Synthesis of 16 New Hybrids from Tetrahydropyrans Derivatives and Morita˗Baylis˗Hillman Adducts: In Vitro Screening against Leishmania donovani

Abstract

Leishmaniases are a group of neglected tropical diseases (NTDs) caused by protozoan parasites from >20 Leishmania species. Visceral leishmaniasis (VL), also known as kala-aza, is the most severe form of leishmaniasis, usually fatal in the absence of treatment in 95% of cases. The Morita-Baylis-Hillman adducts (MBHAs) are being explored as drug candidates against several diseases, one of them being leishmaniasis. We present here the design, synthesis and in vitro screening against Leishmania donovani of sixteen new molecular hybrids from analgesic/anti-inflammatory tetrahydropyrans derivatives and Morita-Baylis-Hillman adducts. First, acrylates were synthesized from analgesic/anti-inflammatory tetrahydropyrans using acrylic acid under TsOH as a catalyst (70%–75% yields). After the 16 new MBHAs were prepared in moderate to good yields (60%–95%) promoted by microwave irradiation or low temperature (0 °C) in protic and aprotic medium. The hybrids were evaluated in vitro on the promastigote stage of Leishmania donovani by determining their inhibitory concentrations 50% (IC50), 50% hemolysis concentration (HC50), selectivity index (HC50/IC50,), and comparing to Amphotericin B, chosen as the anti-leishmanial reference drug. The hybrid which presents the bromine atom in its chemical structure presents high leishmanicide activity and the high selectivity index in red blood cells (SIrb > 180.19), compared with the highly-toxic reference drug (SIrb = 33.05), indicating that the bromine hybrid is a promising compound for further biological studies.

Vasorelaxant Activity of Morita-Baylis-Hillman Adducts Derived from Eugenol on Superior Mesenteric Artery of Normotensive Rats

“…O planejamento dos AMBH sintetizados e avaliados neste trabalho foi guiado a partir da estratégia de hibridação molecular, 27 explorando a versatilidade sintética e biológica dessa classe de compostos. 28 Ademais, considerando a potencialidade do eugenol como um bióforo natural, com efeitos vasorrelaxantes já bem caracterizados, decidiu-se incorporar sua subunidade, na forma de híbridos moleculares. Dessa forma, investigou-se o efeito vasorrelaxante dos AMBH (1a-1c) em artéria mesentérica superior de ratos normotensos, e verificar se a subunidade estrutural do eugenol incorporada na forma de híbridos moleculares (3a-3c) é capaz de promover um incremento na atividade vasorrelaxante.…”

Selection of electronically deficient products as very good antifungal condidates

“…anti-malaria [12,13], Leishmanicidal [14] and anti-proliferative activity on human tumor cell lines [15].…”