title: Design, synthesis and investigation on the structure-activity relationships of N-substituted 2-aminothiazole derivatives as antitubercular agents.
abstract: Tuberculosis (TB) is one of the deadliest infectious diseases of all times, and its recent resurgence is a supreme matter of concern. Co-infection with HIV and, in particular, the continuous isolation of new resistant strains, makes the discovery of novel anti-TB agents a strategic priority. The research of novel agents should be driven by the accessibility of the synthetic procedure and, in particular, by the lack of cross-resistance with the drugs already marketed. Moreover, in order to shorten the duration of the therapy, and therefore decrease the rate of resistance, these molecules should be active also against the nonreplicating persistent form (NRP-TB) of the infection. The availability of an in-house small library of compounds prompted us to investigate their anti-TB activity. Two compounds, embodying a 2-aminothiazole scaffold, were found to possess a certain inhibitory activity toward Mycobacterium tuberculosis H37Rv, and therefore a medicinal chemistry campaign was initiated in order to increase the activity of the hit compounds and, especially, construct a plausible body of structure-activity relationships. The potency of the hit compound was successfully improved, and, much more importantly, some of the molecules synthesized were found to be active toward the persistent phenotype, and, also, toward a panel of resistant strains. These findings encourage further investigations around this interesting antitubercular chemotype.
authors: Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/A, Parma 43124, Italy. Electronic address: marco.pieroni@unipr.it.
authors: Marco
authors: M
authors: Pieroni
authors: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St., Chicago, IL 60612, USA.
authors: Baojie
authors: B
authors: Wan
authors: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St., Chicago, IL 60612, USA.
authors: Sanghyun
authors: S
authors: Cho
authors: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St., Chicago, IL 60612, USA.
authors: Scott G
authors: SG
authors: Franzblau
authors: Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/A, Parma 43124, Italy.
authors: Gabriele
authors: G
authors: Costantino
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014376:Tuberculosis / Q000188:drug therapy*; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D013844:Thiazoles; C004483:2-aminothiazole
keywords: 2-Aminothiazoles; CAP; DMF; DOTS; Drug discovery; EDG; EWG; INH; LORA; MABA; MDR-TB; MIC; MOX; Medicinal chemistry; Mtb; Mycobacterium tuberculosis; N,N-dimethyl formamide; NRP-TB; R-TB; RMP; Resistance; SDR-TB; SI; SM; TB; Tuberculosis; XDR-TB; capreomycin; directly observed therapy short-course; electron-donating group; electron-withdrawing group; extensively drug-resistant tuberculosis; isoniazid; low oxygen recovery assay; microplate Alamar Blue assay; minimum inhibitory concentration; moxifloxacin; multidrug-resistant tuberculosis; nonreplicating persistent tuberculosis; replicating tuberculosis; rifampin; single drug resistant tuberculosis; streptomycin; supporting information; tuberculosis