1-(1-Arylethylpiperidin-4-yl)thymine Analogs as Antimycobacterial TMPK Inhibitors

Yanlin Jian; Fabian Hulpia; Martijn D. P. Risseeuw; He Eun Forbes; Guy Caljon; Hélène Munier-Lehmann; Helena I. M. Boshoff; Serge Van Calenbergh

doi:10.3390/molecules25122805

Molecules (Jun 2020)

1-(1-Arylethylpiperidin-4-yl)thymine Analogs as Antimycobacterial TMPK Inhibitors

Yanlin Jian,
Fabian Hulpia,
Martijn D. P. Risseeuw,
He Eun Forbes,
Guy Caljon,
Hélène Munier-Lehmann,
Helena I. M. Boshoff,
Serge Van Calenbergh

Affiliations

Yanlin Jian: Laboratory for Medicinal Chemistry (FFW), Ghent University, Ottergemsesteenweg 460, B-9000 Gent, Belgium
Fabian Hulpia: Laboratory for Medicinal Chemistry (FFW), Ghent University, Ottergemsesteenweg 460, B-9000 Gent, Belgium
Martijn D. P. Risseeuw: Laboratory for Medicinal Chemistry (FFW), Ghent University, Ottergemsesteenweg 460, B-9000 Gent, Belgium
He Eun Forbes: Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA
Guy Caljon: Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, Universiteitsplein 1 (S7), B-2610 Wilrijk, Belgium
Hélène Munier-Lehmann: Unit of Chemistry and Biocatalysis, Department of Structural Biology and Chemistry, Institut Pasteur, CNRS UMR3523, 28 Rue du Dr. Roux, CEDEX 15 75724 Paris, France
Helena I. M. Boshoff: Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA
Serge Van Calenbergh: Laboratory for Medicinal Chemistry (FFW), Ghent University, Ottergemsesteenweg 460, B-9000 Gent, Belgium

DOI: https://doi.org/10.3390/molecules25122805
Journal volume & issue: Vol. 25, no. 12
p. 2805

Abstract

Read online

A series of Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitors based on a reported compound 3 were synthesized and evaluated for their capacity to inhibit MtbTMPK catalytic activity and the growth of a virulent M. tuberculosis strain (H37Rv). Modifications of the scaffold of 3 failed to afford substantial improvements in MtbTMPK inhibitory activity and antimycobacterial activity. Optimization of the substitution pattern of the D ring of 3 resulted in compound 21j with improved MtbTMPK inhibitory potency (three-fold) and H37Rv growth inhibitory activity (two-fold). Moving the 3-chloro substituent of 21j to the para-position afforded isomer 21h, which, despite a 10-fold increase in IC50-value, displayed promising whole cell activity (minimum inhibitory concentration (MIC) = 12.5 μM).

Published in Molecules

ISSN: 1420-3049 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Chemistry: Organic chemistry
Website: http://www.mdpi.com/journal/molecules

About the journal

Abstract

Keywords