Caracterização química e potencial farmacológico de espécies de Psychotria e modelagem molecular de substâncias majoritárias

Abstract

Psychotria (Rubiaceae) species are used in folk medicine to treat inflammatory diseases and disorders of the central nervous system, chemically characterized by the presence of a variety of secondary metabolites. In addition, several species of this genus occur in Mato Grosso do Sul. In this sense, the objective of this work was to perform the chemical characterization and pharmacological potential of Psychotria species and molecular modeling of major substances. Article 1: To evaluate the antiproliferative and anticholinesterase effect of the methanolic extract of Psychotria deflexa, P. carthagenensis, P. leiocarpa, P. capillacea, P. poeppigiana, P. brachybotrya and Palicourea crocea and quantification of alkaloids. Alkaloids were quantified spectrophotometrically and showed values between 47.6 to 21.9 µg/g. P. leiocarpa methanolic extract showed inhibition of cell growth against ovarian cells (GI50: 3.28 µg/mL), leukemia (GI50: 5.26 µg/mL), non-tumor keratinocytes (GI50: 27.20 µg/mL), prostate (GI50: 34.92 µg/mL), breast (GI50: 35.80 µg/mL). P. capillacea presented ovary (GI50: 2.33 µg/mL) and glioma (GI50: 16.66 µg/mL). Acetylcholinesterase inhibition was significant in the hippocampus for P. deflexa (57%), P. brachybotrya (50%) and P. leiocarpa (40%) extracts, followed by P. poeppigiana and P. capillacea (both 21%) when compared to the control. Article 2: To evaluate the inflammatory effect and acetylcholinesterase inhibition of methanolic extract and vincosamide from Psychotria leiocarpa. The methanolic extract of P. leiocarpa leaves resulted in the isolation of the alkaloid vincosamide, which were evaluated of anti-inflammatory, anti-acetylcholinesterase activity and molecular docking. Oral administration of the methanolic extract showed no signs of toxicity to the treated animals. The anti-inflammatory activity of methanolic extract (30, 100 and 300 mg/kg) and vincosamide (3, 30 and 100 mg/kg) showed significant inhibition when evaluated in paw edema, pleurisy and termal and mechanical hyperalgesic models. The anti-acetylcholinesterase activity of methanolic extract (30 and 100 mg/kg) and vincosamide (30 mg/kg) in vitro was significant in the frontal cortex. The molecular coupling of vincosamide demonstrated significant interactions with the catalytic and peripheral acetylcholinesterase enzyme site, corroborating the activity in the inhibition assay. Article 3: Carry out chemical composition, evaluate antioxidant activity, acetylcholinesterase inhibition and molecularly screen the major sesquiterpenes of Psychotria poeppigiana essential oil. Nineteen substances were identified, with predominance of sesquiterpenes, being germacrene D (29.38%) and bicyclogermacrene (25.21%) the majority. The essential oil showed a reduction in malondialdehyde generation (IC50 = 12.78 ± 1.36 µg/mL) when compared to the BHT control (IC50 = 38.71 ± 3.22 µg/mL). Acetylcholinesterase inhibition performed in four brain structures of Wistar rats was pronounced in the hippocampus (81.50%), cerebral cortex (70.0%) and hypothalamus (55.88%). Enzyme-binder molecular modeling showed that the main constituents of the oil can interact in the catalytic and peripheral active sites of the enzyme. Article 4: To evaluate the inhibition of antioxidant, acetylcholinesterase, antinociceptive activities and quantify the alkaloids of the methanolic extract of P. poeppigiana leaves. The total ion chromatogram of the methanolic extract was analyzed by UHPLC-HRMS/MS and showed two alkaloids (calycanthine and hodgkinsine), one coumarin (scopoletin), one iridoid (asperuloside) and two terpenes (vomifoliol and loliolide). High levels of phenols, flavonoids, flavonols and condensed tannins were found in the extract. Significant antioxidant activity was evidenced in the DPPH, β-carotene and MDA test. Methanolic extract (30 and 100 mg/kg) inhibited acetylcholinesterase in vivo in the hippocampus, cerebral cortex, hypothalamus and striatum when compared to the control. It is noteworthy that there are few reports in the literature regarding chemical and biological studies for the species in question. In this sense, this study corroborates the literature and popular use data described for the family and gender regarding the chemical constituents and biological activities reported.