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Design, Synthesis, and Pharmacological Evaluation of Mefloquine‐Based Ligands as Novel Antituberculosis Agents
Author(s) -
Mao Jialin,
Wang Yuehong,
Wan Baojie,
Kozikowski Alan P.,
Franzblau Scott G.
Publication year - 2007
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200700112
Subject(s) - mefloquine , mycobacterium tuberculosis , tuberculosis , pharmacology , cytotoxicity , medicine , regimen , drug , malaria , chemistry , immunology , chloroquine , biochemistry , in vitro , pathology
Tuberculosis (TB) is presently regarded as one of the most dangerous infective diseases worldwide and one of the major AIDS‐associated infections. To shorten the current treatment regimen, there is an urgent need to identify new anti‐TB agents which are active against both replicating TB (R‐TB) and nonreplicating TB (NRP‐TB). Mefloquine, a well‐known antimalarial drug was found to possess reasonable activity against NRP‐TB, and accordingly, 30 new analogues were synthesized and evaluated for their anti‐TB activity against Mycobacterium tuberculosis H 37 Rv. As the target of mefloquine in Mycobacterium tuberculosis remains unknown, we resorted to modifying mefloquine in a variety of chemically convenient ways, which led us in turn to the active hydrazone 10 a . Further modifications of 10 a led to compound 7 f , with an improved anti‐TB activity/selectivity profile with both less cytotoxicity and less predicted CNS side effects compared with mefloquine. The clear structure–activity relationships (SARs) derived from this study should facilitate our ultimate goal of identifying improved anti‐TB agents.