RESUMO
2-Alkynoic fatty acids display antimycobacterial, antifungal, and pesticidal activities but their antiprotozoal activity has received little attention. In this work we synthesized the 2-octadecynoic acid (2-ODA), 2-hexadecynoic acid (2-HDA), and 2-tetradecynoic acid (2-TDA) and show that 2-ODA is the best inhibitor of the Leishmania donovani DNA topoisomerase IB enzyme (LdTopIB) with an EC(50)=5.3±0.7µM. The potency of LdTopIB inhibition follows the trend 2-ODA>2-HDA>2-TDA, indicating that the effectiveness of inhibition depends on the fatty acid carbon chain length. All of the studied 2-alkynoic fatty acids were less potent inhibitors of the human topoisomerase IB enzyme (hTopIB) as compared to LdTopIB. 2-ODA also displayed in vitro activity against Leishmania donovani (IC(50)=11.0µM), but it was less effective against other protozoa, Trypanosoma cruzi (IC(50)=48.1µM) and Trypanosoma brucei rhodesiense (IC(50)=64.5µM). The antiprotozoal activity of the 2-alkynoic fatty acids, in general, followed the trend 2-ODA>2-HDA>2-TDA. The experimental information gathered so far indicates that 2-ODA is a promising antileishmanial compound.
Assuntos
Alcinos/farmacologia , Antiprotozoários/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Ácidos Graxos Insaturados/farmacologia , Leishmania donovani/enzimologia , Inibidores da Topoisomerase I/farmacologia , Alcinos/síntese química , Alcinos/química , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Linhagem Celular , Relação Dose-Resposta a Droga , Ácidos Graxos Insaturados/síntese química , Ácidos Graxos Insaturados/química , Humanos , Leishmania donovani/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Testes de Sensibilidade Parasitária , Ratos , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacosRESUMO
The hitherto unknown 2,6-hexadecadiynoic acid, 2,6-nonadecadiynoic acid, and 2,9-hexadecadiynoic acid were synthesized in two steps and in 11-18% overall yields starting from either 1,5-hexadiyne or 1,8-nonadiyne. Among all the compounds 2,6-hexadecadiynoic acid displayed the best overall antifungal activity against both the fluconazole-resistant Candida albicans strains ATCC 14053 and ATCC 60193, with a minimum inhibitory concentration (MIC of 11 microM), and against Cryptococcus neoformans ATCC 66031 (MIC < 5.7 microM). 2,9-Hexadecadiynoic acid did not display any significant cytotoxicity against the fluconazole-resistant C. albicans strains, but it showed fungitoxicity against C. neoformans ATCC 66031 with a MIC value of < 5.8 microM. Other FA, such as 2-hexadecynoic acid, 5-hexadecynoic acid, 9-hexadecynoic acid, and 6-nonadecynoic acid were also synthesized and their antifungal activities compared with those of the novel acetylenic FA. 2-Hexadecynoic acid, a known antifungal FA, exhibited the best antifungal activity (MIC = 9.4 microM) against the fluconazole-resistant C. albicans ATCC 14053 strain, but it showed a MIC value of only 100 microM against C. albicans ATCC 60193. 2,6-Hexadecadiynoic acid and 2-hexadecynoic acid also displayed a MIC of 140-145 microM toward Mycobacterium tuberculosis H37Rv in Middlebrook 7H12 medium. In conclusion, 2,6-hexadecadiynoic acid exhibited the best fungitoxicity profile compared with other analogues. This diynoic FA has the potential to be further evaluated for use in topical antifungal formulations.
Assuntos
Antifúngicos/síntese química , Ácidos Graxos Insaturados/síntese química , Ácidos Graxos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Ácidos Graxos/química , Ácidos Graxos/farmacologia , Ácidos Graxos Insaturados/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The antifungal, naturally occurring acetylenic fatty acid 6-nonadecynoic acid was synthesized in three steps (18 % overall yield), for the first time starting with commercially available 1-tetradecyne. The synthesis developed herein will facilitate the further study of the antifungal properties of this naturally occurring acetylenic fatty acid. The 6-nonadecynoic acid exhibited the best antifungal activity (< 4.3 microM) against Cryptococcus neoformans ATCC 66031 in Sabouraud Dextrose Broth (SDB) media. In our hands, it was not active against Candida albicans ATCC 14053 and Candida albicans ATCC 60193.