RESUMEN
Chikungunya virus (CHIKV) is responsible for the most endemic alphavirus infections called Chikungunya. The endemicity of Chikungunya has increased over the past two decades, and it is a pathogen with pandemic potential. There is currently no approved direct-acting antiviral to treat the disease. As part of our antiviral drug discovery program focused on alphaviruses and the non-structural protein 2 protease, we discovered that J12 and J13 can inhibit CHIKV nsP2 protease and block the replication of CHIKV in cell cultures. Both compounds are metabolically stable to human liver microsomal and S9 enzymes. J13 has excellent oral bioavailability in pharmacokinetics studies in mice and ameliorated Chikungunya symptoms in preliminary efficacy studies in mice. J13 exhibited an excellent safety profile in in vitro safety pharmacology and off-target screening assays, making J13 and its analogs good candidates for drug development against Chikungunya.
Asunto(s)
Antivirales , Fiebre Chikungunya , Virus Chikungunya , Modelos Animales de Enfermedad , Animales , Virus Chikungunya/efectos de los fármacos , Ratones , Fiebre Chikungunya/tratamiento farmacológico , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Humanos , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/síntesis química , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga , Estructura Molecular , Cisteína Endopeptidasas/metabolismo , Microsomas Hepáticos/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
Human African Trypanosomiasis (HAT), caused by Trypanosoma brucei gambiense and rhodesiense, is a parasitic disease endemic to sub-Saharan Africa. Untreated cases of HAT can be severely debilitating and fatal. Although the number of reported cases has decreased progressively over the last decade, the number of effective and easily administered medications is very limited. In this work, we report the antitrypanosomal activity of a series of potent compounds. A subset of molecules in the series are highly selective for trypanosomes and are metabolically stable. One of the compounds, (E)-N-(4-(methylamino)-4-oxobut-2-en-1-yl)-5-nitrothiophene-2-carboxamide (10), selectively inhibited the growth of T. b. brucei, T. b. gambiense and T. b. rhodesiense, have excellent oral bioavailability and was effective in treating acute infection of HAT in mouse models. Based on its excellent bioavailability, compound 10 and its analogs are candidates for lead optimization and pre-clinical investigations.