Benign-by-Design SAHA Analogues for Human and Animal Vector-Borne Parasitic Diseases

Rossi, Michele; Martinengo, Bianca; Diamanti, Eleonora; Salerno, Alessandra; Rizzardi, Nicola; Fato, Romana; Bergamini, Christian; Souza de Oliveira, Andressa; de Araújo Marques Ferreira, Thais; Andrade Holanda, Cleonice; Romeiro, Luiz Antonio Soares; Soeiro, Maria de Nazaré Correia; Nunes, Krislayne; Ferreira de Almeida Fiuza, Ludmila; Meuser Batista, Marcos; Fraga, Carlos A. M.; E. A. Alkhalaf, Hamed; Elmahallawy, Ehab Kotb; Ebiloma, Godwin U.; De Koning, Harry P.; Vittorio, Serena; Vistoli, Giulio; Blanquart, Christophe; Bertrand, Philippe; Bolognesi, Maria Laura

Abstract

The search for new drugs fulfilling One Health and Green Chemistry requirements is an urgent call. Here, for the first time, we envisaged developing SAHA analogues by starting from the cashew nutshell liquid (CNSL) agro-industrial waste and employing a metathesis approach. This sustainable combination (comprising principles #7 and #9) allowed a straightforward synthesis of compounds 13–20. All of them were found to not be toxic on HepG2, IMR-32, and L929 cell lines. Then, their potential against major human and animal vector-borne parasitic diseases (VBPDs) was assessed. Compound 13 emerged as a green hit against the trypomastigote forms of T. b. brucei. In silico studies showed that the T. b. brucei HDAC (TbDAC) catalytic pocket could be occupied with a similar binding mode by both SAHA and 13, providing a putative explanation for its antiparasitic mechanism of action (13, EC50 = 0.7 ± 0.2 μM).

• Journal Article Type: Letter
• Online Publication Date: Aug 13, 2024
• Publication Date: Aug 13, 2024
• Deposit Date: Dec 13, 2024
• Journal: ACS Medicinal Chemistry Letters
• Print ISSN: 1948-5875
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 15
• Issue: 9
• DOI: https://doi.org/10.1021/acsmedchemlett.4c00242