Antileishmanial activity of terpenylquinones on Leishmania infantum and their effects on Leishmania topoisomerase IB. (December 2019)

• Record Type: Journal Article
• Authors: Pérez-Pertejo, Yolanda; Escudero-Martínez, José M.; Reguera, Rosa M.; Balaña-Fouce, Rafael; García, Pablo A.; Jambrina, Pablo G.; San Feliciano, Arturo; Castro, María-Ángeles
• Is Part Of: International journal for parasitology. Volume 11(2019)
• Page Start: 70
• Page End: 79
• Publication Date: 2019-12
• Subjects: Leishmania infantum -- Terpenylquinones -- Naphthoquinones -- Anthraquinones -- Acridinequinone -- DNA-Topoisomerase IB; VL Visceral Leishmaniasis -- LTopIB Leishmania Type IB DNA Topoisomerase -- AMB Amphotericin B deoxycholate -- MTF Miltefosine -- CPT Camptothecin -- iRFP Infrared Fluorescent Protein -- FBS Foetal Bovine Serum -- SI Selectivity Index -- NQ Naphthoquinone -- AQ Anthraquinone -- BAcQ Benzoacridinequinone; Parasitic diseases -- Chemotherapy -- Periodicals; Drug resistance -- Periodicals; 616.96061
• DOI: 10.1016/j.ijpddr.2019.10.004
• Languages: English
• ISSNs: 2211-3207

Abstract

Abstract: Leishmania is the aethiological agent responsible for the visceral leishmaniasis, a serious parasite-borne disease widely spread all over the World. The emergence of resistant strains makes classical treatments less effective; therefore, new and better drugs are necessary. Naphthoquinones are interesting compounds for which many pharmacological properties have been described, including leishmanicidal activity. This work shows the antileishmanial effect of two series of terpenyl-1, 4-naphthoquinones (NQ) and 1, 4-anthraquinones (AQ) obtained from natural terpenoids, such as myrcene and myrceocommunic acid. They were evaluated both in vitro and ex vivo against the transgenic iRFP-Leishmania infantum strain and also tested on liver HepG2 cells to determine their selectivity indexes. The results indicated that NQ derivatives showed better antileishmanial activity than AQ analogues, and among them, compounds with a diacetylated hydroquinone moiety provided better results than their corresponding quinones. Regarding the terpenic precursor, compounds obtained from the monoterpenoid myrcene displayed good antiparasitic efficiency and low cytotoxicity for mammalian cells, whereas those derived from the diterpenoid showed better antileishmanial activity without selectivity. In order to explore their mechanism of action, all the compounds have been tested as potential inhibitors of Leishmania type IB DNA topoisomerases, but only some compounds that displayed the quinone ring were able to inhibit the recombinant enzyme in vitro . This fact together with the docking studies performed on LTopIB suggested the existence of another mechanism of action, alternative or complementary to LTopIB inhibition. In silico druglikeness and ADME evaluation of the best leishmanicidal compounds has shown good predictable druggability. Graphical abstract: Image 1 Highlights: 15 out of 37 compounds arrested L. infantum amastigotes at EC50 < 10 μM. Naphthoquinones showed better antileishmanial activity than anthraquinones. Those from myrcene showed good antiparasitic efficiency and low cytotoxicity. Docking predicted good LTopIB interaction, and a few members inhibited the enzyme. In silico drug-likeness evaluation predicts good druggability and low in vivo toxicity.