Design, synthesis, antibacterial activity and docking study of some new trimethoprim derivatives.
In present study, nineteen novel trimethoprim (TMP) derivatives were designed, synthesized and evaluated for their antibacterial potential. Hydroxy trimethoprim 2 (HTMP) was synthesized by following the demethylation of 4-methoxy group at trimethoxy benzyl ring of TMP. Structure-activity relationship (SAR) studies were explored on HTMP by incorporating various substituents leading to the identification of some new compounds with improved antibacterial activities. The results revealed that the introduction of benzyloxy (4a-e) and phenyl ethanone (5a-e) group at 4-position of dimethoxy benzyl ring leads to overall increase in the antibacterial activity. The most potent antibacterial compound discovered is benzyloxy derivative 4b with MIC value of 5.0μM against Staphylococcus aureus and 4.0μM against Escherichia coli strains higher than the standard TMP (22.7μM against S. aureus and 55.1μM against E. coli). Substitution at 4-NH2group was not tolerated and the resulting Schiff base derivatives 3a-h demonstrated very little or no antibacterial activity in the tested concentration domain. We further performed exploratory docking studies on dihydrofolate reductase (DHFR) to rationalize the in vitro biological data and to demonstrate the mechanism of antibacterial activity. For the ability to cross lipophilic outer membrane, logP was computed. It was found that the compounds possessing high hydrophobicity have high activity against E. coli.
Department of Chemistry, Hazara University, Mansehra 21120, Pakistan; Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan. Electronic address: umerrashid@ciit.net.pk.
Umer
U
Rashid
Department of Chemistry, Hazara University, Mansehra 21120, Pakistan.
Waqas
W
Ahmad
Department of Pharmacy, The University of Lahore, Defense Road Campus, Lahore 53700, Pakistan.
Syed Fahad
SF
Hassan
Department of Animal Sciences, Quaid-i-Azam University, 45320 Islamabad, Pakistan.
Naveeda Akhtar
NA
Qureshi
Department of Chemistry, Hazara University, Mansehra 21120, Pakistan.
Basit
B
Niaz
Department of Chemistry, Hazara University, Mansehra 21120, Pakistan.
Bakhtiar
B
Muhammad
Department of Biochemistry, Hazara University, Mansehra 21120, Pakistan.
Sameera
S
Imdad
Department of Biochemistry, Hazara University, Mansehra 21120, Pakistan.
Muhammad
M
Sajid
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology; D004927:Escherichia coli Infections / Q000188:drug therapy; D006801:Humans; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D014295:Trimethoprim / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D014295:Trimethoprim; D013762:Tetrahydrofolate Dehydrogenase
Antibacterial; Dihydrofolate reductase; Docking; Hydrophobicity; Trimethoprim