Author: Tomchick, Diana R. ; Rathod, Pradipsinh K. ; Russo, Thomas A. ; Deng, Xiaoyi ; Hutson, Alan ; Umland, Timothy C. ; Kokkonda, Sreekanth ; Chen, Hong ; Olson, Ruth ; Beanan, Janet ; Carlino-MacDonald, Ulrike ; Phillips, Margaret A. ; Alvarado, Cassandra L. ; Charman, Susan A. ; El Mazouni, Farah ; Posner, Bruce

New antimicrobials are needed for the treatment of extensively drug-resistant Acinetobacter baumannii . The de novo pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated drug target for malaria and human autoimmune diseases. We provide genetic evidence that A. baumannii DHODH ( Ab DHODH) is essential for bacterial survival in rodent infection models. We chemically validate the target by repurposing a unique library of ~450 triazolopyrimidine/imidazopyrimidine analogs developed for our malaria DHODH program to identify 21 compounds with submicromolar activity on Ab DHODH. The most potent (DSM186, DHODH IC 50 28 nM) had a minimal inhibitory concentration of ≤1 µg/ml against geographically diverse A. baumannii strains, including meropenem-resistant isolates. A structurally related analog (DSM161) with a long in vivo half-life conferred significant protection in the neutropenic mouse thigh infection model. Encouragingly, the development of resistance to these compounds was not identified in vitro or in vivo. Lastly, the X-ray structure of Ab DHODH bound to DSM186 was solved to 1.4 Å resolution. These data support the potential of Ab DHODH as a drug target for the development of antimicrobials for the treatment of A. baumannii and potentially other high-risk bacterial infections.

09 Jun 2016·Journal of Medicinal ChemistryQ1 · MEDICINE

Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity

Q1 · MEDICINE

Article

Author: Jose M. Coteron ; Xiaoyi Deng ; Susan A. Charman ; María Santos Martínez-Martínez ; Werner Kaminsky ; Karen L. White ; Santiago Ferrer Bazaga ; Jeremy N. Burrows ; Pradipsinh K. Rathod ; Sreekanth Kokkonda ; Gong Chen ; John White ; Margaret A. Phillips ; Maria Belen Jimenez-Diaz ; Diana R. Tomchick ; Laura de las Heras ; Maria Marco ; Didier Leroy ; David Waterson ; Dave Matthews ; Iñigo Angulo-Barturen ; Farah El Mazouni ; Kakali Rani Rudra ; Julia Morizzi ; Krishne Manjalanagara ; Eileen Ryan

Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen.

01 Feb 2016·SAR and QSAR in Environmental ResearchQ3 · ENVIRONMENTAL SCIENCE & ECOLOGY

QSAR study on the antimalarial activity ofPlasmodium falciparumdihydroorotate dehydrogenase (PfDHODH) inhibitors

Q3 · ENVIRONMENTAL SCIENCE & ECOLOGY

Article

Author: Yan, A ; Hou, X ; Chen, X ; Zhang, M

Plasmodium falciparum, the most fatal parasite that causes malaria, is responsible for over one million deaths per year. P. falciparum dihydroorotate dehydrogenase (PfDHODH) has been validated as a promising drug development target for antimalarial therapy since it catalyzes the rate-limiting step for DNA and RNA biosynthesis. In this study, we investigated the quantitative structure-activity relationships (QSAR) of the antimalarial activity of PfDHODH inhibitors by generating four computational models using a multilinear regression (MLR) and a support vector machine (SVM) based on a dataset of 255 PfDHODH inhibitors. All the models display good prediction quality with a leave-one-out q(2) >0.66, a correlation coefficient (r) >0.85 on both training sets and test sets, and a mean square error (MSE) <0.32 on training sets and <0.37 on test sets, respectively. The study indicated that the hydrogen bonding ability, atom polarizabilities and ring complexity are predominant factors for inhibitors' antimalarial activity. The models are capable of predicting inhibitors' antimalarial activity and the molecular descriptors for building the models could be helpful in the development of new antimalarial drugs.

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Indication	Highest Phase	Country/Location	Organization	Date
Malaria	Preclinical	United States	University of Washington	18 Mar 2009

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