Isopropyl Gallate, a Gallic Acid Derivative: In Silico and In Vitro Investigation of Its Effects on Leishmania major

Abstract

Isopropyl gallate (IPG) is a polyphenol obtained from alterations in the gallic acid molecule via acid catalysis with previously reported leishmanicidal and trypanocidal activities. The present study aims to evaluate in silico binding activity towards some targets for antileishmanial chemotherapy against Leishmania major species, and ADMET parameters for IPG, as well as in vitro antileishmanial and cytotoxic effects. Molecular docking was performed using AutoDockVina and BIOVIA Discovery Studio software, whereas in silico analysis used SwissADME, PreADMET and admetSAR software. In vitro antileishmanial activity on promastigotes and amastigotes of Leishmania major, cytotoxicity and macrophages activation were assessed. IPG exhibited affinity for pteridine reductase (PTR1; −8.2 kcal/mol) and oligopeptidase B (OPB; −8.0 kcal/mol) enzymes. ADMET assays demonstrated good lipophilicity, oral bioavailability, and skin permeability, as well as non-mutagenic, non-carcinogenic properties and low risk of cardiac toxicity for IPG. Moreover, IPG inhibited the in vitro growth of promastigotes (IC50 = 90.813 µM), presented significant activity against amastigotes (IC50 = 13.45 μM), promoted low cytotoxicity in macrophages (CC50 = 1260 μM), and increased phagocytic capacity. These results suggest IPG is more selectively toxic to the parasite than to mammalian cells. IPG demonstrated acceptable in silico pharmacokinetics parameters, and reduced infection and infectivity in parasitized macrophages, possibly involving macrophage activation pathways and inhibition of leishmania enzymes.

Synthesis and biological evaluation of novel benzothiazole derivatives as potential anticancer and antiinflammatory agents

“…Based on the ADME prediction results, it could be seen that the physicochemical properties, ADME indexes and pharmacokinetic properties of B7 were within the permissible parameters ( Ogbodo et al, 2023 ). From the toxicity prediction results, B7 had certain hepatotoxicity, but it was not irritating and corrosive to eyes and skin, and was not carcinogenic ( Melo et al, 2022 ). Based on the above results, it was clear that B7 was a compound with better drug-like properties and deserved further studies.…”

“… Legend: + (toxic); - (non-toxic); acute oral toxicity (c) level category—category I and II (toxic compound) and category III and IV (non-toxic compound), based on U.S. Environmental Protection Agency (EPA) criteria ( Melo et al, 2022 ). …”

“…In this study, a series of novel benzothiazole derivatives was synthesized, and their anti-proliferative and anti-inflammatory The protein expression levels of A431 and A549 cells treated with B7 or 4i. (A) The protein expression levels of A431 cells treated with B7 or 4i for 2 h; (B) The protein expression levels of A549 cells treated with B7 or 4i for 2 h. (Melo et al, 2022).…”

Microemulsion based on methyl 3,4,5-trihydroxybenzoate for the topical treatment of cutaneous leishmaniasis: an in vivo assay

“…The in silico binding affinity mechanism involves the inhibition of Leishmania pteridine reductase (PTR1) and oligopeptidase B (OPB) targets by an isopropyl gallate derivative, which had a high power of comparison with amphotericin B (Melo et al 2022). This evidence suggests that it is a promising alternative for the treatment of leishmaniasis, as it was selectively more toxic to the parasite than to mammal cells.…”