Synthesis, QSAR modeling, and molecular docking of novel fused 7‐deazaxanthine derivatives as adenosine A2A receptor antagonists

• Published in: Chemical biology & drug design 2022-12, Vol.100 (6), p.1025-1032
• Main Authors: Muzychka, Liubov V., Verves, Evgenii V., Yaremchuk, Iryna O., Zinchenko, Anna M., Shishkina, Svitlana V., Semenyuta, Ivan V., Hodyna, Diana M., Metelytsia, Larysa O., Kovalishyn, Vasyl, Smolii, Oleg B.
• Format: Article
• Language: English
• Subjects: A2A antagonists; Fused 7‐deazaxanthine; machine learning; molecular docking; QSAR
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.13975

Predictive QSAR models for the search of new adenosine A2A receptor antagonists were developed by using OCHEM platform. The predictive ability of the regression models has coefficient of determination q2 = 0.65−0.71 with cross‐validation and independent test set. The inhibition activities of novel fused 7‐deazaxanthine compounds were predicted by the developed QSAR models. A preparative method for the synthesis of pyrimido[5′,4′:4,5]pyrrolo[1,2‐a][1,4]diazepine derivatives was developed, and 11 new adenosine A2A receptor antagonists were obtained. Preliminary investigations into the toxicology of fused 7‐deazaxanthine compounds toward commonly used model organism to assess toxicity invertebrate cladoceran D. magna were also described. Classic QSAR modeling methods were applied to the in silico prediction of A2A inhibitors. Eleven representatives of the new heterocyclic system pyrimido[5′,4′:4,5]pyrrolo[1,2‐a][1,4]diazepine were synthesized, and their activity against the A2A receptor was evaluated. Molecular docking demonstrated that the potential biological activity of novel fused 7‐deazaxanthine derivatives.