RESUMO
The protozoan diseases Human African Trypanosomiasis (HAT), Chagas disease (CD), and leishmaniases span worldwide and therefore their impact is a universal concern. The present regimen against kinetoplastid protozoan infections is poor and insufficient. Target-based design expands the horizon of drug design and development and offers novel chemical entities and potential drug candidates to the therapeutic arsenal against the aforementioned neglected diseases. In this review, we report the most promising targets of the main kinetoplastid parasites, as well as their corresponding inhibitors. This overview is part of the Special Issue, entitled "Advances of Medicinal Chemistry against Kinetoplastid Protozoa (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) Infections: Drug Design, Synthesis and Pharmacology".
Assuntos
Antiprotozoários/farmacologia , Doença de Chagas/tratamento farmacológico , Desenho de Fármacos , Leishmaniose/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Tripanossomíase Africana/tratamento farmacológico , Animais , Antiprotozoários/síntese química , Antiprotozoários/classificação , Doença de Chagas/parasitologia , Doença de Chagas/transmissão , Descoberta de Drogas , Humanos , Insetos Vetores/efeitos dos fármacos , Insetos Vetores/parasitologia , Leishmania/efeitos dos fármacos , Leishmania/genética , Leishmania/crescimento & desenvolvimento , Leishmania/metabolismo , Leishmaniose/parasitologia , Leishmaniose/transmissão , Estágios do Ciclo de Vida/efeitos dos fármacos , Estágios do Ciclo de Vida/genética , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Estrutura Molecular , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Relação Estrutura-Atividade , Trypanosoma brucei gambiense/efeitos dos fármacos , Trypanosoma brucei gambiense/genética , Trypanosoma brucei gambiense/crescimento & desenvolvimento , Trypanosoma brucei gambiense/metabolismo , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/genética , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/metabolismo , Tripanossomíase Africana/parasitologia , Tripanossomíase Africana/transmissãoRESUMO
The design, synthesis and pharmacological evaluation of the 4-substituted-2-[3-(adamant-1-yl)-4-fluorophenyl]thiazoles 1a-j, the 4-substituted-2-[4-(adamant-1-yl)phenyl]thiazoles 2a-h, the 2-substituted-4-[4-(adamant-1-yl)phenyl]thiazoles 3a-e, the N-substituted 2-phenylthiazol-4-ethylamides 4a, b and the N-substituted 4-phenylthiazol-2-ethylamides 4c, d is described. Compounds 1a and 2a exhibit trypanocidal activity in the range of IC50 = 0.42 µM and IC50 = 0.80 µM, respectively. Both of these derivatives bear a lipophilic end, which consists of a 4-(1-adamantyl) phenyl or a 3-(1-adamantyl)phenyl moiety, a 1,3-thiazole ring and a functional end, which comprises of an alkylamine and can be considered as promising candidates for the treatment of Trypanosoma brucei infections.
RESUMO
In this work, the synthesis and the pharmacological evaluation of diphenoxyadamantane alkylamines Ia-f and IIa-f is described. The new diphenoxy-substituted adamantanes share structural features present in trypanocidal and antitubercular agents. 1-Methylpiperazine derivative Ia is the most potent against T. brucei compound, whilst its hexylamine congener IIf exhibits a significant antimycobacterial activity.
Assuntos
Adamantano/farmacologia , Aminas/farmacologia , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Adamantano/análogos & derivados , Adamantano/química , Aminas/síntese química , Aminas/química , Antituberculosos/síntese química , Antituberculosos/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/químicaRESUMO
The aim of the present investigation was to develop matrix tablet formulations for the in vitro controlled release of 2 new tuberculocidal adamantane aminoethers (compounds I and II), congeneric to the adamantane derivative SQ109, which is in final clinical trials, using carefully selected excipients, such as polyvinylpyrrolidone, sodium alginate and lactose. The tablets were prepared using the direct compression method and dissolution experiments were conducted using the US Pharmacopoeia type II apparatus (paddle method) in gastric and intestinal fluids. The results confirm that both analogues, albeit more lipophilic than SQ109, showed satisfactory in vitro release characteristics from solid pharmaceutical formulations. In conclusion, these formulations merit further assessment by conducting in the future bioavailability in vivo studies.