Novel heterocyclic hybrids of pyrazole targeting dihydrofolate reductase: design, biological evaluation and in silico studies

Abstract

A novel series of pyrazole analogues including hydrazones, pyrazolo[4,3-c]-pyridazines, pyrazolo[3,4e][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-1H-pyrazol-4(5H)-ylidene) hydrazine 3a or 6-amino-7-cyano-3-methyl-5H-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 IC 50 values 0.11 ± 1.05 and 0.09 ± 0.91 mM, in comparison with methotrexate (IC 50 ¼ 0.14 ± 1.25 mM). 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.

Biologically Active Quinoline‐Hydrazone Conjugates as Potential Trypanosoma cruzi DHFR‐TS Inhibitors: Docking, Molecular Dynamics, MM/PBSA and Drug‐Likeness Studies

“…Previous in vitro enzymatic studies and computational approaches have demonstrated that molecules containing quinoline or hydrazone moieties could be very promising competitive DHFR‐TS inhibitors against protozoal species such as T. gondii and P. falciparum [26–33,40] . In addition, DHFR and TS constitute a bifunctional common and dimeric enzyme protein found ubiquitously in all dividing cells of eukaryotic organisms.…”

“…Previous in vitro enzymatic studies and computational approaches have demonstrated that molecules containing quinoline or hydrazone moieties could be very promising competitive DHFR-TS inhibitors against protozoal species such as T. gondii and P. falciparum. [26][27][28][29][30][31][32][33]40] In addition, DHFR and TS constitute a bifunctional common and dimeric enzyme protein found ubiquitously in all dividing cells of eukaryotic organisms. Indeed, structural alignment of the crystal structures from DHFR-TS of the protozoal species T. gondii and P. falciparum with the structure of DHFR-TS from trypanosomatidae species showed highly conserved nature around the binding site.…”

“…The development of effective drugs to block these enzymes has attracted the attention of medicinal chemists in combating diseases caused by protozoan parasites. [25] Previous in vitro enzymatic studies and computational approaches have demonstrated that molecules containing either quinoline (GÀ J) [26][27][28][29] or hydrazone (KÀ N) [30][31][32][33] moieties could be very promising competitive DHFR-TS inhibitors against protozoa species ( Figure 2).…”

“…Previous in vitro enzymatic studies and computational approaches have demonstrated that molecules containing either quinoline (G−J ) [26–29] or hydrazone (K−N) [30–33] moieties could be very promising competitive DHFR‐TS inhibitors against protozoa species (Figure 2).…”

Synthesis and biological evaluation of new derivatives of thieno-thiazole and dihydrothiazolo-thiazole scaffolds integrated with a pyrazoline nucleus as anticancer and multi-targeting kinase inhibitors

“…42,43 It is emerged as a useful pharmacophore in the synthesis of potent anticancer drugs. 44,45 Moreover, multiple studies identied various thiazolyl-pyrazole compounds as potential anticancer agents. As an example, Lv and coworkers have reported that the thiazolylpyrazoline derivative I displayed potent cytotoxic activity against breast cancer cell line (MCF-7) with IC 50 of 0.07 mM via EGFR inhibition with IC 50 ; 0.06 mM.…”