Novel antitubercular agents based on 2,4-disubstituted 5-(aryl-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidines

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health challenge, especially with the rise of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. Current treatment regimens are prolonged and associated with significant toxicity, underscoring the need for novel therapeutic agents. This study investigates a new series of 2,4-disubstituted 5-(aryl-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidine derivatives as potential antitubercular agents. The most promising compound, 74, exhibited potent anti-TB activity, including against MDR strains, with a MIC<sub>99</sub> of 2 µM. Structure-activity relationship studies identified critical substitutions at positions 2- and 4- of the core scaffold that enhanced antimycobacterial potency, while bulkier aromatic moieties at position 5- were preferred. Despite its high efficacy, 74 demonstrated significant cytotoxicity, inhibition of cytochrome P450 enzymes and cardiotoxicity through hERG channel inhibition, highlighting challenges in further development. Pharmacokinetic studies of 74 revealed favorable systemic exposure with a prolonged half-life, suggesting its potential for less frequent dosing. Nonetheless, in vitro assays demonstrated rapid metabolic turnover, likely due to high intrinsic clearance, and the compound's elevated logD values further indicate the need for structural modifications to improve both solubility and metabolic stability. Efforts to introduce more polar substituents at the 4-position led to a loss of anti-TB activity, emphasizing the complexity of balancing potency and safety.

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Publication Details

Journal
Biomedicine & Pharmacotherapy
Published
2025-09-13
DOI
https://doi.org/10.1016/j.biopha.2025.118537
Citations
1
Primary Topic
Synthesis and Reactivity of Heterocycles
Type
article
Field-Weighted Citation Impact
0.94
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article

Novel antitubercular agents based on 2,4-disubstituted 5-(aryl-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidines

Ondřej Soukup, Aleš Šorf, Ľubica Múčková, Katarzyna Ewa Greber et al.
1 citations
Biomedicine & Pharmacotherapy
Synthesis and Reactivity of Heterocycles
0.94
article

Novel antitubercular agents based on 2,4-disubstituted 5-(aryl-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidines

Ondřej Soukup, Aleš Šorf, Ľubica Múčková, Katarzyna Ewa Greber, Tomáš Rozsypal, Jiří Janoušek, Pavel Boštík, Lukáš Prchal, Krzesimir Ciura, Jan Marek, Martin Hrubý, Jana Žďárová Karasová, Jaroslav Roh, Markéta Benková, Jan Bartáček, Martin Kufa, Martin Vrbický, Radek Sleha, Pavel Drabina, Martin Krátký, Lenka Fikejzlová, Michaela Hympánová, Jan Korábečný, Vladimír Finger, Jitka Odvarkova, Martin Novák, Ondrej Kovar, Oksana Ozhelevska, Ivone C. Igreja, Iveta Kaderavková, Johannes Jagob
article en
1 citations

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health challenge, especially with the rise of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. Current treatment regimens are prolonged and associated with significant toxicity, underscoring the need for novel therapeutic agents. This study investigates a new series of 2,4-disubstituted 5-(aryl-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidine derivatives as potential antitubercular agents. The most promising compound, 74, exhibited potent anti-TB activity, including against MDR strains, with a MIC<sub>99</sub> of 2 µM. Structure-activity relationship studies identified critical substitutions at positions 2- and 4- of the core scaffold that enhanced antimycobacterial potency, while bulkier aromatic moieties at position 5- were preferred. Despite its high efficacy, 74 demonstrated significant cytotoxicity, inhibition of cytochrome P450 enzymes and cardiotoxicity through hERG channel inhibition, highlighting challenges in further development. Pharmacokinetic studies of 74 revealed favorable systemic exposure with a prolonged half-life, suggesting its potential for less frequent dosing. Nonetheless, in vitro assays demonstrated rapid metabolic turnover, likely due to high intrinsic clearance, and the compound's elevated logD values further indicate the need for structural modifications to improve both solubility and metabolic stability. Efforts to introduce more polar substituents at the 4-position led to a loss of anti-TB activity, emphasizing the complexity of balancing potency and safety.

Biomedicine & PharmacotherapyVol. 191
University of Pardubice (CZ), University of Gdańsk (PL), Czech Academy of Sciences, Institute of Macromolecular Chemistry (CZ), University Hospital Hradec Králové (CZ), University of Defence (RS), University of Hradec Králové (CZ), Gdańsk Medical University (PL), University of Defence (CZ)
Openalex Percentile: Top 22%
Synthesis and Reactivity of Heterocycles
0.94
DOIOpen Access PDFOpenAlex
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