Kinase Inhibitors of Novel Pyridopyrimidinone Candidates: Synthesis and In Vitro Anticancer Properties

Abstract

A new class of pyridopyrimidinone compounds containing different nitrogenous heterocycles were synthesized starting from the key precursor 2-hydrazinyl-5-phenyl-7-(pyridin-3-yl)pyrido[2,3-d]pyrimidin-4(3H)-one via condensation with series of aromatic aldehydes and cyclization using different reagents as ethyl acetoacetate, ethyl cyanoacetate, diethyl malonate, and ammonium isothiocyanate. The bioassay results showed compound 6 to be highly effective towards three human cancer cell lines (HepG2, PC-3, and HCT-116) in vitro with promising activity values (IC50: 0.5 μM) relative to the standard doxorubicin (IC50: 0.6 μM). Kinase inhibitory evaluation of compound 6 displays hopeful inhibitory action against BRAF V600E, EGFR, and PDGFRβ at100 μM. The molecular docking studies supported the initial kinase assay.

Synthesis and Anticancer Perspective of Pyridopyrimidine Scaffold - An Overview

“…Thiazolo [3,2-a] pyrimidine (8a-g) derivatives with arylidene and arylethylidene substitution were synthesized by the reaction of 2-thioxopyridopyrimidine (3) with sodium acetate, chloroacetic acid, appropriate aldehyde, or aromatic ketone in presence of a mixture of an a/acetic anhydride and acetic acid. Additionally, different tricyclic pyridotriazolopyrimidines (9)(10)(11)(12)(13) are obtained with different substitutions on the triazole ring obtained by subjecting hydrazine derivatives (4) into different reaction conditions (Fig. 3).…”

“…IC 50 = 115.38 nM and IC 50 =726.25 nM for 6b and 8d respectively for the direct inhibition of CDK6. Nagy M. Khalifa et al, [2] described "pyrido [2,3d] pyrimidin-4-ones" as inhibitors of various kinases, like., tyrosine kinases, phosphoinositide-3-kinase, and cyclin-dependent kinases 4/6 because of the inhibition of cell growth in different cell lines [11][12][13]. In this study they reported the synthesis of 5-phenyl-7-(pyridin-3yl)-2-thioxo substituted 2,3-dihydropyrido [2,3-d] pyrimidin-4(1H)-one (3) by refluxing sufficient quantities of "6-amino-2,3-dihydro-2thioxopyrimidin-4(1H)-one" (1) and "α, βunsaturated ketone" (2) for about 10h in dry DMF.…”

“…Few derivatives were also prepared by reacting hydrazonoyl chlorides (11a-j) and 2thioxopyridopyrimidine (3) with triethylamine in dioxane media, the reaction is further progressed by S-alkylation resulted in the formation of Salkylated products (12) which further undergoes smiles rearrangement yields an intermediate (13), which upon in-situ consumption by the liberation of H 2 S to produce one of the products which are fused triazole derivatives 15A or 15B. Based on the spectral evaluation of the isolated components (15a-j) it was confirmed that form A was present rather than B (Fig.…”

“…Nicotinonitriles (1)(2)(3)(4)(5), were cyclized by using different reagents results in the formation of bicyclic "pyrido [2,3-d]pyrimidines" (6-10), (11)(12)(13)(14)(15), (16)(17)(18)(19)(20), and (24-27) with different substitution, where most of them were inactive against all 3 tested cell lines, Further, ketone group present at 2nd position is isostatically replaced with thione group in pyrido [2,3d]pyrimidine-2(1H)-ones (24)(25)(26)(27), resulted in two weakly active molecules, namely, 30 (X = Br; R = 3,4-(OCH 2 O)C 6 H 3 ) and 32 (X = OCH 3 ; R=2thienyl). But further improved cytotoxic activity was observed by the thioalkylation of that 2thione group of (28-32) mainly with methyl or ethyl group yields potentially active molecules 33, 34, 36, and 37.…”

“…Further Nitration of compound (8) with nitrating mixture i.e., concentrated sulfuric acid and concentrated nitric acid results in the formation of compound (9), which was modified by reacting it with POCl 3 with absolute ethanol into diethyl derivative (10). This diethyl derivative (10) undergoes cyclization with ethyl imidothiocarbamate under reflux produced compound (13). Compound (13) was also be synthesized by treatment of compound (9) with SOCl 2 followed by the addition of absolute ethanol to give compound (11), which undergoes halogenation with POCl 3 where chlorobenzene as the solvent resulted in the formation of compound (12).…”