Amino acid conjugated antimicrobial drugs: Synthesis, lipophilicity- activity relationship, antibacterial and urease inhibition activity

Amino acid conjugated antimicrobial drugs: Synthesis, lipophilicity- activity relationship,... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Medicinal Chemistry Elsevier

Amino acid conjugated antimicrobial drugs: Synthesis, lipophilicity- activity relationship, antibacterial and urease inhibition activity

Amino acid conjugated antimicrobial drugs: Synthesis, lipophilicity- activity relationship, antibacterial and urease inhibition activity

European Journal of Medicinal Chemistry 145 (2018) 140e153 Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech Research paper Amino acid conjugated antimicrobial drugs: Synthesis, lipophilicity- activity relationship, antibacterial and urease inhibition activity a a b c Atta Ullah , Fatima Iftikhar , Muhammad Arfan , Syeda Tayyaba Batool Kazmi , d c a a Muhammad Naveed Anjum , Ihsan-ul Haq , Muhammad Ayaz , Sadia Farooq , a, e, * Umer Rashid Department of Chemistry, Hazara University, Mansehra 21120, Pakistan Department of Chemistry, School of Natural Sciences (SNS), National University of Sciences and Technology (NUST), H-12, Islamabad 44000, Pakistan Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan Department of Applied Chemistry, Government College University Faisalabad, 38000, Pakistan Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan article i nf o abstract Article history: Present work describes the in vitro antibacterial evaluation of some new amino acid conjugated anti- Received 7 September 2017 microbial drugs. Structural modification was attempted on the three existing antimicrobial pharma- Received in revised form ceuticals namely trimethoprim, metronidazole, isoniazid. Twenty one compounds from seven series of 14 December 2017 conjugates of these drugs were synthesized by coupling with some selected Boc-protected amino acids. Accepted 27 December 2017 The effect of structural features and lipophilicity on the antibacterial activity was investigated. The Available online 29 December 2017 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 Keywords: strains of bacteria. Our results identified a close...
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Publisher
Elsevier
Copyright
Copyright © 2017 Elsevier Masson SAS
ISSN
0223-5234
eISSN
1768-3254
D.O.I.
10.1016/j.ejmech.2017.12.089
Publisher site
See Article on Publisher Site

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 IC50 = 6.23 ± 0.09 μM. Docking studies on the crystal structure of B. pasteurii urease (PDB ID 4UBP) were carried out.

Journal

European Journal of Medicinal ChemistryElsevier

Published: Feb 10, 2018

References

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