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Carbamoyl Triazoles, Known Serine Protease Inhibitors, Are a Potent New Class of Antimalarials.

McConville, Matthew, Fernández, Jorge, Angulo-Barturen, Íñigo, Bahamontes-Rosa, Noemi, Ballell-Pages, Lluis, Castañeda, Pablo, de Cózar, Cristina, Crespo, Benigno, Guijarro, Laura, Jiménez-Díaz, María Belén, Martínez-Martínez, Maria S, de Mercado, Jaime, Santos-Villarejo, Ángel, Sanz, Laura M, Frigerio, Micol, Washbourn, Gina, Ward, Steve ORCID:, Nixon, Gemma L, Biagini, Giancarlo ORCID:, Berry, Neil G, Blackman, Michael J, Calderón, Félix and O'Neill, Paul M (2015) 'Carbamoyl Triazoles, Known Serine Protease Inhibitors, Are a Potent New Class of Antimalarials.'. Journal of medicinal chemistry, Vol 58, Issue 16, pp. 6448-6455.

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Screening of the GSK corporate collection, some 1.9 million compounds, against Plasmodium falciparum (Pf), revealed almost 14000 active hits that are now known as the Tres Cantos Antimalarial Set (TCAMS). Followup work by Calderon et al. clustered and computationally filtered the TCAMS through a variety of criteria and reported 47 series containing a total of 522 compounds. From this enhanced set, we identified the carbamoyl triazole TCMDC-134379 (1), a known serine protease inhibitor, as an excellent starting point for SAR profiling. Lead optimization of 1 led to several molecules with improved antimalarial potency, metabolic stabilities in mouse and human liver microsomes, along with acceptable cytotoxicity profiles. Analogue 44 displayed potent in vitro activity (IC50 = 10 nM) and oral activity in a SCID mouse model of Pf infection with an ED50 of 100 and ED90 of between 100 and 150 mg kg(-1), respectively. The results presented encourage further investigations to identify the target of these highly active compounds.

Item Type: Article
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials
QX Parasitology > Protozoa > QX 135 Plasmodia
WA Public Health > Preventive Medicine > WA 110 Prevention and control of communicable diseases. Transmission of infectious diseases
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):
Depositing User: Mary Creegan
Date Deposited: 03 Sep 2015 08:38
Last Modified: 06 Feb 2018 13:10


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