Amino acid conjugated antimicrobial drugs: Synthesis, lipophilicity- activity relationship, antibacterial and urease inhibition activity.
Present work describes the in vitro antibacterial evaluation of some new amino acid conjugated antimicrobial drugs. Structural modification was attempted on the three existing antimicrobial pharmaceuticals namely trimethoprim, metronidazole, isoniazid. Twenty one compounds from seven series of conjugates of these drugs were synthesized by coupling with some selected Boc-protected amino acids. The effect of structural features and lipophilicity on the antibacterial activity was investigated. The synthesized compounds were evaluated against five standard American type culture collection (ATCC) i.e. Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi strains of bacteria. Our results identified a close relationship between the lipophilicity and the activity. Triazine skeleton proved beneficial for the increase in hydrophobicity and potency. Compounds with greater hydrophobicity have shown excellent activities against Gram-negative strains of bacteria than Gram-positive. 4-amino unsubstituted trimethoprim-triazine derivative 7b have shown superior activity with MIC = 3.4 μM (2 μg/mL) for S. aureus and 1.1 μM (0.66 μg/mL) for E. coli. The synthesized compounds were also evaluated for their urease inhibition study. Microbial urease from Bacillus pasteurii was chosen for this study. Triazine derivative 7a showed excellent inhibition with IC50 = 6.23 ± 0.09 μM. Docking studies on the crystal structure of B. pasteurii urease (PDB ID 4UBP) were carried out.
['Ullah|Atta|A|', 'Iftikhar|Fatima|F|', 'Arfan|Muhammad|M|', 'Batool Kazmi|Syeda Tayyaba|ST|', 'Anjum|Muhammad Naveed|MN|', 'Haq|Ihsan-Ul|IU|', 'Ayaz|Muhammad|M|', 'Farooq|Sadia|S|', 'Rashid|Umer|U|']
D000596:Amino Acids D000900:Anti-Bacterial Agents D001407:Bacillus D004305:Dose-Response Relationship, Drug D004791:Enzyme Inhibitors D004926:Escherichia coli D057927:Hydrophobic and Hydrophilic Interactions D007538:Isoniazid D008795:Metronidazole D008826:Microbial Sensitivity Tests D015394:Molecular Structure D011550:Pseudomonas aeruginosa D012485:Salmonella typhi D013211:Staphylococcus aureus D013329:Structure-Activity Relationship D014295:Trimethoprim D014510:Urease
Amino acid conjugates Structural modification Trimethoprim Metronidazole Isoniazid Lipophilicity-activity relationship