Hit-to-lead optimization of a 2-aminobenzimidazole series as new candidates for chagas disease

Júnior, Celso de Oliveira Rezende; Martinez, Pablo David Grigol; Ferreira, Rafael Augusto Alves; Koovits, Paul J.; Soares, Bruna Miranda; Ferreira, LeonardoL.G.; Michelan-Duarte, Simone; Chelucci, Rafael Consolin; Andricopulo, Adriano D.; Matheeussen, An; Pelt, Natascha Van; Caljon, Guy; Maes, Louis; Campbell, Simon F.; Kratz, Jadel M.; Mowbray, Charles E.; Dias, Luiz C.

doi:10.1016/j.ejmech.2022.114925

Cited by 9 publications

(3 citation statements)

References 30 publications

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“…The class of 2-aminobenzimidazoles was identified by high-throughput screening (HTS) technology applied to a compound library of GlaxoSmithKline (GSK) in order to develop novel libraries of molecules targeting leishmaniasis [ 97 ] and trypanosomiasis [ 113 , 114 ]. Subsequent hit optimization studies explored antiparasitic potency, cytotoxicity, adsorption, metabolism, and excretion as parameters for the progression of the most promising derivatives.…”

Section: Benzimidazole-based Compounds Active Against Malaria Leishma...mentioning

confidence: 99%

“…A follow-up study was published by Rezende Júnior et al [ 114 ], where novel benzimidazoles structurally related to hit 21a were synthesized and tested for their activity against T. cruzi , and for their ADME-Tox properties. Keeping the 1-alkyl-2-acylamino benzimidazole as the scaffold, diverse decorations in the 5/6 positions of the benzimidazole ring, 1-alkyl chains, and 2-acylamino fragments were introduced.…”

Section: Benzimidazole-based Compounds Active Against Malaria Leishma...mentioning

confidence: 99%

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State-of-the-art Review on the Antiparasitic Activity of Benzimidazolebased Derivatives: Facing Malaria, Leishmaniasis, and Trypanosomiasis

Francesconi,

Rizzo,

Schenone

et al. 2024

CMC

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Protozoan parasites represent a significant risk for public health worldwide, afflicting particularly people in more vulnerable categories and cause large morbidity and heavy economic impact. Traditional drugs are limited by their toxicity, low efficacy, route of administration, and cost, reflecting their low priority in global health management. Moreover, the drug resistance phenomenon threatens the positive therapy outcome. This scenario claims the need of addressing more adequate therapies. Among the diverse strategies implemented, the medicinal chemistry efforts have also focused their attention on the benzimidazole nucleus as a promising pharmacophore for the generation of new drug candidates. Hence, the present review provides a global insight into recent progress in benzimidazole-based derivatives drug discovery against important protozoan diseases, such as malaria, leishmaniasis and trypanosomiasis. The more relevant chemical features and structure-activity relationship studies of these molecules are discussed for the purpose of paving the way towards the development of more viable drugs for the treatment of these parasitic infections.

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Section: Benzimidazole-based Compounds Active Against Malaria Leishma...mentioning

confidence: 99%

Section: Benzimidazole-based Compounds Active Against Malaria Leishma...mentioning

confidence: 99%

State-of-the-art Review on the Antiparasitic Activity of Benzimidazolebased Derivatives: Facing Malaria, Leishmaniasis, and Trypanosomiasis

Francesconi,

Rizzo,

Schenone

et al. 2024

CMC

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“…2-Aminobenzimidazole is an important structural motif in drug discovery and is found in various bioactive compounds. − Among its various derivatives, N -substituted 2-aminobenzimidazoles 3 possess crucial pharmaceutical properties. − For instance, norastemizole has been used as an anti-allergy drug, , astemizole and emedastine are employed in antihistamine treatments, ,− and CID-1088438 has been reported as a potent NF-κB inhibitor (Scheme a). Given the medical applications of N -substituted 2-aminobenzimidazoles, synthetic chemists have been developing several strategies for making this class of compounds.…”

Section: Introductionmentioning

confidence: 99%

NaI-Mediated Electrochemical Cyclization–Desulfurization for the Synthesis of N-Substituted 2-Aminobenzimidazoles

Nguyen,

Huynh,

Ratanathawornkiti

et al. 2023

J. Org. Chem.

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An electrochemical method for the synthesis of Nsubstituted 2-aminobenzimidazoles through a NaI-mediated desulfurization−cyclization process is reported. This electrosynthesis method utilizes cost-effective NaI as both a mediator and an electrolyte in a catalytic amount (0.2 equiv), replacing traditional oxidizing reagents. N-Substituted o-phenylenediamines and isothiocyanates undergo a thiourea formation/cyclization/desulfurization process to provide N-substituted 2-aminobenzimidazoles (55 examples, up to 98% yield) in a single reaction vessel. Importantly, this electrochemical methodology is applicable to gram-scale synthesis, maintaining reaction efficiency.

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Structure‐Metabolism Relationships of Benzimidazole Derivatives with anti‐Trypanosoma cruzi Activity for Chagas Disease

Espinoza‐Chávez,

de Oliveira Rezende Júnior,

Laureano de Souza

et al. 2024

ChemMedChem

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This study introduces further insights from the hit‐to‐lead optimization process involving a series of benzimidazole derivatives acting as inhibitors of the cruzain enzyme, which targets Trypanosoma cruzi, the causative parasite of Chagas disease. Here, we present the design, synthesis and biological evaluation of 30 new compounds as a third generation of benzimidazole analogues with trypanocidal activity, aiming to enhance our understanding of their pharmacokinetic profiles and establish a structure‐metabolism relationships within the series. The design of these new analogues was guided by the analysis of previous pharmacokinetic results, considering identified metabolic sites and biotransformation studies. This optimization resulted in the discovery of two compounds (42e and 49b) exhibiting enhanced metabolic stability, anti‐Trypanosoma cruzi activity compared to benznidazole (the reference drug for Chagas disease), as well as being non‐cruzain inhibitors, and demonstrating a satisfactory in vitro pharmacokinetic profile. These findings unveil a new subclass of aminobenzimidazole and rigid compounds, which offer potential for further exploration in the quest for discovering novel classes of antichagasic compounds.

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Hit-to-lead optimization of a 2-aminobenzimidazole series as new candidates for chagas disease

Cited by 9 publications

References 30 publications

State-of-the-art Review on the Antiparasitic Activity of Benzimidazolebased Derivatives: Facing Malaria, Leishmaniasis, and Trypanosomiasis

State-of-the-art Review on the Antiparasitic Activity of Benzimidazolebased Derivatives: Facing Malaria, Leishmaniasis, and Trypanosomiasis

NaI-Mediated Electrochemical Cyclization–Desulfurization for the Synthesis of N-Substituted 2-Aminobenzimidazoles

Structure‐Metabolism Relationships of Benzimidazole Derivatives with anti‐Trypanosoma cruzi Activity for Chagas Disease

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