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

Abstract

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 IC 50 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.

Neuroprotective Profile of Triazole Grandisin Analogue against Amyloid-Beta Oligomer-Induced Cognitive Impairment

“…Our research group has experience synthesizing small bioactive molecules using different medicinal chemistry approaches, such as bioisosterism and molecular hybridization. − Our synthesis strategy is most often inspired by natural products, such as tetrahydrofuran neolignans, whose privileged scaffold offer versatility for diverse biological applications. ,,− Grandisin (Figure , compound 5 ), a neolignan obtained from Virola surinamensis, a plant commonly found on the banks of the Amazon River, possesses anti-inflammatory and antioxidant properties. Carvalho and colleagues (2010) demonstrated that grandisin reduced inflammation in formalin-induced and croton-oil-induced paw and ear edema, respectively .…”