Browsing by Author "Nurasyikin Hamzah"

Dihydrofolate reductase (DHFR) is a key enzyme required for bacterial growth because it reduces 7,8-dihydrofolate (DHF) to 5,6,7,8-tetrahydrofolate (THF), an essential compound for DNA synthesis and cell survival. Since DHFR plays a critical role in bacterial survival, it has become an important target for developing drugs to treat infections. With Escherichia coli (E. coli) infections on the rise, there is an urgent need to develop novel antibacterial agents specifically targeting E. coli DHFR to combat this growing threat. In response to this challenge, four new SBDTC derivatives and their sixteen corresponding metal complexes were designed, synthesised, and thoroughly characterised, followed by in vitro and in silico studies. Structural analysis revealed that SB2OME, SB3OME, and SB3NO were formed through substitution at the β-nitrogen of SBDTC, while SB4OME resulted from substitution at the α-nitrogen. Upon complexation, SB2OME, SB3OME, and SB4OME functioned as tridentate ligands via NOS donor atoms, while SB3NO acted as a bidentate ligand through OS donor atoms. ADMET predictions indicated that the SBDTC derivatives adhered to drug-likeness criteria while the metal complexes exhibited some violations. Nonetheless, all compounds were predicted to have low toxicity profiles. Subsequently, antibacterial activity evaluated using minimum inhibitory concentration (MIC) assays, revealed notable efficacy against both gram-positive and gram-negative bacteria. Most metal complexes significantly enhanced the antibacterial activity of their SBDTC derivatives alone. Cu(II), Zn(II), Co(II), and Ni(II) complexes derived from SB4OME reduced the MIC of SB4OME against E. coli (ATCC 25922) by half (MIC = 0.437 mg/mol) outperforming trimethoprim (MIC = 1.750 mg/mol). Molecular docking studies on SB4OME and its metal complexes demonstrated interactions with active site residues of E. coli DHFR (PDB ID: 1RX7), similar to the natural substrate (folic acid) and the commercial antibiotic (trimethoprim), justifying their superior in in-vitro activity. To further validate their efficacy, Molecular dynamicss (MD) simulations were performed on SB4OME and its Cu(II), Co(II), and Ni(II) complexes over a 100 ns timeframe. All systems exhibited stability throughout the simulation, with optimal stability observed from 30 ns onward. Among all these compounds, the DHFR-CUSB4 complex demonstrated the most favourable binding free energy (-36.67 kcal/mol) in MMPBSA calculations, surpassing both folic acid and trimethoprim. Furthermore, several of the investigated compounds, including Cu(SB4OME)₂, demonstrated stable binding at the mutated residues L28R and I94L, highlighting their potential to overcome trimethoprim resistance associated with these clinically relevant DHFR mutations. In conclusion, the exceptional performance of Cu(SB4OME)₂ in both in vitro and in silico studies underscores its potential as a promising antibacterial agent and a targeted inhibitor of E. coli DHFR.

In order to explore the potential of benzimidazole as neuraminidase inhibitors, a series of alkyl benzimidazole carboxylates 5(a-g) and alkyl benzimidazole carboxylic acids 6(a-g) were synthesised by following a four-step strategies involving esterification, nucleophilic aromatic substitution (SNAr), reduction, cyclisation and hydrolysis reactions. The reactions were carried out by both conventional and microwave methods and the modes of heating were compared and studied. Most of the compounds synthesised from the microwave method were found to give better yield in short reaction time although isolated yields were slightly lower compared with conventional method. All isolated compounds obtained were elucidated using 1H NMR, 13C NMR, DEPT-135, HSQC, 19F NMR analysis and ESI-mass spectroscopy. Molecular docking was later performed on both series in order to gain insight of possible binding modes and the preferred orientations/conformations of benzimidazole derivatives complexed in the active site of neuraminidase. Based on docking analysis, 6f was found to interact better in neuraminidase active site compared other compounds due to the presence 3-pentyl at position C2. Only pure compounds of carboxylic acid series 6(a-g) were further evaluated via neuraminidase inhibition assay as they could be dissolved in buffer solution. Although the results showed poor inhibitory activity towards neuraminidase enzyme, it is in good agreement with the docking results where 6f showed good inhibition among tested compounds.