Synthesis, structure-activity relationship and trypanocidal activity of pyrazole-imidazoline and new pyrazole-tetrahydropyrimidine hybrids as promising chemotherapeutic agents for Chagas disease

• Published in: European journal of medicinal chemistry Vol. 182; pp. 111610 - 111622
• Main Authors: Monteiro, M.E., Lechuga, G., Lara, L.S., Souto, B.A., Viganó, M.G., Bourguignon, S.C., Calvet, C.M., Oliveira, F.O.R., Alves, C.R., Souza-Silva, F., Santos, M.S., Pereira, M.C.S.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.11.2019; Elsevier
• Subjects: Chagas disease; Chemistry, Medicinal; Chemotherapy; Cruzipain inhibitor; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Pyrazolederivatives; SAR analysis; Science & Technology; Trypanosoma cruzi; Chagas disease; Chemotherapy; Cruzipain inhibitor; Pyrazolederivatives; SAR analysis; Trypanosoma cruzi; CYSTEINE PROTEASE; DESIGN; POSACONAZOLE; TRYPANOSOMA-CRUZI; KETONE CRUZAIN INHIBITORS; RANDOMIZED-TRIAL; IDENTIFICATION; IN-VITRO; DERIVATIVES; BENZNIDAZOLE
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111610

Drug therapy for Chagas disease remains a major challenge as potential candidate drugs have failed clinical trials. Currently available drugs have limited efficacy and induce serious side effects. Thus, the discovery of new drugs is urgently needed in the fight against Chagas' disease. Here, we synthesized and evaluated the biological effect of pyrazole-imidazoline (1a-i) and pyrazole-tetrahydropyrimidine (2a-i) derivatives against relevant clinical forms of Trypanosoma cruzi. The structure-activity relationship (SAR), drug-target search, physicochemical and ADMET properties of the major active compounds in vitro were also assessed in silico. Pyrazole derivatives showed no toxicity in Vero cells and also no cardiotoxicity. Phenotypic screening revealed two dichlorinated pyrazole-imidazoline derivatives (1c and 1d) with trypanocidal activity higher than that of benznidazole (Bz) against trypomastigotes; these were also the most potent compounds against intracellular amastigotes. Replacement of imidazoline with tetrahydropyrimidine in the pyrazole compounds completely abolished the trypanocidal activity of series 2(a-i) derivatives. The physicochemical and ADMET properties of the compounds predicted good permeability, good oral bioavailability, no toxicity and mutagenicity of 1c and 1d. Pyrazole nucleus had high frequency hits for cruzipain in drug-target search and structure activity relationship (SAR) analysis of pyrazole-imidazoline derivatives revealed enhanced activity when chlorine atom was inserted in meta-positions of the benzene ring. Additionally, we found evidence that both compounds (1c and 1d) have the potential to interact non-covalently with the active site of cruzipain and also inhibit the cysteine proteinase activity of T. cruzi. Collectively, the data presented here reveal pyrazole derivatives with promise for further optimization in the therapy of Chagas disease. [Display omitted] •Biological activity of pyrazole derivatives against Trypanosoma cruzi.•Dichlorinated pyrazole-imidazoline derivatives (1c and 1d) were selected by SAR analysis.•Compounds 1c and 1d showed promising physicochemical and ADMET properties.•Molecular docking study revealed that 1c and 1d bind to the active site of cruzipain.•Compounds 1c and 1d inhibit cysteine proteinase activity.