effects. Compounds 10 (MIC₉₀; 0.9 μM), 11 (MIC₉₀; 0.2 μM), 12 (MIC₉₀; 0.8 μM) and compound 15 (MIC₉₀; 0.8 μM), the most active compounds in this series, demonstrate activities on par with INH and superior to those reported for the fluoroquinolones. The SAR analysis suggests that the nature of substituents at positions -1 and -3 of the quinolone nucleus influences anti-MTB activity. Aqueous solubility evaluation and in vitro metabolic stability of compound 12 highlights favourable drug-like properties for this compound class.