Synthesis of new N,S -acetal analogs derived from juglone with cytotoxic activity against Trypanossoma cruzi
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Synthesis of new N,S-acetal analogs derived from juglone with cytotoxic activity against Trypanossoma cruzi Paulo Anastácio Furtado Pacheco 1 & Thais de Menezes Ribeiro 1 & Raíssa Maria dos Santos Galvão 2 & Eldio Gonçalves dos Santos 2 & Ana Flávia Martins Faria 2 & Natalia Lidmar von Ranke 3 & Murilo Lamim Bello 3 & Carlos Rangel Rodrigues 3 & Vitor Francisco Ferreira 1 & André Luis Almeida Souza 4 & Daiana de Jesús Hardoim 5 & Katia da Silva Calabrese 5 & Robson Xavier Faria 6 & David Rodrigues da Rocha 1 Received: 6 September 2019 / Accepted: 30 April 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract A series of 11 new N,S-acetal juglone derivatives were synthesized and evaluated against T. cruzi epimastigote forms. These compounds were obtained in good to moderate yields using a microwave irradiation protocol. Among all compounds, two N,Sacetal analogs, showed significant trypanocidal activity. Notably, one compound 11g exhibited selectivity index 10-fold higher than the reference drug benznidazole for epimastigote. The compound 11h was more effective for amastigote forms. Both prototypes exhibited S.I. higher than the benznidazole description. Thus, both compounds proving to be useful candidate molecules to further studies in infected animals. Keywords N,S-acetal . Trypanosoma cruzi . Naphtoquinones
Introduction Chagas’ disease (CD) (or American trypanosomiasis) is a chronic disease, caused by the flagellated protozoan Trypanosoma cruzi, which affects about 6-8 million people worldwide, mainly in Latin America (Bonney et al. 2019; Rassi and Rassi 2012). Even though the incidence of new cases has decreased over the last years, the disease remains a serious public health problem with a vast socioeconomic impact especially in endemic countries (Pérez-Molina and Molina 2018). It is estimated that
approximately 12,000 people die every year from complications related to CD (Bonney et al. 2019; Pérez-Molina and Molina 2018). The calculated global healthcare costs with CD may reach $627·46 million (Bonney et al. 2019). Moreover, due to intense migratory flow over recent years, the disease has extended its geographical boundaries, becoming a major concern also in nonendemic countries (Antinori et al. 2017; Pinto Dias 2013). Currently, the only two available drugs for treating T. cruzi infection are benznidazole (1) and nifurtimox (2), both launched almost 50 years ago (Fig. 1) (Bermudez et al. 2016).
Robson Xavier Faria and David Rodrigues da Rocha contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10863-020-09834-8) contains supplementary material, which is available to authorized users. * Robson Xavier Faria [email protected] * David Rodrigues da Rocha [email protected] 1
Departamento de Química Orgânica, Programa de Pós-Graduação em Química, Universidade Federal Fluminense, Outeiro de São João Batista, s/n, Niterói, RJ 24020-141, Brazil
2
Postgraduate Program in Sciences and Biotechnology,
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