Novel Leu-Val Based Dipeptide as Antimicrobial and Antimalarial Agents: Synthesis and Molecular Docking.

James A Ezugwu,David I Ugwu,Ogechi C Ekoh,Uchechukwu C Okoro,Solomon I Attah,China R Bhimapaka,Sunday N Okafor,Mercy A Ezeokonkwo

doi:10.3389/fchem.2020.583926

James A Ezugwu, David I Ugwu + Show 6 more

Open Access

https://doi.org/10.3389/fchem.2020.583926

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Abstract

The increase of antimicrobial resistance (AMR) and antimalarial resistance are complex and severe health issues today, as many microbial strains have become resistant to market drugs. The choice for the synthesis of new dipeptide-carboxamide derivatives is as a result of their wide biological properties such as antimicrobial, anti-inflammatory, and antioxidant activities. The condensation reaction of substituted benzenesulphonamoyl pentanamides with the carboxamide derivatives using peptide coupling reagents gave targeted products (8a-j). The in silico antimalarial and antibacterial studies showed good interactions of the compounds with target protein residues and a higher dock score in comparison with standard drugs. In the in vivo study, compound 8j was the most potent antimalarial agent with 61.90% inhibition comparable with 67% inhibition for Artemisinin. In the in vitro antimicrobial activity, compounds 8a and 8b (MIC 1.2 × 10−3 M and 1.1 × 10−3 M) were most potent against S. aureus; compound 8a, 8b, and 8j with MIC 6.0 × 10−3 M, 5.7 × 10−4 M, and 6.5 × 10−4 M, respectively, were the most active against B. subtilis; compound 8b (MIC 9.5 × 10−4 M) was most active against E.coli while 8a, 8b and 8d were the most active against S. typhi. Compounds 8c and 8h (MIC 1.3 × 10−3 M) each were the most active against C. albicans, while compound 8b (MIC 1.3 × 10−4 M) was most active against A. niger.

Highlights

Infectious diseases and their resistance to many available commercial drugs have remained the most challenging task for human existence
To synthesize the compounds (8a-j) we adopted the use of classical peptide coupling reagent, 1-hydroxybenzotriazole (HOBt) and 1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl) in the amidation of compounds (7ae) with substituted benzenesulfonamides derived from L-leucine
In the 1H-Nuclear magnetic resonance (NMR) spectrum of 8a, the methylene group of leucine displayed a multiplet at δ1.30–1.41 and –methane group of leucine and valine showed multiplet at δ3.95–4.04 due to the interactions with the near amide group protons

Summary

Introduction

Infectious diseases and their resistance to many available commercial drugs have remained the most challenging task for human existence. Carboxamides have been accounted for as antimicrobial and antioxidant (Eze et al, 2019), carbonic anhydrase enzyme inhibitor and antioxidant (Deniz et al, 2019), anticancer (Kumar et al, 2009), anthelmintic (Ugwu et al, 2018a), antitubercular (Ugwu et al, 2014), antitrypanosomal (Ugwu et al, 2018b), and anti-inflammatory and analgesic (Ugwu et al, 2018c) agents. Peptides have been reported as an antimicrobial (Jatinder et al, 2015), carbonic anhydrase I, II, IV, and XII inhibitor (Zehra Küçükbay et al, 2016; Küçükbay et al, 2019), antiplasmodial (Amit et al, 2015; Jatinder et al, 2015), and antihypertensive agent (Kitts and Weiler, 2003). In a continuation of our work, we synthesized novel Leu-Val dipeptide carboxamide scaffolds bearing sulfonamide moieties with potent antimalarial and antimicrobial properties. The quest for leu-val combination skeleton was as a result of antimalarial properties of ala-gly dipeptides (Ugwuja et al, 2019), antimalarial and antioxidant property of val-val dipeptides by Ezugwu et al (2020), and an antimalarial property of quinine derivatives containing some amino acid, dipeptide, or tripeptide (Panda et al, 2013)

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