title: Searching for new cures for tuberculosis: design, synthesis, and biological evaluation of 2-methylbenzothiazoles.
abstract: The actual development and clinical use of new therapeutics for tuberculosis (TB) have remained stagnant for years because of the complexity of the disease process, the treatment of which at present requires the administration of drug combinations over a 6 month period. There is thus an urgent need for the discovery and development of novel, more active, and less toxic anti-TB agents. In this study, we report on the chemistry and biology of a series of potent 5-(2-methylbenzothiazol-5-yloxymethyl)isoxazole-3-carboxamide derivatives, which proved to be active against replicating Mycobacterium tuberculosis (Mtb) H(37)Rv. The most potent compounds 7j and 7s were found to inhibit Mtb growth at micromolar concentrations, with MIC values of 1.4 and 1.9 microM, respectively. Impressively, all active compounds were nontoxic toward Vero cells (IC(50) > 128 microM). Moreover, the best of these compounds were also tested against protozoan parasites, and some of these compounds were found to show activity, especially against Plasmodium falciparum. These studies thus suggest that certain 2-methylbenzothiazole based compounds may serve as promising lead scaffolds for further elaboration as anti-TB drugs and as possible antimalaria drugs.
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Huang
authors.forename: Jialin
authors.initials: J
authors.lastname: Mao
authors.forename: Baojie
authors.initials: B
authors.lastname: Wan
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Wang
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010648:Phenylacetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C545543:((5-(2-methylbenzothiazol-5-yloxymethyl)isoxazole-3-carbonyl)amino)phenylacetic acid methyl ester; D000962:Antimalarials; D000995:Antitubercular Agents; D052160:Benzothiazoles; D007555:Isoxazoles; D010648:Phenylacetates; D014344:Trypanocidal Agents