Novel heterocyclic hybrids of pyrazole targeting dihydrofolate reductase: design, biological evaluation andinsilicostudies

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 theirin vitroantimicrobial and DHFR inhibition activity. Compounds bearing benzenesulphonamide moiety incorporated with 3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene) hydrazine3aor 6-amino-7-cyano-3-methyl-5H-pyrazolo[4,3-c]pyridazine6arevealed 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 IC(50)values 0.11 +/- 1.05 and 0.09 +/- 0.91 mu M, in comparison with methotrexate (IC50= 0.14 +/- 1.25 mu M). Thein silicostudies 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.