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

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 com- pounds 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-po- sition 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 sug- gested 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.