Mariz Gomes da Silva Luana Maria, de Oliveira Jamerson Ferreira, Silva Willams Leal, da Silva Anekecia Lauro, de Almeida Junior Antônio Sérgio Alves, Barbosa Dos Santos Victor Hugo, Alves Luiz Carlos, Brayner Dos Santos Fábio André, Costa Vlaudia Maria Assis, Aires André de Lima, de Lima Maria do Carmo Alves, Albuquerque Monica Camelo Pessoa de Azevedo
Keizo Asami Immunopathology Laboratory (LIKA), Federal University of Pernambuco, 50740-465, Recife, PE, Brazil.
Chemistry Laboratory and Therapeutic Inovation, Federal University of Pernambuco, 50670-901, Recife, PE, Brazil.
Chem Biol Interact. 2018 Mar 1;283:20-29. doi: 10.1016/j.cbi.2018.01.016. Epub 2018 Jan 31.
Schistosomiasis is considered a serious public health problem in 78 countries and territories located in Africa, Asia and America and it is estimated in more than 249 million people infected by any of the species of Schistosoma. The exclusive use of praziquantel (PZQ), effective drug against all species of Schistosoma, has been the basis of the development of a possible resistance against the strains of this parasite. In addition, PZQ is not effective against young forms of worms. Thus, there is a need for the development of new drugs with schistosomicidal activity. The objective of this work was to synthesize and to evaluate the therapeutic potential of new benzodioxole derivatives (3-14) candidates for schistosomicidal drugs. All compounds synthesized showed in vitro schistosomicidal activity. The derivative 12 was considered the best compound, since it took 100% of worms to mortality in the first 72 h of exposure at the concentration of 100 μM and 83.3% at the concentration of 50 μM. Furthermore, male and female adult worms, incubated for 24 h with the compound 12 showed tegument damages characterized by extensive desquamation and edema, tuber destruction, bubble formation and exposure of the muscle layer. This compound has a restricted structure, where the thiazolidinone is attached to the 4-position of the 1,3-benzodioxol ring. The structural conformation of derivative 12 was probably responsible for the promising schistosomicidal activity, where the presence of an electron/conformational restriction of the thiazolidine ring, as well as the action of bromine as a bulk substitute, favored an increase in biological activity. In addition, tegumentary changes caused by derivative 12 may also have been responsible for the death of adult worms of Schistosoma mansoni. Therefore, we verified that the results obtained in this study make benzodioxole derivatives possible candidates for prototypes of new schistosomicidal drugs.
血吸虫病在非洲、亚洲和美洲的78个国家和地区被视为严重的公共卫生问题，据估计，超过2.49亿人感染了任何一种血吸虫。吡喹酮（PZQ）是针对所有血吸虫种类的有效药物，其单一使用已成为这种寄生虫菌株可能产生耐药性的发展基础。此外，吡喹酮对幼虫无效。因此，需要开发具有杀血吸虫活性的新药。这项工作的目的是合成并评估新型苯并二氧杂环戊烯衍生物（3 - 14）作为杀血吸虫药物候选物的治疗潜力。所有合成的化合物均表现出体外杀血吸虫活性。衍生物12被认为是最佳化合物，因为在100μM浓度下暴露的前72小时内，它使100%的蠕虫死亡，在50μM浓度下为83.3%。此外，与化合物12孵育24小时的雄性和雌性成虫显示出体表损伤，其特征为广泛的脱皮和水肿、结节破坏、气泡形成以及肌肉层暴露。该化合物具有受限结构，其中噻唑烷酮连接到1,3 - 苯并二氧杂环戊烯环的4位。衍生物12的结构构象可能是其有前景的杀血吸虫活性的原因，其中噻唑烷环的电子/构象限制以及溴作为大体积取代基的作用有利于生物活性的增加。此外，衍生物12引起的体表变化也可能是曼氏血吸虫成虫死亡的原因。因此，我们证实本研究获得的结果使苯并二氧杂环戊烯衍生物有可能成为新型杀血吸虫药物原型的候选物。
