Identification of a Potential Antimalarial Drug Candidate from a Series of 2-Aminopyrazines by Optimization of Aqueous Solubility and Potency across the Parasite Life Cycle

Manach, Claire Le; Nchinda, Aloysius T.; Paquet, Tanya; Cabrera, Diego Gonzàlez; Younis, Yassir; Han, Ze; Bashyam, Sridevi; Zabiulla, Mohammed K; Taylor, Dale; Lawrence, Nina; White, Karen L.; Charman, Susan A.; Waterson, David; Witty, Michael; Wittlin, Sergio; Botha, Mariette; Nondaba, Sindisiswe H.; Reader, Janette; Birkholtz, Lyn‐Marié; Jiménez-Dı́az, Marı́a Belén; Martínez, María Santos; Ferrer, Santiago; Angulo-Barturen, Íñigo; Meister, Stephan; Antonova‐Koch, Yevgeniya; Winzeler, Elizabeth A.; Street, Leslie J.; Chibale, Kelly

doi:10.1021/acs.jmedchem.6b01265

Cited by 52 publications

(60 citation statements)

References 14 publications

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“…Furthermore, the metabolic stability of this compound in dog and monkey models indicated the potential as a single‐dose cure for malaria. Accordingly, this compound is being prepared as a preclinical candidate . MMV085499 ( 465 ) is a 2‐aminopyrazine related to 463 and 464 which features in the malaria category of the Pathogen Box, but is currently unreported.…”

Section: Malariamentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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The Pathogen Box is a 400‐strong collection of drug‐like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition to malaria and tuberculosis. This library represents an ensemble of numerous successful drug discovery programmes from around the globe, aimed at providing a powerful resource to stimulate open source drug discovery for diseases threatening the most vulnerable communities in the world. This review seeks to provide an in‐depth analysis of the literature pertaining to the compounds in the Pathogen Box, including structure–activity relationship highlights, mechanisms of action, related compounds with reported activity against different diseases, and, where appropriate, discussion on the known and putative targets of compounds, thereby providing context and increasing the accessibility of the Pathogen Box to the drug discovery community.

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Section: Malariamentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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“…Using previously acquired data, we assessed the solubility and in vitro metabolic stability of the most promising compounds from this study (Table ) . This data indicated that all compounds displayed good solubility in acidic media, with reduced solubility at pH 6.5, which presumably is a consequence of their inherent basicity.…”

Section: Resultsmentioning

confidence: 97%

“…However, bioisosteric replacement of the pyridine with a pyrazine resulted in a cohort of potent compounds with improved ADME characteristics, leading ultimately to the identification of 3 as a preclinical candidate…”

Section: Introductionmentioning

confidence: 99%

Exploring the Antiplasmodial 2‐Aminopyridines as Potential Antitrypanosomal Agents

et al. 2019

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Recently we reported the results of a screen of the Pathogen Box in which we identified 4‐(2‐amino‐5‐(4‐(methylsulfonyl) phenyl) pyridin‐3‐yl)‐2‐methoxyphenol (MMV010576, 1) as our priority antitrypanosomal hit. This compound had previously been identified as a potent and selective antiplasmodial agent, where a focused optimization campaign, resulted in a medium‐sized library of compounds, with favorable drug‐like properties, one of which (MMV048, 2, 5‐(4‐(methylsulfonyl)phenyl)‐6′‐(trifluoromethyl)‐[3,3′‐bipyridin]‐2‐amine) is currently undergoing clinical trials for malaria. Accordingly, we investigated this library, in order to elucidate structural activity relationship details of this class of compounds as inhibitors of Trypanosoma brucei. Our study has identified several structural features important for antitrypanosomal activity, which are distinct from those required for antiplasmodial activity. Results from this study can be exploited to develop potent antitrypanosomal agents.

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“…17 Further, cell-based medicinal optimization has led to the delivery of a clinical candidate, MMV390048 ( 1 ), a 2-aminopyridine, 21 and a preclinical development candidate, UCT943 ( 2 ), from the aminopyrazine class 22 (Figure 5). Our integrated screening cascade depicted in Figure 3 was critical in the selection and progression of these candidates and was propelled by the need to identify new chemical entities endowed with novel MoA and pan-activity against all parasite life cycle stages.…”

Section: Approaches To Novel Antimalarial and Anti-tb Leadsmentioning

confidence: 99%

Insights into Integrated Lead Generation and Target Identification in Malaria and Tuberculosis Drug Discovery

Okombo

Chibale

2017

Acc. Chem. Res.

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ConspectusNew, safe and effective drugs are urgently needed to treat and control malaria and tuberculosis, which affect millions of people annually. However, financial return on investment in the poor settings where these diseases are mostly prevalent is very minimal to support market-driven drug discovery and development. Moreover, the imminent loss of therapeutic lifespan of existing therapies due to evolution and spread of drug resistance further compounds the urgency to identify novel effective drugs. However, the advent of new public–private partnerships focused on tropical diseases and the recent release of large data sets by pharmaceutical companies on antimalarial and antituberculosis compounds derived from phenotypic whole cell high throughput screening have spurred renewed interest and opened new frontiers in malaria and tuberculosis drug discovery.This Account recaps the existing challenges facing antimalarial and antituberculosis drug discovery, including limitations associated with experimental animal models as well as biological complexities intrinsic to the causative pathogens. We enlist various highlights from a body of work within our research group aimed at identifying and characterizing new chemical leads, and navigating these challenges to contribute toward the global drug discovery and development pipeline in malaria and tuberculosis. We describe a catalogue of in-house efforts toward deriving safe and efficacious preclinical drug development candidates via cell-based medicinal chemistry optimization of phenotypic whole-cell medium and high throughput screening hits sourced from various small molecule chemical libraries. We also provide an appraisal of target-based screening, as invoked in our laboratory for mechanistic evaluation of the hits generated, with particular focus on the enzymes within the de novo pyrimidine biosynthetic and hemoglobin degradation pathways, the latter constituting a heme detoxification process and an associated cysteine protease-mediated hydrolysis of hemoglobin. We further expound on the recombinant enzyme assays, heme fractionation experiments, and genomic and chemoproteomic methods that we employed to identify Plasmodium falciparum falcipain 2 (PfFP2), hemozoin formation, phosphatidylinositol 4-kinase (PfPI4K) and Mycobacterium tuberculosis cytochrome bc1 complex as the targets of the antimalarial chalcones, pyrido[1,2-a]benzimidazoles, aminopyridines, and antimycobacterial pyrrolo[3,4-c]pyridine-1,3(2H)-diones, respectively.In conclusion, we argue for the expansion of chemical space through exploitation of privileged natural product scaffolds and diversity-oriented synthesis, as well as the broadening of druggable spaces by exploiting available protein crystal structures, -omics data, and bioinformatics infrastructure to explore hitherto untargeted spaces like lipid metabolism and protein kinases in P. falciparum. Finally, we audit the merits of both target-based and whole-cell phenotypic screening in steering antimalarial and antituberculosis chemical matter t...

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Identification of a Potential Antimalarial Drug Candidate from a Series of 2-Aminopyrazines by Optimization of Aqueous Solubility and Potency across the Parasite Life Cycle

Cited by 52 publications

References 14 publications

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Exploring the Antiplasmodial 2‐Aminopyridines as Potential Antitrypanosomal Agents

Insights into Integrated Lead Generation and Target Identification in Malaria and Tuberculosis Drug Discovery

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