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CC BY 4.0 · SynOpen 2025; 09(01): 73-83
DOI: 10.1055/s-0043-1775424
paper

Synthesis, In Vitro and In Silico Molecular Docking Studies of Novel Phthalimide–Pyrimidine Hybrid Analogues to Thalidomide as Potent Antitubercular Agents

Wael Shehta
a   Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, 44519, Egypt
,
Norah A. Alsaiari
b   Department of Chemistry, Faculty of Science and Arts at Sharurah, Najran University, Najran 11001, Saudi Arabia
,
Basant Farag
a   Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, 44519, Egypt
,
Marwa M. Abdel-Aziz
c   Medical Microbiology at the Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt
,
Shaker Youssif  ∗
a   Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, 44519, Egypt
,
Sherin M Elfeky
d   Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 355516, Egypt
,
Samar El-Kalyoubi
e   Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Port Said University, Port Said, 42511, Egypt
,
Nermine A. Osman
f   Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44511, Egypt
› Author AffiliationsThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Abstract

Condensation reaction of aromatic aldehydes with 2-(6-amino-2-chloropyrimidin-4-yl)isoindoline-1,3-dione and 2-(6-amino-2-hydrazineylpyrimidin-4-yl)isoindoline-1,3-dione afforded 2-(2-chloro-6-((3 alkylbenzylidene)amino) pyrimidin-4-yl)isoindoline-1,3-dione derivatives 6a–f and 2-(6-amino-2-(2-(arylidene)hydrazinyl)pyrimidin-4-yl)isoindoline-1,3-dione derivatives 8a–f, respectively, as phthalimide–aminopyrimidine hybrids. The compounds showed a wide range of antitubercular activities against sensitive MDR and XDR M. tuberculosis strains, with 8f and 6a showing the highest activity; these compounds inhibited sensitive M. tuberculosis with MIC of 0.48 and 0.98 μg/mL, respectively, comparable to isonizide (INH) (MIC = 0.12 μg/mL). Both 8f and 6a inhibited the MDR strain with MIC of 1.95 and 7.81 μg/mL, respectively, and XRD with MIC of 7.81 and 15.63 μg/mL, respectively. Both 8f and 6a inhibited mycobacterial InhA enzyme in vitro (IC50 = 0.717± 0.033 μM and 1.646± 0.069 μM, respectively). Molecular docking simulations revealed that 8f and 6a were also capable of interacting at the catalytic site of the InhA enzyme via binding with NAD+ and Tyr158, in a manner similar to that of the native ligand. Compounds 6a and 8f exhibited physicochemical properties of oral bioavailable drug-like compounds with high gastrointestinal absorption. Predictions showed that the compounds are unlikely to have side effects on the CNS and no anticipated hepatotoxicity, mutagenicity, or acute oral toxicity was identified in models.

Key words

Mycobacterium tuberculosis - ADMET studies - docking simulation - enzyme inhibition - phthalimide–pyrimidine hybrids

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0043-1775424.
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Publication History

Received: 09 September 2024

Accepted after revision: 18 October 2024

Article published online:
10 February 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by/4.0/)

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