New insights into the structural requirements for pro-apoptotic agents based on 2,4-diaminoquinazoline, 2,4-diaminopyrido[2,3-d]pyrimidine and 2,4-diaminopyrimidine derivatives

As a continuation of our work on new anti-tumoral derivatives with selective pro-apoptotic activity in cancer cells, we describe the synthesis and the preliminary evaluation of the cytotoxic and pro-apoptotic activities of a series of pyrimidin-2,4-diamine derivatives that are structurally related to quinazolin-2,4-diamine and pyrido[2,3-d]pyrimidin-2,4-diamine derivatives. We also describe the structure–activity relationship studies carried out on four series’ of quinazolin-2,4-diamine, 2-(alkylsulfanyl)-N-alkyl- and 2-(alkylsulfanyl)-N-alkylarylpyrido[2,3-d]pyrimidine and pyrimidin-2,4-diamine derivatives.The proposed preliminary pharmacophore consists of a flat heterocyclic ring, preferably a pyrido[2,3-d]pyrimidine, with two equivalent alkylarylamine chains, preferably N-benzyl- or N-ethylphenylamine, located in positions 2 and 4 of the ring, and with a preferred ALogP in the range 4.5–5.5. The nitrogen present in the central ring can act as hydrogen bond acceptors (HBA) whereas the amino group in the 4-position can act as a donor (HBD) or an HBA and the amino group in the 2-position can act as an HBD. On the basis of the analyzed structural profiles, different mechanisms of action can be suggested for the quinazolin-2,4-diamine, the 2-(alkylsulfanyl)-N-alkylpyrido[2,3-d]pyrimidin-4-amine and the pyrido[2,3-d]pyrimidin-2,4-diamine derivatives.

Graphical abstractStructural variations carried out for the analyzed compounds. Selected structural features related with the target biological activity: X = N; Z = NH; n = m = 1–2; R = R″ = C6H5; R′ = H; R″ = H, OCH3.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► We present the results of a SAR study carried out on four pro-apoptotic compound series. ► We proposed a preliminary pharmacophore. ► As a scaffold: a flat heterocyclic ring, preferably a pyrido[2,3-d]pyrimidine ring. ► Two equivalent chains, N-benzyl- or N-ethylphenylamine, located in positions 2 and 4. ► A preferred ALogP in the range 4.5–5.5.