Novel heterocyclic hybrids of pyrazole targeting dihydrofolate reductase: design, biological evaluation and insilico studies. (1st January 2020)

• Record Type: Journal Article
• Authors: Othman, Ismail M. M.; Gad-Elkareem, Mohamed A. M.; Amr, Abd El-Galil E.; Al-Omar, Mohamed A.; Nossier, Eman S.; Elsayed, Elsayed A.
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 35:Number 1(2020)
• Page Start: 1491
• Page End: 1502
• Publication Date: 2020-01-01
• Subjects: Pyrazole -- antimicrobial -- in silico studies -- dihydrofolate reductase -- molecular docking; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2020.1791842
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: A novel series of pyrazole analogues including hydrazones, pyrazolo[4, 3- c ]-pyridazines, pyrazolo[3, 4- e ][1, 2, 4]triazine and pyrazolo[3, 4- d ][1, 2, 3]triazoles was designed, synthesised and screened for their in vitro antimicrobial and DHFR inhibition activity. Compounds bearing benzenesulphonamide moiety incorporated with 3-methyl-5-oxo-1 H -pyrazol-4(5 H )-ylidene) hydrazine 3a or 6-amino-7-cyano-3-methyl-5 H -pyrazolo[4, 3- c ]pyridazine 6a revealed excellent and broad spectrum antimicrobial activity comparable to ciprofloxacin and amphotericin B as positive antibiotic and antifungal controls, respectively. Furthermore, these derivatives proved to be the most active DHFR inhibitors with IC50 values 0.11 ± 1.05 and 0.09 ± 0.91 µM, in comparison with methotrexate (IC50 = 0.14 ± 1.25 µM). The in silico studies were done to calculate the drug-likeness and toxicity risk parameters of the newly synthesised derivatives. Additionally, the high potency of the pyrazole derivatives bearing sulphonamide against DHFR was confirmed with molecular docking and might be used as an optimum lead for further modification.