Planejamento, síntese e atividade contra Trichomonas vaginalis de hidroxichalconas e ferrocenilchalconas
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Data
2017-04-20
Autores
Oliveira, Lígia Rodrigues e [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
A tricomoníase, causada pelo protozoário Trichomonas vaginalis, é considerada a doença sexualmente transmissível (DST) não-viral mais comum do mundo. Para o tratamento da tricomoníase, nitrocompostos como o metronidazol são os mais prescritos, embora existam cepas resistentes e severos efeitos adversos. Dessa forma, é premente a busca de novos agentes tricomonicidas. No presente trabalho, foram planejadas hidroxichalconas (série I) avaliando a importância da posição da hidroxila no anel A e o anel B substituído por grupos preconizados pelo Método Manual de Topliss, além da substituição do anel B fenílico por anéis π-isoeletrônicos e hidrofóbicos. A série II foi composta por ferrocenilchalconas, avaliando a importância do ferroceno como grupo doador de ferro como anel B, tendo o anel A substituído por grupos preconizados pelo Método Manual de Topliss e anéis π-isoeletrônicos. As chalconas das séries I e II foram sintetizadas por meio da reação de condensação aldólica de Claisen-Schmidt, com rendimentos que variaram de 17 a 98%. Em linhas gerais, as ferrocenilchalconas foram sintetizadas com rendimentos superiores às hidroxichalconas, devido às últimas serem purificadas por etapas adicionais de recristalização e cromatográficas. As estruturas das substâncias foram confirmadas por Ressonância Magnética Nuclear. As chalconas com hidroxila no anel A exibiram atividade contra Trichomonas vaginalis (ATCC 30236) superior àquelas com hidroxila no anel B, sendo utilizadas para etapas de otimização da bioatividade. Dentre essas, a 4’-hidroxichalcona (4) e a 3’-hidroxichalcona (3) exibiram maior atividade antiprotozoária, demonstrando valores de CI50 iguais a 27,5 e 49,4 µM, respectivamente, enquanto a 2’-hidroxichalcona (2) exibiu CI50 igual a 76,4 µM. Contudo, as hidroxichalconas não apresentaram seletividade, sendo tóxicas às células do hospedeiro (HMVII – células epiteliais vaginais ECACC), em concentrações similares. As otimizações por meio do Método Manual de Topliss conduziram a análogos mais potentes, as 2’-hidroxichalconas 8 e 9, que apresentaram CI50 iguais a 24,4 e 24,7 µM, respectivamente, demonstrando que os efeitos eletrônico e hidrofobicidade foram importantes na bioatividade. As chalconas 2-tiofênicas 21 e 28 exibiram atividade tricomonicida similar aos seus análogos fenílicos 2 e 4, respectivamente, sugerindo uma relação bioisostérica de anéis. As naftilchalconas 22, 25, 26, 29 e 30 foram inativas (CI50 > 100 µM), apesar de apresentarem hidrofobicidade superior aos seus análogos fenílicos 2–4, podendo a perda da atividade estar relacionada ao efeito estérico promovido por uma fenila adicional. Todas as ferrocenilchalconas (31 – 37) foram inativas contra T. vaginalis (CI50 > 100 µM).
Trichomoniasis, caused by the protozoa Trichomonas vaginalis, is considered the most common non-viral sexually transmitted disease (STD) around the world. For the treatment of trichomoniasis, nitro-compounds such as metronidazole are the most prescribed, although there are resistant strains and severe adverse effects. Thus, search for new trichomonicidal agents is urgent. In the present work, hydroxychalcones (series I) were designed, evaluating importance of hydroxyl position on rings A and B, as well as ring B substituted by groups recommended by the Manual Method of Topliss, ring B replaced by π-isoelectronic and hydrophobic rings. Series II was composed by ferrocenylchalcones, assessing the importance of ferrocene as an iron donor group as ring B and ring A substituted by groups recommended by Manual Method of Topliss and replaced by π-isoelectronic rings. Chalcones of series I and II were synthesized via aldol condensation reaction of Claisen-Schmidt, in yields ranging from 17 to 98%. In general, the ferrocenylchalcones were synthesized in higher yields than the hydroxychalcones, because these last were purified by recrystallization and additional chromatographic steps. The structures of the substances were confirmed by Nuclear Magnetic Resonance. Chalcones with hydroxyl on ring A exhibited activity against T. vaginalis (ATCC 30236) higher than those with hydroxyl on ring B, being the first used for bioactivity optimization steps. Among these, the 4’-hydroxychalcone (4) and 3’-hydroxychalcone (3) showed higher antiprotozoal activity, displaying IC50 values of 27.5 and 49.4 μM, respectively. On the other hand, 2'-hydroxychalcone (2) exhibited IC50 of 76.4 μM. However, hydroxychalcones showed no selectivity and were toxic to host cells (HMVII - ECACC vaginal epithelial cells) in similar concentrations. Optimizations through the Manual method of Topliss conduced to more potent analogues, 2’- hydroxychalcones 8 and 9, which showed values of IC50 of 24,4 e 24,7 µM, respectively, demonstrating the importance of electronic and hydrophobic effects over bioactivity. 2-Thiophenylchalcones 21 and 28 showed similar trichomonicidal activity to their phenyl analogues 2 and 4, respectively, suggesting a ring bioisosteric relationship of rings. Naphthylchalcones 22, 25, 26, 29 and 30 were inactive (IC50 > 100 µM), despite higher hydrophobicity than phenyl analogues 2 – 4, indicating lack of activity may be correlated to steric effect caused by an additional and fused phenyl ring. All ferrocenylchalcones (31–37) were inactive against T. vaginalis (IC50 > 100 µM).
Trichomoniasis, caused by the protozoa Trichomonas vaginalis, is considered the most common non-viral sexually transmitted disease (STD) around the world. For the treatment of trichomoniasis, nitro-compounds such as metronidazole are the most prescribed, although there are resistant strains and severe adverse effects. Thus, search for new trichomonicidal agents is urgent. In the present work, hydroxychalcones (series I) were designed, evaluating importance of hydroxyl position on rings A and B, as well as ring B substituted by groups recommended by the Manual Method of Topliss, ring B replaced by π-isoelectronic and hydrophobic rings. Series II was composed by ferrocenylchalcones, assessing the importance of ferrocene as an iron donor group as ring B and ring A substituted by groups recommended by Manual Method of Topliss and replaced by π-isoelectronic rings. Chalcones of series I and II were synthesized via aldol condensation reaction of Claisen-Schmidt, in yields ranging from 17 to 98%. In general, the ferrocenylchalcones were synthesized in higher yields than the hydroxychalcones, because these last were purified by recrystallization and additional chromatographic steps. The structures of the substances were confirmed by Nuclear Magnetic Resonance. Chalcones with hydroxyl on ring A exhibited activity against T. vaginalis (ATCC 30236) higher than those with hydroxyl on ring B, being the first used for bioactivity optimization steps. Among these, the 4’-hydroxychalcone (4) and 3’-hydroxychalcone (3) showed higher antiprotozoal activity, displaying IC50 values of 27.5 and 49.4 μM, respectively. On the other hand, 2'-hydroxychalcone (2) exhibited IC50 of 76.4 μM. However, hydroxychalcones showed no selectivity and were toxic to host cells (HMVII - ECACC vaginal epithelial cells) in similar concentrations. Optimizations through the Manual method of Topliss conduced to more potent analogues, 2’- hydroxychalcones 8 and 9, which showed values of IC50 of 24,4 e 24,7 µM, respectively, demonstrating the importance of electronic and hydrophobic effects over bioactivity. 2-Thiophenylchalcones 21 and 28 showed similar trichomonicidal activity to their phenyl analogues 2 and 4, respectively, suggesting a ring bioisosteric relationship of rings. Naphthylchalcones 22, 25, 26, 29 and 30 were inactive (IC50 > 100 µM), despite higher hydrophobicity than phenyl analogues 2 – 4, indicating lack of activity may be correlated to steric effect caused by an additional and fused phenyl ring. All ferrocenylchalcones (31–37) were inactive against T. vaginalis (IC50 > 100 µM).
Descrição
Palavras-chave
Tricomoníase, Método manual de Topliss, Bioisosterismo, Hidroxichalconas, Ferrocenilchalconas, Trichomoniasis, Hydroxychalcones, Ferrocenyl chalcones, Bioisosterism, Manual method of Topliss