Triazolophthalazines: Easily Accessible Compounds with Potent Antitubercular Activity.
Tuberculosis (TB) remains one of the major causes of death worldwide, in particular because of the emergence of multidrug-resistant TB. Herein we explored the potential of an alternative class of molecules as anti-TB agents. Thus, a series of novel 3-substituted triazolophthalazines was quickly and easily prepared from commercial hydralazine hydrochloride as starting material and were further evaluated for their antimycobacterial activities and cytotoxicities. Four of the synthesized compounds were found to effectively inhibit the Mycobacterium tuberculosis (M.tb) H37 Rv strain with minimum inhibitory concentration (MIC) values <10 μg mL(-1) , whereas no compounds displayed cytotoxicity against HCT116 human cell lines (IC50 >100 μm). More remarkably, the most potent compounds proved to be active to a similar extent against various multidrug-resistant M.tb strains, thus uncovering a mode of action distinct from that of standard antitubercular agents. Overall, their ease of preparation, combined with their attractive antimycobacterial activities, make such triazolophthalazine-based derivatives promising leads for further development.
Laboratoire de Synthèse et Physicochimie de Molécules d'Intérêt Biologique (SPCMIB), CNRS-UMR5068, Université Paul Sabatier-Toulouse III, 118 Route de Narbonne, 31062, Toulouse Cedex 9, France.|ITAV, Université de Toulouse, CNRS, UPS, 1 place Pierre Potier, 31106, Toulouse Cedex 1, France.
Damien
D
Veau
Laboratoire de Synthèse et Physicochimie de Molécules d'Intérêt Biologique (SPCMIB), CNRS-UMR5068, Université Paul Sabatier-Toulouse III, 118 Route de Narbonne, 31062, Toulouse Cedex 9, France.
Serhii
S
Krykun
Dipartimento di Biologica e Biotecnologie 'Lazzaro Spallanzani', via Ferrata 1, 27100, Pavia, Italy.
Giorgia
G
Mori
Dipartimento di Biologica e Biotecnologie 'Lazzaro Spallanzani', via Ferrata 1, 27100, Pavia, Italy.
Beatrice S
BS
Orena
Dipartimento di Biologica e Biotecnologie 'Lazzaro Spallanzani', via Ferrata 1, 27100, Pavia, Italy.
Maria R
MR
Pasca
ITAV, Université de Toulouse, CNRS, UPS, 1 place Pierre Potier, 31106, Toulouse Cedex 1, France.
Céline
C
Frongia
ITAV, Université de Toulouse, CNRS, UPS, 1 place Pierre Potier, 31106, Toulouse Cedex 1, France.
Valérie
V
Lobjois
Laboratoire de Synthèse et Physicochimie de Molécules d'Intérêt Biologique (SPCMIB), CNRS-UMR5068, Université Paul Sabatier-Toulouse III, 118 Route de Narbonne, 31062, Toulouse Cedex 9, France. stefan.chassaing@itav.fr.|ITAV, Université de Toulouse, CNRS, UPS, 1 place Pierre Potier, 31106, Toulouse Cedex 1, France. stefan.chassaing@itav.fr.
Stefan
S
Chassaing
Laboratoire de Synthèse et Physicochimie de Molécules d'Intérêt Biologique (SPCMIB), CNRS-UMR5068, Université Paul Sabatier-Toulouse III, 118 Route de Narbonne, 31062, Toulouse Cedex 9, France. christian.lherbet@itav.fr.
Christian
C
Lherbet
Laboratoire de Synthèse et Physicochimie de Molécules d'Intérêt Biologique (SPCMIB), CNRS-UMR5068, Université Paul Sabatier-Toulouse III, 118 Route de Narbonne, 31062, Toulouse Cedex 9, France. baltas@chimie.ups-tlse.fr.
Michel
M
Baltas
D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000737:chemistry; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010793:Phthalazines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014376:Tuberculosis
D000995:Antitubercular Agents; D002934:Cinnamates; D010793:Phthalazines; C029010:cinnamic acid
antimycobacterial activity; cytotoxicity; organic synthesis; triazolophthalazines; tuberculosis