Structural Investigation of Anti-Trypanosoma cruzi 2-Iminothiazolidin-4-ones Allows the Identification of Agents with Efficacy in Infected Mice
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- 作者：Diogo Rodrigo Magalhaes Moreira ; Salvana Priscylla Manso Costa ; Marcelo Zaldini Hernandes ; Marcelo Montenegro Rabello ; Gevanio Bezerra de Oliveira Filho ; Cristiane Moutinho Lagos de Melo ; Lucas Ferreira da Rocha ; Carlos Alberto de Simone ; Rafaela Salgado Ferreira ; Jordana Rodrigues Barbosa Fradico ; C谩ssio Santana Meira ; Elisalva Teixeira Guimar茫es ; Rajendra Mohan Srivastava ; Val茅ria R锚go Alves Pereira ; Milena Botelho Pereira Soares ; Ana Cristina Lima Leite
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：December 27, 2012
- 年：2012
- 卷：55
- 期：24
- 页码：10918-10936
- 全文大小：707K
- 年卷期：v.55,no.24(December 27, 2012)
- ISSN：1520-4804
文摘
We modified the thiazolidinic ring at positions N3, C4, and C5, yielding compounds 6鈥?b>24. Compounds with a phenyl at position N3, 15鈥?b>19, 22鈥?b>24, exhibited better inhibitory properties for cruzain and against the parasite than 2-iminothiazolidin-4-one 5. We were able to identify one high-efficacy trypanocidal compound, 2-minothiazolidin-4-one 18, which inhibited the activity of cruzain and the proliferation of epimastigotes and was cidal for trypomastigotes but was not toxic for splenocytes. Having located some of the structural determinants of the trypanocidal properties, we subsequently wished to determine if the exchange of the thiazolidine for a thiazole ring leaves the functional properties unaffected. We therefore tested thiazoles 26鈥?b>45 and observed that they did not inhibit cruzain, but they exhibited trypanocidal effects. Parasite development was severely impaired when treated with 18, thus reinforcing the notion that this class of heterocycles can lead to useful cidal agents for Chagas disease.