Synthesis of Some Polysubstituted Nicotinonitriles and Derived Pyrido[2,3-d]pyrimidines asIn VitroCytotoxic and Antimicrobial Candidates

Abstract

The synthesis of polysubstituted pyridines, in addition to some derived pyrido[2,3-d]pyrimidine ring systems supported with chemotherapeutically active functionalities, is described. They were evaluated for theirin vitrocytotoxic effects against three different human tumor cell lines (human colon carcinoma HT29, hepatocellular carcinoma Hep-G2, and Caucasian breast adenocarcinoma MCF7). Nine compounds displayed variable cytotoxic potential, among which alkylthio analogs33,34, and37emerged as the most active members, being almost twice as active as doxorubicin against the colon carcinoma HT29 cell line. In addition, the same three analogs showed a clear differential cytotoxic profile as they exhibited a marginal inhibitory effect on the growth of the normal nontransformed human foreskin fibroblast Hs27 cell line. Meanwhile, nineteen compounds were able to exhibit significant antibacterial activity against both Gram-positive and Gram-negative bacteria, together with moderate antifungal activities. The pyrido[2,3-d]pyrimidine-2(1H)-thione30together with its alkylthio derivatives33and34stemmed as the most active antimicrobial members being equipotent to ampicillin againstS. aureus,E. coli,andP. aeruginosa,together with a noticeable antifungal activity againstC. albicans.Compounds33and34could be considered as a promising template for possible dual antimicrobial-anticancer candidates.

One‐potandtwo‐potmethods for chalcone derived pyrimidines synthesis and applications

“…A significant yield (80%-85%) was achieved due to the uniform heating of MW radiation. [210] Another quinolinyl pyrimidine series (66) achieved from the reaction of chalcone (63) with guanidine hydrochloride in DMF in the presence of NaH at reflux, achieved 45%-68% yield. [211] One more quinolinepyrimidine series (67) successfully synthesized from (64) and guanidine nitrate in basic media with 78%-84% yield [212] (Scheme 16).…”

Synthesis and Anticancer Perspective of Pyridopyrimidine Scaffold - An Overview

“…Few of the fused ring systems like pyridopyrimidines and quinolines have been reported by Hassan M. Faidallah [42] because of strongly observed antineoplastic [43], antiproliferative [44], and cytotoxic [45] effects. "2-amino-4,6-disubstituted nicotinonitriles" (1-5) are the main intermediates were prepared from the Hantzsch-type synthetic method, mainly by cyclocondensation of substituted acetophenone with the suitable aromatic aldehyde (piperonal or thiophene-2-carbaldehyde) and a source of nitrogen like ammonium acetate, which is a onepot multi-component reaction.…”

Recent Progress on Nicotinonitrile Scaffold‐based Anticancer, Antitumor, and Antimicrobial Agents: A Literature Review

“…Faidallah et al . performed the synthesis of the key intermediates 2‐amino‐4,6‐disubstituted nicotinonitriles 10 – 14 by one‐pot four‐component reactions of the appropriate aromatic aldehyde (piperonal or thiophene‐2‐carbaldehyde) with the substituted acetophenone, malononitrile, and ammonium acetate in EtOH (Scheme ) . Next, reaction of compounds 10 – 14 with formic acid, acetic anhydride, or phenyl isothiocyanate in pyridine afforded the pyrimidines 15 – 29 , whereas treatment of 10 – 12 with benzoyl isothiocyanate afforded the thiourea derivatives 30 – 32 .…”

“…Analogously, when compounds 10 – 14 were directly fused with thiourea at 260–300°C, the corresponding pyrimidine‐2(1 H )‐thiones 37 – 41 were obtained. Finally, alkylthio derivatives 42 – 46 were achieved via thioalkylation of the 2‐thione derivatives 37 – 41 with either methyl or ethyl iodide in 1 N NaOH medium (Scheme ) .…”