Design, synthesis, and pharmacological evaluation of mefloquine-based ligands as novel antituberculosis agents.
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.
Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
Jialin
J
Mao
Yuehong
Y
Wang
Baojie
B
Wan
Alan P
AP
Kozikowski
Scott G
SG
Franzblau
D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D015195:Drug Design; D005260:Female; D006801:Humans; D008024:Ligands; D015767:Mefloquine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014709:Vero Cells
D000995:Antitubercular Agents; D008024:Ligands; D015767:Mefloquine