Molecular Docking and Biophysical Studies for Antiproliferative Assessment of Synthetic Pyrazolo-Pyrimidinones Tethered with Hydrazide-Hydrazones

Abstract

Chemotherapy represents the most applied approach to cancer treatment. Owing to the frequent onset of chemoresistance and tumor relapses, there is an urgent need to discover novel and more effective anticancer drugs. In the search for therapeutic alternatives to treat the cancer disease, a series of hybrid pyrazolo[3 ,4-d]pyrimidin-4(5H)-ones tethered with hydrazide-hydrazones, 5a–h, was synthesized from condensation reaction of pyrazolopyrimidinone-hydrazide 4 with a series of arylaldehydes in ethanol, in acid catalysis. In vitro assessment of antiproliferative effects against MCF-7 breast cancer cells, unveiled that 5a, 5e, 5g, and 5h were the most effective compounds of the series and exerted their cytotoxic activity through apoptosis induction and G0/G1 phase cell-cycle arrest. To explore their mechanism at a molecular level, 5a, 5e, 5g, and 5h were evaluated for their binding interactions with two well-known anticancer targets, namely the epidermal growth factor receptor (EGFR) and the G-quadruplex DNA structures. Molecular docking simulations highlighted high binding affinity of 5a, 5e, 5g, and 5h towards EGFR. Circular dichroism (CD) experiments suggested 5a as a stabilizer agent of the G-quadruplex from the Kirsten ras (KRAS) oncogene promoter. In the light of these findings, we propose the pyrazolo-pyrimidinone scaffold bearing a hydrazide-hydrazone moiety as a lead skeleton for designing novel anticancer compounds.

Synthesis and In Silico Docking of New Pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine-based Cytotoxic Agents

“…Hereby, literature has shown that six key proteins (MCL-1, CDK6, HER-2/neu, LOX5, USP7 and DHFR) [ 33 ] or (DHFR, VEGFR2, HER-2/neu, hCA-IX, CDK6 and LOX5) [ 32 ] were used in the in silico docking studies of the most potent compounds in order to investigate their predicted anticancer potential. In this study, to develop a new generation of more potent multitargeted anticancer agents and motivated by previous research on that topic [ 28 , 32 , 34 ], we took advantage of the reported structure–activity relationships (SARs) of pyrazolo-pyrido-pyrimidine analogs. Thus, in order to assess the ability of the top-ranked active compounds to inhibit six anti-cancer drug targets (DHFR, VEGFR2, HER-2/neu, hCA-IX, CDK6 and LOX5), we carried out docking study for complexes consisting of compound 7e and the target proteins.…”

“…Hereby, literature has shown that six key proteins (MCL-1, CDK6, HER-2/neu, LOX5, USP7 and DHFR) [33] or (DHFR, VEGFR2, HER-2/neu, hCA-IX, CDK6 and LOX5) [32] were used in the in silico docking studies of the most potent compounds in order to investigate their predicted anticancer potential. In this study, to develop a new generation of more potent multitargeted anticancer agents and motivated by previous research on that topic [28,32,34], we took advantage of the reported structure-activity relationships (SARs) of pyrazo- The highest cytotoxicity for A2780 cancer cell lines was found again for compound 7e (EC 50 = 9.1 ± 1.6 µM). In this series, compounds 7g and 7b (EC 50 = 14.5 ± 2.2 and 14.6 ± 2.2 µM, respectively) showed noteworthy activity as compared to other analogs, and their EC 50 values ranged between 18.0 ± 3.0 and 27.5 ± 8.1µM.…”

“…Inspired by the above findings, and in continuation of our previous work on the synthesis of novel fused-pyrimidine scaffolds [ 27 , 28 , 29 ], we aimed to design and synthesize new pyrazolo[4,3- e ]pyrido[1,2- a ]pyrimidine derivatives. Hereby, we report for the first time the cytotoxic activity of these newly synthesized compounds toward five human tumor cell lines, A375, HT29, MCF7, A2780, FaDu as well as non-malignant NIH 3T3 and HEK293 cells.…”

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

“…Flow-cytometry studies have found that 235 exhibited the highest apoptosis activity followed by 234, 236, and 237 when compared to the control 0.5% DMSO vehicle. This represents the apoptotic activity of these compounds ( Horchani et al, 2021 ).…”

Biological Evaluation and Molecular Docking Studies of Novel 1,3,4-Oxadiazole Derivatives of 4,6-Dimethyl-2-sulfanylpyridine-3-carboxamide

“…The versatility of N -acyl hydrazones in medical chemistry is based on the ease of their synthesis, as they are usually formed in a condensation reaction between aldehydes or ketones with hydrazides [ 14 , 15 , 16 ]. Literature studies show that the N -acyl hydrazone moiety is characterized by various activities, e.g., anticancer [ 17 , 18 , 19 , 20 ], antimicrobial [ 21 , 22 , 23 , 24 ], anticonvulsant [ 25 ]. The analgesic and anti-inflammatory effect seems to be particularly important [ 26 , 27 ], and researchers have shown that many of the derivatives exhibit a mechanism of action related to the inhibition of cyclooxygenase [ 28 , 29 ].…”