New Class of Antitrypanosomal Agents Based on Imidazopyridines

Silva, Daniel G.; Gillespie, J. Robert; Ranade, Ranae M.; Herbst, Zackary M.; Nguyen, Uyen; Buckner, Frederick S.; Montanari, Carlos Alberto; Gelb, Michael H.

doi:10.1021/acsmedchemlett.7b00202

Cited by 26 publications

(34 citation statements)

References 14 publications

(23 reference statements)

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“…The efficacy experiment was conducted using the "acuteestablished" infection model with luciferase expressing T. cruzi. 7 In this model, mice were infected with 2 × 10 4 Tulahuen strain (DTU VI) on day 0, a dose that is >95% lethal by 20 days postinfection. The infection was allowed to become established for 7 days before treatment was given from day 7−11 postinfection.…”

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confidence: 99%

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

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Gillespie

Herbst

et al. 2018

ACS Med. Chem. Lett.

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Better therapeutics are greatly needed to treat patients infected with trypanosomatid parasites such as Trypanosoma cruzi or Trypanosoma brucei. This report describes 28 new imidazopyridines and triazolopyrimidines with potent and selective antitrypanosomal activity. Drug-like properties were demonstrated in a number of in vitro assays. In vivo efficacy was observed for 19 and 20 in acute mouse models of T. cruzi infection. Compounds 19 and 20 represent potential leads for new anti-Chagas disease drugs.

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confidence: 99%

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

Pendem

Gillespie

Herbst

et al. 2018

ACS Med. Chem. Lett.

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“…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%

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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“…The most promising benzothiazole compound B was a new lead against T. brucei (EC 50 of 0.03 μM; Figure 1). [12] Guided by these previous studies Silva and coworkers [13] further modified the benzothiazole core of B to the imidazopyrimidine rings in compounds C and D. A basic nitrogen atom inserted at the 6position of the imidazopyrimidine core resulted in the most significant increase in activity with a 1000-fold change in EC 50 against T. brucei (C vs D). The main results of our previous works [11][12][13][14] are summarized in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Structure−Activity Relationships of Imidazopyridine/Pyrimidine‐ and Furopyridine‐Based Anti‐infective Agents against Trypanosomiases

et al. 2020

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Neglected tropical diseases remain among the most critical public health concerns in Africa and South America. The drug treatments for these diseases are limited, which invariably leads to fatal cases. Hence, there is an urgent need for new antitrypanosomal drugs. To address this issue, a large number of diverse heterocyclic compounds were prepared. Straightforward synthetic approaches tolerated pre‐functionalized structures, giving rise to a structurally diverse set of analogs. We report on a set of 57 heterocyclic compounds with selective activity potential against kinetoplastid parasites. In general, 29 and 19 compounds of the total set could be defined as active against Trypanosoma cruzi and T. brucei brucei, respectively (antitrypanosomal activities <10 μM). The present work discusses the structure−activity relationships of new fused‐ring scaffolds based on imidazopyridine/pyrimidine and furopyridine cores. This library of compounds shows significant potential for anti‐trypanosomiases drug discovery.

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New Class of Antitrypanosomal Agents Based on Imidazopyridines

Cited by 26 publications

References 14 publications

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

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

Phenotypic Drug Discovery for Human African Trypanosomiasis: A Powerful Approach

Synthesis and Structure−Activity Relationships of Imidazopyridine/Pyrimidine‐ and Furopyridine‐Based Anti‐infective Agents against Trypanosomiases

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