PHYTOCHEMICAL STUDY OF Baccharis sphenophylla AND PROSPECTION OF THE CHEMICAL PHARMACOLOGICAL POTENTIAL ANTI-Trypanosoma cruzi OF SPECIAL METABOLITES AND DERIVATIVES
Hexane and MeOH extracts from the aerial parts of Baccharis sphenophylla Dusén ex Malme (Asteraceae) showed activity against trypomastigotes and amastigotes forms of Trypanosoma cruzi – the etiological agent of Chagas disease. Thus, both were subjected to successive purification steps using column chromatography and countercurrent chromatography (CCC) to obtain the phenylpropanoid (E)-p-hexacosyl coumarate (1), the sesquiterpenoids oplopanone (2) and spathulenol (3), the diterpenoids 7α-hydroxy-ent-abieta-8(14),13(15)-dien-16,12β-olide (4), ent-kaur-16-en-19-oic (5), grandifloric (6) and 15β-tiglinoyloxy-ent-kaur-16-en-19-oic (7) acids, sphenophyllol (8) and gaudichaudol C (9), the flavonoids hispidulin (10) and eupafolin (11), and a mixture of chlorogenic di-O-caffeoylquinic acids (12–14). The isolated compounds were characterized by spectroscopic and spectrometric techniques and subsequently evaluated in vitro for activity against trypomastigotes and amastigotes of T. cruzi. Furthermore, the activity of compounds 1–14 against mammalian NCTC cells was evaluated. Compounds 1, 10 and 11 showed activity against amastigote forms and compounds 5, 7 and 9 showed activity against trypomastigote forms. Given the significant activity determined for compounds 5 and 7, the phenotypic mechanism of action was investigated. It was revealed that compounds 5 and 7 act by generating osmotic stress, disturbing the acidocalcisome organelle and raising the parasite ATP levels. Subsequently, the chemopharmacological potential of compounds 1–14 was investigated in silico using the SwissADME® tool. As a result, compounds 2–11 showed adequate levels of bioavailability and gastrointestinal absorption, essential criteria in the development of new drugs for Chagas disease. Aiming to improve the chemopharmacological profile of compound 1 – which, although active, presented reduced ADME parameters in silico – and, in order to understand relationships between the chemical structure of compound 1 and biological activity, a series of derivatives were studied in silico, prepared synthetically and evaluated for anti-T. cruzi activity. Thus, it was determined that both the size of the side chain and the presence of a hydroxyl in the C-4 position of the phenylpropanoid unit are determining pharmacophores for the presence and increase in activity. Finally, the results obtained suggest compounds 5, 7, 9 as well as derivatives from compound 1 hexyl (E)-p-coumarate and heptyl (E)-floretate could be used as molecular prototypes in the development of new alternative chemotherapies for Chagas disease.