Triazolopyrimidines and Imidazopyridines: Structure–Activity Relationships and in Vivo Efficacy for Trypanosomiasis

Pendem, Nagendar; Gillespie, J. Robert; Herbst, Zackary M.; Ranade, Ranae M.; Molasky, Nora; Faghih, Omeed; Turner, Rachael; Gelb, Michael H.; Buckner, Frederick S.

doi:10.1021/acsmedchemlett.8b00498

Cited by 22 publications

(22 citation statements)

References 8 publications

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“…Furthermore, these doses were lower than the curative dose of fexinidazole [9] (200 mg/kg) and comparable to that of acoziborole (25 mg/kg) [14]. A detailed structure activity relationship of TP class of compounds against both T. brucei and T. cruzi has been described by Nagendar and co-workers [23]. Although, one of their compounds, compound 20, had a brain-to-plasma ratio of 0.23, it was not profiled in the stage 2 HAT model, due to higher plasma protein binding (98.5%), which might affect free concentration in brain required for achieving stage 2 efficacy.…”

Section: Discussionmentioning

confidence: 71%

Anti-Trypanosomal Proteasome Inhibitors Cure Hemolymphatic and Meningoencephalic Murine Infection Models of African Trypanosomiasis

et al. 2020

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Current anti-trypanosomal therapies suffer from problems of longer treatment duration, toxicity and inadequate efficacy, hence there is a need for safer, more efficacious and ‘easy to use’ oral drugs. Previously, we reported the discovery of the triazolopyrimidine (TP) class as selective kinetoplastid proteasome inhibitors with in vivo efficacy in mouse models of leishmaniasis, Chagas Disease and African trypanosomiasis (HAT). For the treatment of HAT, development compounds need to have excellent penetration to the brain to cure the meningoencephalic stage of the disease. Here we describe detailed biological and pharmacological characterization of triazolopyrimidine compounds in HAT specific assays. The TP class of compounds showed single digit nanomolar potency against Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense strains. These compounds are trypanocidal with concentration-time dependent kill and achieved relapse-free cure in vitro. Two compounds, GNF6702 and a new analog NITD689, showed favorable in vivo pharmacokinetics and significant brain penetration, which enabled oral dosing. They also achieved complete cure in both hemolymphatic (blood) and meningoencephalic (brain) infection of human African trypanosomiasis mouse models. Mode of action studies on this series confirmed the 20S proteasome as the target in T. brucei. These proteasome inhibitors have the potential for further development into promising new treatment for human African trypanosomiasis.

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Section: Discussionmentioning

confidence: 71%

Anti-Trypanosomal Proteasome Inhibitors Cure Hemolymphatic and Meningoencephalic Murine Infection Models of African Trypanosomiasis

et al. 2020

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“…Based on the resistance of a T. brucei strain with a β4 mutation at F24 to HB175, it was concluded that this molecule is also a proteasome inhibitor ( Nagendar et al, 2018 ). A comparative study analyzed the effects of HB175 and 16 new imidazopyridines alongside GNF6702 and 12 new triazolopyrimidines, which showed that compounds of both classes kill T. brucei and intracellular T. cruzi at EC50s below 100 nM ( Nagendar et al, 2018 ). While the imidazopyridines were on average slightly more potent, they also showed greater toxicity against a human lymphocytic cell line.…”

Section: Inhibition Of the Proteasomementioning

confidence: 99%

Ubiquitination and the Proteasome as Drug Targets in Trypanosomatid Diseases

Bijlmakers¹

2021

Front. Chem.

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The eukaryotic pathogens Trypanosoma brucei, Trypanosoma cruzi and Leishmania are responsible for debilitating diseases that affect millions of people worldwide. The numbers of drugs available to treat these diseases, Human African Trypanosomiasis, Chagas' disease and Leishmaniasis are very limited and existing treatments have substantial shortcomings in delivery method, efficacy and safety. The identification and validation of novel drug targets opens up new opportunities for the discovery of therapeutic drugs with better efficacy and safety profiles. Here, the potential of targeting the ubiquitin-proteasome system in these parasites is reviewed. Ubiquitination is the posttranslational attachment of one or more ubiquitin proteins to substrates, an essential eukaryotic mechanism that regulates a wide variety of cellular processes in many different ways. The best studied of these is the delivery of ubiquitinated substrates for degradation to the proteasome, the major cellular protease. However, ubiquitination can also regulate substrates in proteasome-independent ways, and proteasomes can degrade proteins to some extent in ubiquitin-independent ways. Because of these widespread roles, both ubiquitination and proteasomal degradation are essential for the viability of eukaryotes and the proteins that mediate these processes are therefore attractive drug targets in trypanosomatids. Here, the current understanding of these processes in trypanosomatids is reviewed. Furthermore, significant recent progress in the development of trypanosomatid-selective proteasome inhibitors that cure mouse models of trypanosomatid infections is presented. In addition, the targeting of the key enzyme in ubiquitination, the ubiquitin E1 UBA1, is discussed as an alternative strategy. Important differences between human and trypanosomatid UBA1s in susceptibility to inhibitors predicts that the selective targeting of these enzymes in trypanosomatids may also be feasible. Finally, it is proposed that activating enzymes of the ubiquitin-like proteins SUMO and NEDD8 may represent drug targets in these trypanosomatids as well.

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“…One compound (11) had modest brain permeability of 9%, but was included for further chemistry despite this marginal activity. Four compounds (13)(14)(15)17) had minimal concentrations in the brain (< 2% of plasma levels) and were no longer pursued. One compound (16) had nearly undetectable plasma and brain levels at the 60-min time point and was also considered unsuitable for further development.…”

Section: Screening For Brain Permeabilitymentioning

confidence: 99%

“…Three scaffolds (1, 2, and 9) have been developed to the level of lead compounds ready for late preclinical studies [5,8,11,[14][15][16]. The optimization of hit compound 1 is shown in Figure 3 (Figure 3), the partially optimized compound (HB-175) is shown, which combines the best substituents of regions I, II, and III [5].…”

Section: Active Compound Series (Highlights)mentioning

confidence: 99%

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Phenotypic Drug Discovery for Human African Trypanosomiasis: A Powerful Approach

et al. 2020

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The work began with the screening of a library of 700,000 small molecules for inhibitors of Trypanosoma brucei growth (a phenotypic screen). The resulting set of 1035 hit compounds was reviewed by a team of medicinal chemists, leading to the nomination of 17 chemically distinct scaffolds for further investigation. The first triage step was the assessment for brain permeability (looking for brain levels at least 20% of plasma levels) in order to optimize the chances of developing candidates for treating late-stage human African trypanosomiasis. Eleven scaffolds subsequently underwent hit-to-lead optimization using standard medicinal chemistry approaches. Over a period of six years in an academic setting, 1539 analogs to the 11 scaffolds were synthesized. Eight scaffolds were discontinued either due to insufficient improvement in antiparasitic activity (5), poor pharmacokinetic properties (2), or a slow (static) antiparasitic activity (1). Three scaffolds were optimized to the point of curing the acute and/or chronic T. brucei infection model in mice. The progress was accomplished without knowledge of the mechanism of action (MOA) for the compounds, although the MOA has been discovered in the interim for one compound series. Studies on the safety and toxicity of the compounds are planned to help select candidates for potential clinical development. This research demonstrates the power of the phenotypic drug discovery approach for neglected tropical diseases.

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Triazolopyrimidines and Imidazopyridines: Structure–Activity Relationships and in Vivo Efficacy for Trypanosomiasis

Cited by 22 publications

References 8 publications

Anti-Trypanosomal Proteasome Inhibitors Cure Hemolymphatic and Meningoencephalic Murine Infection Models of African Trypanosomiasis

Anti-Trypanosomal Proteasome Inhibitors Cure Hemolymphatic and Meningoencephalic Murine Infection Models of African Trypanosomiasis

Ubiquitination and the Proteasome as Drug Targets in Trypanosomatid Diseases

Phenotypic Drug Discovery for Human African Trypanosomiasis: A Powerful Approach

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