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

• Main Authors: Suervy Canuto de Oliveira Sousa, Juliana da Câmara Rocha, Tatjana de Souza Lima Keesen, Everton da Paz Silva, Priscilla Anne Castro de Assis, João Paulo Gomes de Oliveira, Saulo Luís Capim, Francisco José Seixas Xavier, Bruno Guimarães Marinho, Fábio Pedrosa Lins Silva, Claudio Gabriel Lima‐Junior, Mário Luiz Araújo de Almeida Vasconcellos
• Format: Article
• Language: English
• Published: MDPI AG 2017-01-01
• Series: Molecules
• Subjects: Antileishmanial Morita‐Baylis‐Hillman adducts; opioids tetrahydropyrans derivatives; molecular hybridization; Leishmania donovani.
• Online Access: http://www.mdpi.com/1420-3049/22/2/207

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/antiinflammatory 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.