Novel Penicillin Derivatives Against Selected Multiple-Drug Resistant Bacterial Strains: Design, Synthesis, Structural Analysis, in silico and in Vitro Studies

Narmin Hamaamin Hussen; Shokhan Jamal Hamid; Mohammed Nawzad Sabir; Aso Hameed Hasan; Sewara Jalal Mohammed; Araz A K Shali

doi:10.2174/1570179420666230510104319

Novel Penicillin Derivatives Against Selected Multiple-Drug Resistant Bacterial Strains: Design, Synthesis, Structural Analysis, in silico and in Vitro Studies

Curr Org Synth. 2023 May 10. doi: 10.2174/1570179420666230510104319. Online ahead of print.

Authors

Narmin Hamaamin Hussen¹, Shokhan Jamal Hamid², Mohammed Nawzad Sabir¹, Aso Hameed Hasan³, Sewara Jalal Mohammed⁴, Araz A K Shali⁵

Affiliations

¹ Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, University of Sulaimani, Sulaimani 46001, Kurdistan Region-Iraq, Iraq.
² Department of Chemistry, College of Science, University of Garmian, Kalar 46021, Kurdistan Region-Iraq, Iraq.
³ University of Garmian Chemistry Kalar Iraq.
⁴ Department of Chemistry, College of Science, University of Sulaimani, Qlyasan Street, Sulaimani 46001, Kurdistan Regional-Iraq, Iraq.
⁵ Department of Biology, College of Science, University of Sulaimani, Qlyasan Street, Sulaimani 46001, Kurdistan Regional-Iraq, Iraq.

PMID: 37218207
DOI: 10.2174/1570179420666230510104319

Abstract

Introduction: The rising numbers of multiple drug-resistant (MDR) pathogens and the consequent antibacterial therapy failure that resulted in severe medical conditions push to illustrate new molecules with extended activity against the resistant strains. In this manner, chemical derivatization of known antibiotics is proposed to save efforts in drug discovery, and penicillins serve as an ideal in this regard.

Method: Seven synthesized 6-aminopenicillanic acid-imine derivatives (2a-g) were structure elucidated using FT-IR, 1H NMR, 13C NMR, and MS spectroscopy. In silico molecular docking and ADMET studies were made. The analyzed compounds obeyed Lipinski's rule of five and showed promising in vitro bactericidal potential when assayed against E. coli, E. cloacae, P. aeruginosa, S. aureus, and A. baumannii. MDR strains using disc diffusion and microplate dilution techniques.

Result: The MIC values were 8 to 32 µg/mL with more potency than ampicillin, explained by better membrane penetration and more ligand-protein binding capacity. The 2g entity was active against E. coli. This study was designed to find new active penicillin derivatives against MDR pathogens.

Conclusion: The products showed antibacterial activity against selected MDR species and good PHK, PHD properties, and low predicted toxicity, offering them as future candidates that require further preclinical assays.

Keywords: ADMET.; Penicillins; antibacterial assay; chemical derivatization; computational modelling; imine.