1. Amino acid conjugated antimicrobial drugs: Synthesis, lipophilicity- activity relationship, antibacterial and urease inhibition activity.
- Author
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Ullah A, Iftikhar F, Arfan M, Batool Kazmi ST, Anjum MN, Haq IU, Ayaz M, Farooq S, and Rashid U
- Subjects
- Amino Acids chemistry, Anti-Bacterial Agents chemical synthesis, Anti-Bacterial Agents chemistry, Bacillus drug effects, Bacillus enzymology, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Escherichia coli drug effects, Hydrophobic and Hydrophilic Interactions, Isoniazid chemical synthesis, Isoniazid chemistry, Metronidazole chemical synthesis, Metronidazole chemistry, Microbial Sensitivity Tests, Molecular Structure, Pseudomonas aeruginosa drug effects, Salmonella typhi drug effects, Staphylococcus aureus drug effects, Structure-Activity Relationship, Trimethoprim chemical synthesis, Trimethoprim chemistry, Urease antagonists & inhibitors, Urease metabolism, Amino Acids pharmacology, Anti-Bacterial Agents pharmacology, Enzyme Inhibitors pharmacology, Isoniazid pharmacology, Metronidazole pharmacology, Trimethoprim pharmacology
- Abstract
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 IC
50 = 6.23 ± 0.09 μM. Docking studies on the crystal structure of B. pasteurii urease (PDB ID 4UBP) were carried out., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)- Published
- 2018
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