title: Hologram QSAR studies of antiprotozoal activities of sesquiterpene lactones.
abstract: Infectious diseases such as trypanosomiasis and leishmaniasis are considered neglected tropical diseases due the lack for many years of research and development into new drug treatments besides the high incidence of mortality and the lack of current safe and effective drug therapies. Natural products such as sesquiterpene lactones have shown activity against T. brucei and L. donovani, the parasites responsible for these neglected diseases. To evaluate structure activity relationships, HQSAR models were constructed to relate a series of 40 sesquiterpene lactones (STLs) with activity against T. brucei, T. cruzi, L. donovani and P. falciparum and also with their cytotoxicity. All constructed models showed good internal (leave-one-out q2 values ranging from 0.637 to 0.775) and external validation coefficients (r2test values ranging from 0.653 to 0.944). From HQSAR contribution maps, several differences between the most and least potent compounds were found. The fragment contribution of PLS-generated models confirmed the results of previous QSAR studies that the presence of α,β-unsatured carbonyl groups is fundamental to biological activity. QSAR models for the activity of these compounds against T. cruzi, L. donovani and P. falciparum are reported here for the first time. The constructed HQSAR models are suitable to predict the activity of untested STLs.
authors.affiliation: Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, Av. Lineu Prestes, 580, 05508-000 São Paulo, Brazil. trossini@usp.br.
authors.forename: Gustavo H G
authors.initials: GH
authors.lastname: Trossini
authors.affiliation: Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, Av. Lineu Prestes, 580, 05508-000 São Paulo, Brazil. maltarollo@usp.br.
authors.forename: Vinícius G
authors.initials: VG
authors.lastname: Maltarollo
authors.affiliation: Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, Pharma Campus, Corrensstraße 48, D-48149 Münster, Germany. thomschm@uni-muenster.de.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Schmidt
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007893:Leishmania donovani / Q000254:growth & development*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy; D016778:Malaria, Falciparum / Q000188:drug therapy; D008956:Models, Chemical; D010963:Plasmodium falciparum / Q000254:growth & development*; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D007783:Lactones; D012717:Sesquiterpenes