Repurposing of 5‐nitrofuran‐3,5‐disubstituted isoxazoles: A thriving scaffold to antitrypanosomal agents

• Published in: Archiv der Pharmazie (Weinheim) Vol. 356; no. 4; pp. e2200472 - n/a
• Main Authors: Carvalho, Diego B., Neves, Amarith R., Portapilla, Gisele B., Soares, Ozildeia, Santos, Larissa B. B., Oliveira, Jefferson R. S., Vianna, Luan S., Judice, Wagner A. S., Cardoso, Iara A., Luccas, Pedro H., Nonato, M. Cristina, Lopes, Norberto P., Albuquerque, Sergio, Baroni, Adriano C. M.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 01.04.2023; Wiley Subscription Services, Inc
• Subjects: Chagas disease; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; cruzain; Drug Repositioning; isoxazole core; Isoxazoles - chemistry; Isoxazoles - pharmacology; Life Sciences & Biomedicine; Nitrofurans - chemistry; Nitrofurans - pharmacology; nitroreductases; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Structure-Activity Relationship; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma cruzi; NITROFURAZONE; TRYPANOSOMA-CRUZI; Chagas disease; CHAGAS-DISEASE; cruzain; nitroreductases; structure-activity relationship; REGIMENS; isoxazole core; BENZNIDAZOLE
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.202200472

Chagas disease (CD) is a neglected disease caused by the protozoan Trypanosoma cruzi. The two drugs used in the treatment schedules exhibit adverse effects and severe toxicity. Thus, searching for new antitrypanosomal agents is urgent to provide improved treatments to those affected by this disease. 5‐Nitrofuran‐isoxazole analogs were synthesized by cycloaddition reactions [3+2] between chloro‐oximes and acetylenes in satisfactory yields. We analyzed the structure–activity relationship of the analogs based on Hammett's and Hansch's parameters. The 5‐nitrofuran‐isoxazole analogs exhibited relevant in vitro antitrypanosomal activity against the amastigote forms of T. cruzi. Analog 7s was the trending hit of the series, showing an IC50 value of 40 nM and a selectivity index of 132.50. A possible explanation for this result may be the presence of an electrophile near the isoxazole core. Moreover, the most active analogs proved to act as an in vitro substrate of type I nitroreductase rather than the cruzain, enzymes commonly investigated in molecular target studies of CD drug discovery. These findings suggest that 5‐nitrofuran‐isoxazole analogs are promising in the studies of agents for CD treatment. 5‐Nitrofuran‐isoxazole analogs were synthesized by cycloaddition reactions between chloro‐oximes and acetylenes in satisfactory yields. The structure–activity relationship of the analogs regarding their antitrypanosomal activity was analyzed based on Hammett's and Hansch's parameters. Analog 7s was the hit compound of the series, showing an IC50 value of 40 nM and a selectivity index of 132.50.