Design, Synthesis, and Biological Evaluation of Benzimidazole Derivatives as Potential Lassa Virus Inhibitors

Abstract

The Lassa virus (LASV) causes Lassa fever, a highly infectious and lethal agent of acute viral hemorrhagic fever. At present, there are still no effective treatments available, creating an urgent need to develop novel therapeutics. Some benzimidazole compounds targeting the arenavirus envelope glycoprotein complex (GPC) are promising inhibitors of LASV. In this study, we synthesized two series of LASV inhibitors based on the benzimidazole structure. Lentiviral pseudotypes bearing the LASV GPC were established to identify virus entry inhibitors. Surface plasmon resonance (SPR) was further used to verify the binding activities of the potential compounds. Compounds 7d−Z, 7h−Z, 13c, 13d, and 13f showed relatively excellent antiviral activities with IC50 values ranging from 7.58 to 15.46 nM and their SI values above 1251. These five representative compounds exhibited stronger binding affinity with low equilibrium dissociation constants (KD < 8.25 × 10−7 M) in SPR study. The compound 7h−Z displayed the most potent antiviral activity (IC50 = 7.58 nM) with a relatively high SI value (2496), which could be further studied as a lead compound. The structure–activity relationship indicated that the compounds with lipophilic and spatially larger substituents might possess higher antiviral activity and a much larger safety margin. This study will provide some good guidance for the development of highly active compounds with a novel skeleton against LASV.

Entry inhibitors as arenavirus antivirals

“…Further compounds having a benzimidazole core were synthesized using ST-193 and LHF-535 as the lead structures. Five compounds (7d − Z, 7h − Z, 13c, 13d, and 13f) restricted pseudotyped LASV entry comparable to the parent compound LHF-535 and showed low cytotoxicity ( Chen et al, 2023 ). The entire ST-193 class of inhibitors seems to antagonize the pH-dependent fusion required for viral entry by binding to and stabilizing the prefusion structure of the GP2-SSP complex ( Nunberg and York, 2012 ; Shankar et al, 2016 ).…”

Poultry Meat Quality Preservation By Plant Extracts: An Overview

“…In fact, more than 6000 different flavonoids have been identified in plants so far (Hichri et al, 2011). They are abundant in green plants, and are present mainly as glycosides in leaves, flowers, stems and roots (Chen et al, 2023). Flavonoids' antioxidant capacities are modulated by the location of the catechol B-ring on the pyran C-ring, along with the quantity and arrangement of hydroxylic groups present on the catechol group within the B-ring (Dias et al, 2021).…”

Design, synthesis, molecular docking and molecular dynamic studies of novel benzimidazole–thiazole derivatives as potent and selective COX-2 inhibitors

“…Benzimidazole derivatives have become increasingly important in the past few years due to their diverse range of biological activities. These derivatives have been found to possess many beneficial properties, including anticancer, 19 anti-inflammatory, [20][21][22][23] analgesic, 24 antimicrobial, 25,26 antihelminthic, 27 antiprotozoal, 28 antiviral, 29,30 antifungal, 31 antioxidant, 32,33 antidiabetic, 34 antihistaminic, 35 antitubercular, 36 acetylcholinesterase inhibitor (anti-Alzheimer), 37,38 anti-HIV (Human Immunodefficiency Virus), 39 and anti-hypertensive properties. 40 They have shown promising results in the treatment of various diseases.…”