Borgo Jimena, Elso Orlando G, Gomez Jessica, Coll Mauro, Catalán Cesar A N, Mucci Juan, Alvarez Guzmán, Randall Lía M, Barrera Patricia, Malchiodi Emilio L, Bivona Augusto E, Martini María Florencia, Sülsen Valeria P
Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), CONICET-Universidad de Buenos Aires, Junín 956, piso 2, Buenos Aires C1113AAD, Argentina.
Cátedra de Farmacognosia, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, piso 2, Buenos Aires C1113AAD, Argentina.
Pharmaceutics. 2023 Feb 15;15(2):647. doi: 10.3390/pharmaceutics15020647.
species (Asteraceae) have been a rich source of terpenoid compounds, mainly sesquiterpene lactones, several of which show antiprotozoal activity. In the search for new trypanocidal compounds, var. and were studied. Two sesquiterpene lactones, santhemoidin C and 2-oxo-8-deoxyligustrin, respectively, were isolated. These compounds were assessed in vitro against stages, showing IC values of 11.80 and 4.98 on epimastigotes, 56.08 and 26.19 on trypomastigotes and 4.88 and 20.20 µM on amastigotes, respectively. Cytotoxicity was evaluated on Vero cells by the MTT assay. The effect of the compounds on trypanothyone reductase (TcTR), -sialidase (TcTS) and the prolyl oligopeptidase of 80 kDa (Tc80) as potential molecular targets of was investigated. Santhemoidin C inhibited oligopeptidase activity when tested against recombinant Tc80 using a fluorometric assay, reaching an IC of 34.9 µM. Molecular docking was performed to study the interaction between santhemoidin C and the Tc80 protein, reaching high docking energy levels. Plasma membrane shedding and cytoplasmic vacuoles, resembling autophagosomes, were detected by transmission microscopy in parasites treated with santhemoidin C. Based on these results, santhemoidin C represents a promising candidate for further studies in the search for new molecules for the development of trypanocidal drugs.
菊科植物一直是萜类化合物的丰富来源，主要是倍半萜内酯，其中几种具有抗寄生虫活性。在寻找新的杀锥虫化合物的过程中，对[具体品种1]变种和[具体品种2]进行了研究。分别分离出了两种倍半萜内酯，即桑菊素C和2-氧代-8-脱氧女贞素。这些化合物在体外针对[不同阶段]进行了评估，对前鞭毛体的IC值分别为11.80和4.98，对锥鞭毛体的IC值分别为56.08和26.19，对无鞭毛体的IC值分别为4.88和20.20μM。通过MTT法在Vero细胞上评估细胞毒性。研究了这些化合物对锥虫硫酮还原酶（TcTR）、唾液酸酶（TcTS）和80 kDa脯氨酰寡肽酶（Tc80）作为锥虫潜在分子靶点的影响。使用荧光测定法测试桑菊素C对重组Tc80时，其抑制寡肽酶活性，IC值达到34.9μM。进行了分子对接以研究桑菊素C与Tc80蛋白之间的相互作用，达到了较高的对接能量水平。在用桑菊素C处理的寄生虫中，通过透射显微镜检测到了类似于自噬体的质膜脱落和细胞质空泡。基于这些结果，桑菊素C是进一步研究寻找杀锥虫药物开发新分子的有前途的候选物。
