Amide Functionalized Novel Pyrrolo-pyrimidine Derivative as Anticancer Agents: Synthesis, Characterization and Molecular Docking Studies.

Background: The development of new therapies targeting crucial kinases involved in cancer progression is a promising area of research. Pyrazolo pyrimidine derivatives have emerged as potential candidates for this purpose.

Objective: This study aims to synthesize pyrazolo pyrimidine derivatives (5a-5r), evaluate their molecular docking against key kinases, and assess their anticancer activity.

Methods: The synthesis involved a multi-step procedure starting with the cyclization of 6-amino-2- methylpyrimidin-4(3H)-one (1) to form 2-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-4-ol (2). This was followed by chlorination to yield 4-chloro-2-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine (3) and nucleophilic substitution to produce 2-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-4-amine (4). The final derivatives (5a-5r) were synthesized through amide bond formation with various carboxylic acids using DCC and DMAP. Structural elucidation was confirmed via NMR, mass spectrometry, and HRMS. Molecular docking studies were conducted against Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), and cyclin-dependent kinase 4 (CDK4). Anticancer activity was evaluated against MCF-7, SET-2, and HCT-116 cell lines.

Results: Structural elucidation confirmed the successful synthesis of the derivatives. Molecular docking studies revealed promising binding affinities for selected derivatives, particularly those with heterocyclic substitutions. Anticancer activity evaluation showed diverse potency profiles, with several derivatives demonstrating IC50 values comparable to the reference drug, doxorubicin. Derivatives featuring nitro and heterocyclic moieties exhibited significant anticancer activity.

Conclusion: The synthesized pyrazolo pyrimidine derivatives showed potential as lead compounds for further development due to their promising binding affinities and significant anticancer activity, particularly those with nitro and heterocyclic moieties.