Convenient Synthesis of Some Novel 4-Benzyl-1(2H)-Phthalazinone Derivatives of expected anticancer activity

Samir El Rayes,Ibrahim Ali,Hamdy Abd Elazeem,Sara Eltorky

doi:10.3390/ecsoc-23-06605

Abstract

Series of new synthesized biologically active phthalazinone derivatives were obtained. Starting from the amino acid methyl esters of 4-benzyl-1(2H)-phthalazinone 2a,b which were synthesized from the aceto hydrazide of 4-benzyl-1(2H)-phthalazinone 1 via azide coupling method. The hydrazides 3a,b were prepared from hydrazinolysis of corresponding esters 2a,b. N-alkyles-2-(4-Benzyl-1-oxo-1H-phthalazin-2-yl)-methyl-acetamide 4a-f and the dipeptides methyl {2-[2-(4-Benzyl-1-oxo-1H-phthalazin-2-yl)-acetylamino]-acetylamino}-alkanoates 6a-c were obtained by the reaction of corresponding hydrazide 3a with amines and amino acid esters respectively via azide coupling method. Similarly; N-alkyles-3-[2-(4-Benzyl-1-oxo-1H-phthalazin-2-yl)-acetylamino] 5a-f and the dipeptides methyl{3-[2-(4-Benzyl-1-oxo-1H-phthalazin-2-yl)-acetylamino]-propionylamino} alkanoates 7a-c were obtained by the reaction of corresponding hydrazide 3b with amines and amino acid esters respectively via azide coupling method

Highlights

Cancer is one of the most difficult diseases to treat and it is a major disease responsible for deaths worldwide, it can be considered as one of the foremost health problems[1]
As extension of these studies, we achieve N-alkylation of 4-Benzyl-2H-phthalazin-1-one to the corresponding methyl-4-Benzyl-1-oxo-1H-phthalazin-2-yl-acetate to the corresponding (4Benzyl-1-oxo-1H-phthalazin-2-yl)-acetic acid hydrazide (1) which used as a precursor for the preparation of our targeted newly phthalazinone molecules
The product was methyl-4-Benzyl-1-oxo1H-phthalazin-2-yl-acetate prove that the N atom in present system is stronger neucleophile more than Oxygen i.e this reaction is new evidence for basis of chemoselective reactivity of heterocyclic amides towards electrophiles scheme[1]

Summary

Introduction

Cancer is one of the most difficult diseases to treat and it is a major disease responsible for deaths worldwide, it can be considered as one of the foremost health problems[1]. Anticancer drugs research is never ending to obtain lower toxicity and more selectivity products towards tumor cells. A series of 4-substituted-2H-phthalazin-1-ones have been investigated as potent orally bioavailable PARP (poly (adenosine diphosphate-ribose) polymerases) inhibitor[19,20,21,22,23,24,25,26] Olaparib I, MRU-868 II and KU0058958 III are the most interesting PARP inhibitors based on the 4-substituted-2H-phthalazin- 1-one scaffold and compound IV inhibits aurora-A kinase based upon a 4-(pyrazole-3ylamino)phenyl-2H-phthalazin-1-one scaffold and has in vitro cytotoxic activity against HCT116 colon cell line[27 ], these commercial phthalazinone derivatives are shown in figure 1

Olaparib I

Discussion

Ph Ph

Ar n