4‐Substituted‐1‐phenyl‐1H‐pyrazolo[3,4‐d]pyrimidine Derivatives: Design, Synthesis, Antitumor and EGFR Tyrosine Kinase Inhibitory Activity

Abstract

Four series of some 4-substituted-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine derivatives 5a-f, 6a-f, 8a-f, and 9a-f were designed to be screened for their antitumor activity. All compounds were evaluated against breast (MCF-7) and lung (A-549) cell lines. Six compounds 5a, 5b, 6b, 6e, 9e, and 9f displaying activity against both cell lines were further estimated for their EGFR-TK inhibitory activity where they revealed 41-91% inhibition and compound 6b elicited the highest activity (91%). A docking study of these compounds into the ATP-binding site of EGFR-TK demonstrated their binding mode where H-bonding interaction with Met793 through N(1) of pyrimidine or N(2) of pyrazole was observed.

A Review on Fused Pyrimidine Systems as EGFR Inhibitors and Their Structure–Activity Relationship

“…The co-crystallized ligand was able to form a hydrogen bond with the MET793 residue, whereas the pyrimidinone 203–206 was binding not only to MET793 but also to the LYS745 residue. These resulted in stronger binding between the molecules and the protein, exhibiting higher EGFR inhibitory potential ( Abbas et al, 2015 ).…”

“… 2) At N 3 : the presence of the carbohydrazide group results in decreased EGFR inhibitory activity but improves selectivity in binding to EGFR ( Horchani et al, 2021 ). 3) At R 1 : the presence of a phenyl group showed good inhibitory properties ( Abbas et al, 2015 ; Gaber et al, 2018 ). Replacing with the dialkylamino group exhibited reduced activity ( Kim et al, 2003 ), whereas replacing with the thio group resulted in a significant loss of activity ( Schenone et al, 2004b ).…”

“…Replacing with the dialkylamino group exhibited reduced activity ( Kim et al, 2003 ), whereas replacing with the thio group resulted in a significant loss of activity ( Schenone et al, 2004b ). 4) At R 2 : the linker can be either S or N; this resulted in compounds with good inhibitory activity ( Abbas et al, 2015 ). The presence of the NH 2 group makes the compound active toward the double mutant EGFR ( Engel et al, 2017 ).…”

“…The N -phenyl compounds were also active ( Traxler et al, 1997 ; Kim et al, 2003 ; Maher et al, 2019 ). Replacing phenyl with piperidine or imidazole increased the potency ( Abbas et al, 2015 ). The presence of acetohydride linkage results in the enhanced binding of the compounds to EGFR ( Abdelgawad et al, 2016 ), whereas the hydrazine reduces the selectivity of the compound to EGFR ( Gaber et al, 2018 ).…”

Exploration of the Chemistry and Biological Properties of Pyrimidine as a Privilege Pharmacophore in Therapeutics

“…Antitumor activity: Pyrrolo[2,3-d]pyrimidines with folate receptor was identified by Wang et al (2015) as potential antitumor compound. Abbas et al (2015) reported 4-(4-fluorophenyl)-6-oxo-2- [(1-Int. J. Biol.…”