2. Academic Validation
  3. Structure-activity relationship study of antitrypanosomal analogues of gibbilimbol B using multivariate analysis and computation-aided drug design

Structure-activity relationship study of antitrypanosomal analogues of gibbilimbol B using multivariate analysis and computation-aided drug design

  • Bioorg Med Chem Lett. 2023 Mar 1:83:129190. doi: 10.1016/j.bmcl.2023.129190.
Luiz P M O Leão 1,  Nátalie de B Vieira 1,  Paula P S Oliveira 1,  Daniela A Chagas-Paula 1,  Marisi G Soares 1,  Thiago B Souza 2,  João L Baldim 3,  Thais A Costa-Silva 4,  Andre G Tempone 5,  Danielle F Dias 6,  João Henrique G Lago 7
Affiliations

Affiliations

  • 1 Institute of Chemistry, Federal University of Alfenas, Minas Gerais 37130-001, Brazil.
  • 2 Pharmacy School, Federal University of Ouro Preto, Minas Gerais 35400-000, Brazil.
  • 3 Federal Institute of Education, Science and Technology of South of Minas Gerais, Minas Gerais 37890-000, Brazil.
  • 4 SENAI Institute of Innovation in Biotechnology, São Paulo 01130-000, Brazil.
  • 5 Center for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo 01246-902, Brazil.
  • 6 Institute of Chemistry, Federal University of Alfenas, Minas Gerais 37130-001, Brazil. Electronic address: [email protected].
  • 7 Center of Natural and Human Sciences, Federal University of ABC, São Paulo 09210-580, Brazil. Electronic address: [email protected].
PMID: 36805048 DOI: 10.1016/j.bmcl.2023.129190
Abstract

Gibbilimbol B and analogues were isolated from the Brazilian plant Piper malacophyllum and displayed activity against trypomastigote forms of Trypanosoma cruzi as well as reduced toxicity against NCTC cells. These results stimulated the preparation of a series of 24 chemically related analogues to study the potential of these compounds against T. cruzi trypomastigotes and explore structure-activity relationships. Initially, 12 compounds were planned, maintaining the same extension of the linear side chain of gibbilimbol B and unsaturation on the C-4 position but changing the functional groups - ester and amide - and variating the substituent at the p-position in the aromatic ring. Other 12 compounds were prepared using a branched side chain containing an ethyl group at the C-2 position. Overall, these structurally-related analogues demonstrated promising activity against trypomastigote forms (EC50 < 20 μM) and no mammalian cytotoxicity to fibroblasts (CC50 > 200 μM). Using multivariate statistics and machine learning analysis, aspects associated with structure/activity were related to their three-dimensional structure and, mainly, to the substituents on the aromatic ring. Obtained results suggested that the presence of t-butyl or nitro groups at p-position with appropriate side chains causes an alteration in the electron topological state, Van der Waals volumes, surface areas, and polarizabilities of tested compounds which seem to be essential for biological activity against T. cruzi parasites.

Keywords

Gibbilimbol B; Multivariate analysis; NCTC; Synthetic analogues; Trypanosoma cruzi; Trypomastigotes.

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