Novel Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Anti-malarial Activity in the Mouse Model*

Booker, Michael L.; Bastos, Cecilia M.; Kramer, Martin; Barker, Robert H.; Skerlj, Renato T.; Sidhu, Amar Bir Singh; Deng, Xingming; Celatka, Cassandra A.; Cortese, Joseph F.; Bravo, Jose; Llado, Keila N. Crespo; Serrano, Adelfa E.; Angulo-Barturen, Íñigo; Jiménez-Dı́az, Marı́a Belén; Viera, Sara; Garuti, Helen; Wittlin, Sergio; Papastogiannidis, Petros; Lin, Jing-wen; Janse, Chris J.; Khan, Shahid M.; Duraisingh, Manoj T.; Coleman, Bradley I.; Goldsmith, Elizabeth J.; Phillips, Margaret A.; Muñoz, Benito; Wirth, Dyann F.; Klinger, Jeffrey D.; Wiegand, Roger C.; Sybertz, Edmund J.

doi:10.1074/jbc.m110.162081

Cited by 124 publications

(161 citation statements)

References 50 publications

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“…The two compounds tested had ED 50 s under these conditions of 12 and 25 mg/kg (GSK2645947 and GSK1057714, respectively; Table 4). This in vivo antimalarial potency, although still not considered high enough, is not far from that of other molecules close to the preclinical candidate stage in this same malarial model (4). Also importantly, this result validates the relevance of the cyclopropyl carboxamide target under in vivo conditions, not always a given when starting from in vitro growth inhibitors.…”

Section: Discussionsupporting

confidence: 58%

Cyclopropyl Carboxamides, a Chemically Novel Class of Antimalarial Agents Identified in a Phenotypic Screen

Sanz

Jiménez-Díaz

Crespo

et al. 2011

Antimicrob Agents Chemother

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Malaria is one of the deadliest infectious diseases in the world, with the eukaryotic parasite Plasmodium falciparum causing the most severe form of the disease. Discovery of new classes of antimalarial drugs has become an urgent task to counteract the increasing problem of drug resistance. Screening directly for compounds able to inhibit parasite growth in vitro is one of the main approaches the malaria research community is now pursuing for the identification of novel antimalarial drug leads. Very recently, thousands of compounds with potent activity against the parasite P. falciparum have been identified and information about their molecular descriptors, antiplasmodial potency, and cytotoxicity is publicly available. Now the challenges are how to identify the most promising chemotypes for further development and how best to progress these compounds through a lead optimization program to generate antimalarial drug candidates. We report here the first chemical series to be characterized from one of those screenings, a completely novel chemical class with the generic name cyclopropyl carboxamides that has never before been described as having antimalarial or other pharmacological activities. Cyclopropyl carboxamides are potent inhibitors of drug-sensitive and -resistant strains of P. falciparum in vitro and show in vivo oral efficacy in malaria mouse models. In the present work, we describe the biological characterization of this chemical family, showing that inhibition of their still unknown target has very favorable pharmacological consequences but the compounds themselves seem to select for resistance at a high frequency.

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Section: Discussionsupporting

confidence: 58%

Cyclopropyl Carboxamides, a Chemically Novel Class of Antimalarial Agents Identified in a Phenotypic Screen

Sanz

Jiménez-Díaz

Crespo

et al. 2011

Antimicrob Agents Chemother

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“…Solubility, passive permeability, metabolic stability, log of the distribution coefficient (D), percent protein bound, and cytochrome P450 (CYP450) assays were performed as previously described (5).…”

Section: Methodsmentioning

confidence: 99%

Aminoindoles, a Novel Scaffold with Potent Activity against Plasmodium falciparum

Barker¹,

Urgaonkar

Mazitschek

et al. 2011

Antimicrob Agents Chemother

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Genz-644442 became the focus of medicinal chemistry optimization; 321 analogs were synthesized and were tested for in vitro potency against P. falciparum and for in vitro absorption, distribution, metabolism, and excretion (ADME) properties. This yielded compounds with IC 50 s of approximately 30 nM. The lead compound, Genz-668764, has been characterized in more detail. It is a single enantiomer with IC 50 s of 28 to 65 nM against P. falciparum in vitro. In the 4-day P. berghei model, when it was dosed at 100 mg/kg of body weight/day, no parasites were detected on day 4 postinfection. However, parasites recrudesced by day 9. Dosing at 200 mg/kg/day twice a day resulted in cures of 3/5 animals. The compound had comparable activity against P. falciparum blood stages in a humanengrafted NOD-scid mouse model. Genz-668764 had a terminal half-life of 2.8 h and plasma trough levels of 41 ng/ml when it was dosed twice a day orally at 55 mg/kg/day. Seven-day rat safety studies showed a no-observableadverse-effect level (NOAEL) at 200 mg/kg/day; the compound was not mutagenic in Ames tests, did not inhibit the hERG channel, and did not have potent activity against a broad panel of receptors and enzymes. Employing allometric scaling and using in vitro ADME data, the predicted human minimum efficacious dose of Genz-668764 in a 3-day once-daily dosing regimen was 421 mg/day/70 kg, which would maintain plasma trough levels above the IC 90 against P. falciparum for at least 96 h after the last dose. The predicted human therapeutic index was approximately 3, on the basis of the exposure in rats at the NOAEL. We were unable to select for parasites with >2-fold decreased sensitivity to the parent compound, Genz-644442, over 270 days of in vitro culture under drug pressure. These characteristics make Genz-668764 a good candidate for preclinical development.Malaria continues to be a major global health burden, endemic in 87 countries with 2.5 billion people at risk (11). Widespread resistance to current antimalarials such as chloroquine (29, 40), atovaquone (33), pyrimethamine (39), and sulfadoxine (37) and, more recently, reduced efficacy of artemisinin derivatives (7, 38) emphasize the urgent need for new antimalarial drugs. At least in part because the majority of people affected live in the poorest parts of the world, the response of the pharmaceutical industry has been sparse or irregular. New collaborations combining the expertise of academia, industry, and public-private partnerships have been suggested to overcome these obstacles, and it is in that spirit

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“…Molecular docking of these compounds was performed into the active site of PfDHODH via MOE docking program. Crystal structure of PfDHODH (PDB ID 3O8A) was selected for these studies (Booker et al 2010). Hit compound 4, with high a MOE score (À14.8259 Kcal/mol), established HBD interactions with Gly181 at the distance of 1.65 Å. Sulfonyl oxygen anchored itself in such a way that enables a strong hydrogen bond with Tyr528.…”

Section: Plasmodium Falciparum Dihydroorate Dehydrogenasementioning

confidence: 99%

In silico identification of promiscuous scaffolds as potential inhibitors of 1-deoxy- d -xylulose 5-phosphate reductoisomerase for treatment of Falciparum malaria

Wadood

Ghufran

Hassan

et al. 2016

Pharmaceutical Biology

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Fosmidomycin is a promising DXR inhibitor, which showed safety as well as efficacy against Plasmodium falciparum malaria in clinical trials. However, due to its poor oral bioavailability and non-drug-like properties, the focus of medicinal chemists is to develop inhibitors with improved pharmacological properties. Objective: This study described the computational design of new and potent inhibitors for deoxyxylulose 5-phosphate reductoisomerase and the prediction of their pharmacokinetic and pharmacodynamic properties. Material and methods: A complex-based pharmacophore model was generated from the complex X-ray crystallographic structure of PfDXR using MOE (Molecular Operating Environment). Furthermore, MOE-Dock was used as docking software to predict the binding modes of hits and target enzyme.Results: Finally, 14 compounds were selected as new and potent inhibitors of PfDXR on the basis of pharmacophore mapping, docking score, binding energy and binding interactions with the active site residues of the target protein. The predicted pharmacokinetic properties showed improved permeability by efficiently crossing blood-brain barrier. While, in silico promiscuity binding data revealed that these hits also have the ability to bind with other P. falciparum drug targets. Discussion and conclusion: In conclusion, innovative scaffolds with novel modes of action, improved efficacy and acceptable physiochemical/pharmacokinetic properties were computationally identified.ARTICLE HISTORY

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Novel Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Anti-malarial Activity in the Mouse Model*

Cited by 124 publications

References 50 publications

Cyclopropyl Carboxamides, a Chemically Novel Class of Antimalarial Agents Identified in a Phenotypic Screen

Cyclopropyl Carboxamides, a Chemically Novel Class of Antimalarial Agents Identified in a Phenotypic Screen

Aminoindoles, a Novel Scaffold with Potent Activity against Plasmodium falciparum

In silico identification of promiscuous scaffolds as potential inhibitors of 1-deoxy- d -xylulose 5-phosphate reductoisomerase for treatment of Falciparum malaria

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