Design, Rational Repurposing, Synthesis, In Vitro Evaluation, Homology Modeling and In Silico Study of Sulfuretin Analogs as Potential Antileishmanial Hit Compounds

Abstract

Direct growth inhibition of infectious organisms coupled with immunomodulation to counteract the immunosuppressive environment might be a beneficial therapeutic approach. Herein, a library of sulfuretin analogs were developed with potential capabilities to inhibit production of the immunosuppressive PGE2 and elicit direct growth inhibition against Leishmania donovani; the major causative agent of the fatal visceral leishmaniasis. Amongst explored library members bearing diverse methoxy and/or hydroxy substitution patterns at rings B and A, analog 1i retaining the C6-hydroxy moiety at ring-A, but possessing methoxy moieties in place of the polar dihydroxy moieties of sulfuretin ring-B, as well as analog 1q retaining the sulfuretin′s polar dihydroxy moieties at ring-B, but incorporating a C6-methoxy moiety instead of the C6-hydroxy moiety at ring-A, were the most promising hit compounds. Cytotoxicity evaluation suggested that analog 1i possesses a safety profile inducing the death of the parasite rather than host cells. In silico simulation provided insights into their possible binding with Leishmania donovani fumarate reductase. The current investigation presents sulfuretin analogs 1i and 1q as potential hit compounds for further development of multifunctional therapeutic agents against visceral leishmaniasis.

In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases

“…Hit discovery and confirmation is an indispensable first step in early drug discovery [ 34 , 35 , 36 , 37 , 38 ]. While a hit compound would show the desired type of activity, its activity might be of low potential and/or it can possess undesirable effects.…”

Design, synthesis, and study of novel phenethyl-based antitumor phospholipids downregulating p38 mitogen-activated protein kinase

“…In silico studies were conducted following literature protocols 32–36 as in supplementary information .…”

Escaping ESKAPE resistance: in vitro and in silico studies of multifunctional carbamimidoyl-tethered indoles against antibiotic-resistant bacteria

“…Repurposing (aka repositioning or reprofiling) is a well-acknowledged strategy in drug discovery that offers several advantages including saving time, money and resources that are needed to develop novel drugs from scratch [47][48][49][50][51][52]. This strategy is not limited to repurposing compounds for indications outside of clinically approved therapeutic areas, but extends also to previously studied molecules that have not been approved or even previously failed [19,53].…”