Targeting Mycobacterium tuberculosis: synthesis, in vitro and in silico evaluation of novel N1-(benzo[d]oxazol-2-yl)-N4-arylidine compounds

Zawal, Amira G., Abdel-Aziz, Marwa M., El?Shanawani, Abdalla A., Abdel-Aziz, Lobna M., Taha, Mohamed, Simons, Claire ORCID: https://orcid.org/0000-0002-9487-1100 and Elbaramawi, Samar S. 2023. Targeting Mycobacterium tuberculosis: synthesis, in vitro and in silico evaluation of novel N1-(benzo[d]oxazol-2-yl)-N4-arylidine compounds. Archiv der Pharmazie 356 (8) , 2300187. 10.1002/ardp.202300187

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Abstract

The development of novel antimycobacterial agents is an urgent challenge to eradicate the increasing emergence and rapid spread of multidrug-resistant strains. Filamentous temperature-sensitive protein Z (FtsZ) is a crucial cell division protein. Alteration of FtsZ assembly leads to cell division inhibition and cell death. To find novel antimycobacterial agents, a series of N1-(benzo[d]oxazol-2-yl)-N4-arylidine compounds 5a–o were synthesized. The activity of the compounds was evaluated against drug-sensitive, multidrug-resistant, and extensive-drug-resistant Mycobacterium tuberculosis. Compounds 5b, 5c, 5l, 5m, and 5o showed promising antimycobacterial activity with minimum inhibitory concentrations (MIC) in the range of 0.48–1.85 µg/mL and with low cytotoxicity against human nontumorigenic lung fibroblast WI-38 cells. The activity of the compounds 5b, 5c, 5l, 5m, and 5o was evaluated against bronchitis causing-bacteria. They exhibited good activity against Streptococcus pneumoniae, Klebsiella pneumoniae, Mycoplasma pneumonia, and Bordetella pertussis. Molecular dynamics simulations of Mtb FtsZ protein-ligand complexes identified the interdomain site as the binding site and key interactions. ADME prediction indicated that the synthesized compounds have drug-likeness. The density function theory studies of 5c, 5l, and 5n were performed to investigate E/Z isomerization. Compounds 5c and 5l are present as E-isomers and 5n as an E/Z mixture. Our experimental outcomes provide an auspicious lead for the design of more selective and potent antimycobacterial drugs.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) Pharmacy
Publisher:	Wiley-VCH Verlag
ISSN:	0365-6233
Date of First Compliant Deposit:	20 June 2023
Date of Acceptance:	15 May 2023
Last Modified:	12 Jul 2024 16:01
URI:	https://orca.cardiff.ac.uk/id/eprint/160474

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