Pyrazolo[3,4-d]pyrimidine derivatives as EGFRT790M and VEGFR-2 dual TK inhibitors: Design, synthesis, molecular docking, ADMET profile and anticancer evaluations

Abstract

Seventeen new pyrazolo[3,4-d]pyrimidine derivatives have been designed, created and tested as dual VEGFR-2 and EGFR inhibitors for their anticancer special effects against A549, HepG2, MCF-7, and HCT-116. In order to determine how the proposed chemicals might interact to the EGFR and VEGFR-2 receptors, molecular docking was used for these derivatives. The data from the docking studies and the results of the biological screening had excellent correlation. Compounds 14 and 15 displayed the best effects against HepG2, while the derivatives 10d, 15 and 18 showed the greatest anticancer activity against MCF-7. Moreover, compounds 15 and 18 exhibited the greatest anticancer effects against HCT-116 but compound 18 exhibited the greatest anticancer effect against A549. Compound 18 exhibited higher activities than Sorafenib against MCF-7, HCT116 and A549 correspond- ingly but lower actions versus HepG2. However, this substance showed greater effects than erlotinib against MCF-7 and HCT116 but lesser effects against A549 and HepG2 in that order. Compound 15 shown lower ac- tivities versus A549 but higher activity against HepG2, MCF-7, and HCT116 than Sorafenib and Erlotinib. De- rivative 18 displayed higher effects as dual VEGFR-2 and EGFRT790M tyrosine kinases inhibitors more than both Sorafenib and Erlotinib respectively. Finally, our derivatives 10d, 15 and 18 demonstrated an excellent ADMET profile when calculated in silico. According to the results, our compounds could serve as a model for future creation, optimization, adaption, and research to create more powerful and selective dual VEGFR-2/EGFRT790M inhibitors with more anticancer potential.