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Eur J Med Chem. 2017 Jan 5;125:807-815. doi: 10.1016/j.ejmech.2016.09.082. Epub 2016 Sep 28.

Synthesis and structure-activity studies of side chain analogues of the anti-tubercular agent, Q203.

Author information

1
Chemistry Platform, Institute Pasteur Korea, 16 Daewangpangyo-ro, 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea; College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 151-742, Republic of Korea.
2
Chemistry Platform, Institute Pasteur Korea, 16 Daewangpangyo-ro, 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea.
3
Tuberculosis Research Laboratory, Institute Pasteur Korea, 16 Daewangpangyo-ro, 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea.
4
Qurient Co. Ltd., 242 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea.
5
College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 151-742, Republic of Korea. Electronic address: pennkim@snu.ac.kr.
6
Chemistry Platform, Institute Pasteur Korea, 16 Daewangpangyo-ro, 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea. Electronic address: silanediol@gmail.com.

Abstract

The anti-tubercular activity of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo [1,2-a]pyridine-3-carboxamide (Q203) is modified by varying its side chain. In this study, we synthesized Q203 analogues with different side chains and studied their effects on anti-tubercular activity. Many analogues showed good potency against M. tuberculosis replicating in liquid broth culture medium (extracellular activity) regardless of chain length and conformational changes. However, a polar character in the side chain region was unfavorable for anti-tubercular activity. The analogues, 25, 28, 35, and 36, displayed excellent activity against M. tuberculosis replicating inside macrophages (intracellular activity) and promising pharmacokinetic (PK) properties with high drug exposure level and long half-life.

KEYWORDS:

Imidazo[1,2-a]pyridine-3-carboxamide (IPA); Pharmacokinetics; Q203; Structure-activity relationship (SAR); Tuberculosis

PMID:
27750198
DOI:
10.1016/j.ejmech.2016.09.082
[Indexed for MEDLINE]

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