Promising Lead Compounds in the Development of Potential Clinical Drug Candidate for Drug-Resistant Tuberculosis

Abstract

According to WHO report, globally about 10 million active tuberculosis cases, resulting in about 1.6 million deaths, further aggravated by drug-resistant tuberculosis and/or comorbidities with HIV and diabetes are present. Incomplete therapeutic regimen, meager dosing, and the capability of the latent and/or active state tubercular bacilli to abide and do survive against contemporary first-line and second line antitubercular drugs escalate the prevalence of drug-resistant tuberculosis. As a better understanding of tuberculosis, microanatomy has discovered an extended range of new promising antitubercular targets and diagnostic biomarkers. However, there are still no new approved antitubercular drugs of routine therapy for several decades, except for bedaquiline, delamanid, and pretomanid approved tentatively. Despite this, innovative methods are also urgently needed to find potential new antitubercular drug candidates, which potentially decimate both latent state and active state mycobacterium tuberculosis. To explore and identify the most potential antitubercular drug candidate among various reported compounds, we focused to highlight the promising lead derivatives of isoniazid, coumarin, griselimycin, and the antimicrobial peptides. The aim of the present review is to fascinate significant lead compounds in the development of potential clinical drug candidates that might be more precise and effective against drug-resistant tuberculosis, the world research looking for a long time.

Extending the Library of 4‐Hydroxycoumarin Derivatives with Potential Pharmacological Activity by a Catalyst‐Free and Purification‐Free Method

“…Although multiple sites can be targeted to functionalize 4hydroxycoumarin, position 3-substituted derivatives are subject of interest for pharmacological use. [14][15][16] The nucleophilic carbon in position 3 leads to the creation of a new carboncarbon bond, which is one of the main pillars of organic synthesis. Several synthetic techniques are employed to make a new carbon-carbon bond, however, the multicomponent reactions such as Mannich reaction is considered one of the most important high-atom economic carbon-carbon bond forming strategy to produce β-amino carbonyl compounds referred to as the Mannich base.…”

Advances in computational frameworks in the fight against TB: The way forward

“…Several compounds have been identified during the last few years with potential anti-tubular properties and are currently undergoing preclinical and clinical studies like, bedaquiline ( Antoci et al, 2021 ; Chakraborti et al, 2021 ; Patil & Jain, 2021 ; Deshkar & Shirure, 2022 ), PA-824 ( Lenaerts et al, 2005 ; Edwards & Field, 2022 ; Xu et al, 2022 ; Yan et al, 2022 ), and delamanid ( Skripconoka et al, 2013 ; Liu et al, 2018 ; Nasiri et al, 2022 ). Existing drugs have also been modified to repurpose them against TB and they include -riminophenazines ( Valinetz et al, 2020 ; Brunaugh et al, 2022 ), b-lactams ( Moon et al, 2018 ; Story-Roller & Lamichhane, 2018 ; Ur Rahman et al, 2018 ), and oxazolidinones ( Balasubramanian et al, 2014 ; Alghamdi et al, 2020 ; Margaryan et al, 2022 ; Ndukwe et al, 2022 ). These are examples of how in silico approaches have been successfully employed in retrieving promising lead compounds in preclinical and clinical studies.…”

Coumarin Hydrazone Oxime Scaffolds as Potent Anti‐tubercular Agents: Synthesis, X‐ray crystal and Molecular Docking Studies

“…Reports have even proved that coumarin class of compounds interfere with the fatty‐acyl‐acyl carrier protein synthase (ACP) activity of the FadD32 enzyme, which is critical to Mycobacterium tuberculosis survival [23] . Coumarin derivatives are known to exhibit antitubercular properties by disrupting cytochrome synthesis, suppressing cell proliferation, activating macrophage, and inhibiting kinase activity [24,25] . Mangasuli et al., demonstrated that coumarin‐based compounds possessed strong binding affinity with MTB 4DQU enzymes [26] .…”

“…[23] Coumarin derivatives are known to exhibit antitubercular properties by disrupting cytochrome synthesis, suppressing cell proliferation, activating macrophage, and inhibiting kinase activity. [24,25] Mangasuli et al, demonstrated that coumarin-based compounds possessed strong binding affinity with MTB 4DQU enzymes. [26] These data clearly suggests that modification to the coumarin skeleton may lead to new anti-TB medicines with enhanced features, such as increased efficacy against both drug-resistant and drug-susceptible strains, lower toxicity, shorter therapy duration, and mycobactericidal capabilities.…”