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.
Highlights
Over the past two decades, several reports have discussed the growing number of cancerous diseases and the prominent role displayed by chemotherapy as the most fruitful treatment for many disseminated types of tumors
Preparation of the key intermediates 2-amino4,6-disubstituted nicotinonitriles 1–5 was performed according to Hantzsch-type synthesis via multicomponent onepot cyclocondensation of the appropriate aromatic aldehyde with the substituted acetophenone, malononitrile, and ammonium acetate as a nitrogen source
Further interpretation of the results revealed that compounds 33, 34, 36, and 37 showed considerable broad spectrum cytotoxic activity against the three tested human tumor cell lines
Summary
Over the past two decades, several reports have discussed the growing number of cancerous diseases and the prominent role displayed by chemotherapy as the most fruitful treatment for many disseminated types of tumors. This has resulted in the activation of much research targeting the discovery of prominent lead structures that would be beneficial in styling novel antitumor chemotherapeutic agents [1,2,3]. The substituents encountered in these derivatives were chosen so as to affect the electronic environment of the compounds, which would synergistically influence the targeted biological activities, in an attempt to obtain novel candidates with both anticancer and antimicrobial potentials
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