Isatin-pyrimidine hybrid derivatives as enoyl acyl carrier protein reductase (InhA) inhibitors against Mycobacterium tuberculosis

Abdalrahman Khalifa; Amira Khalil; Marwa M Abdel-Aziz; Amgad Albohy; Samy Mohamady

doi:10.1016/j.bioorg.2023.106591

Isatin-pyrimidine hybrid derivatives as enoyl acyl carrier protein reductase (InhA) inhibitors against Mycobacterium tuberculosis

Bioorg Chem. 2023 Sep:138:106591. doi: 10.1016/j.bioorg.2023.106591. Epub 2023 May 6.

Authors

Abdalrahman Khalifa¹, Amira Khalil², Marwa M Abdel-Aziz³, Amgad Albohy⁴, Samy Mohamady⁵

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt; Department of Chemistry, Prairie View A&M University, Prairie View, TX 77446, USA.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt.
³ The Regional Center for Mycology & Biotechnology, Al-Azhar University, Cairo, Egypt.
⁴ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt. Electronic address: amgad.albohy@bue.edu.eg.
⁵ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt. Electronic address: samy.mohamady@bue.edu.eg.

PMID: 37201321
DOI: 10.1016/j.bioorg.2023.106591

Abstract

Tuberculosis is a worldwide problem that impose a burden on the economy due to continuous development of resistant strains. The development of new antitubercular drugs is a need and can be achieved through inhibition of druggable targets. Mycobacterium tuberculosis enoyl acyl carrier protein (ACP) reductase (InhA) is an important enzyme for Mycobacterium tuberculosis survival. In this study, we report the synthesis of isatin derivatives that could treat TB through inhibition of this enzyme. Compound 4l showed IC₅₀ value (0.6 ± 0.94 µM) similar to isoniazid but is also effective against MDR and XDR Mycobacterium tuberculosis strains (MIC of 0.48 and 3.9 µg/mL, respectively). Molecular docking studies suggest that this compound binds through the use of relatively unexplored hydrophobic pocket in the active site. Molecular dynamics was used to investigate and support the stability of 4l complex with the target enzyme. This study paves the way for the design and synthesis of novel antitubercular drugs.

Keywords: Enoyl acyl carrier protein (ACP) reductase; InhA inhibitors; Isatin; Molecular docking; Molecular dynamics; Molecular hybridization; Mycobacterium tuberculosis; Pyrimidine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acyl Carrier Protein / pharmacology
Antitubercular Agents / chemistry
Bacterial Proteins / metabolism
Isatin* / pharmacology
Microbial Sensitivity Tests
Molecular Docking Simulation
Mycobacterium tuberculosis*
Oxidoreductases / metabolism
Pyrimidines / pharmacology

Substances

Acyl Carrier Protein
Isatin
Oxidoreductases
Antitubercular Agents
Pyrimidines
Bacterial Proteins