Design, theoretical approaches and new framework of pyrazolo[3,4-d]pyrimidine as potent anticancer agents: Efficient synthesis, ADME-T and molecular docking

Novel 1,3,4-thiadiazole-based pyrazolo[3,4- d ]pyrimidine derivatives ( 7a–7 l ) were synthesised in this study, and their structures were ascertained utilizing a range of spectroscopic methods, including HREI-MS, IR, and NMR ( 1 H/ 13 C). They showed especially strong activity (IC 50 range 1.56–44 μM). With IC 50 values of 2.49 ± 1.9, 1.56 ± 1.3, and 2.97 ± 2.6 μM against Caco-2, HCT116, and A549 cell lines, respectively, compound 7f demonstrated the strongest anticancer properties among all synthesised compounds when compared to the conventional medication doxorubicin (IC 50 = 3.10 to 3.32 μM). Additionally, the anchoring function of the 1,3,4-thiadiazole-substituted pyrazolo[3,4- d ]pyrimidine moiety in interacting with anticancer targets and hydrophobic interaction with the essential amino acid residues has been highlighted by molecular modeling studies. The study shows how certain residues from the colorectal cancer mutant (1WCH) interact with each other in a way that is stable. Furthermore, these compounds intriguing therapeutic potential is highlighted by their favorable drug-likeness and ADME-Tox characteristics, which call for more research into possible clinical applications. These compounds are attractive candidates for further investigation in the search for new therapeutic agents due to their diverse actions, which include anticancer qualities. Rational of the work Based on the results, regarding the potential anticancer activity of pyrazolo[3,4- d ]pyrimidines, we herein, report the design and synthesis of a new series of pyrazolo[3,4- d ]pyrimidine derivatives to evaluate their possible anti-proliferative activity against human colorectal adenocarcinoma cell line and lung carcinoma cell lines. In this work, 1 H -pyrazolo[3,4- d ]pyrimidine moiety was used as a heteroaromatic ring system occupying the 1,3,4-thiadiazole binding region. Also, phenyl ring was utilised as a hydrophobic moiety to occupy the hydrophobic region of the colorectal and lung binding sites. Overall, this line of research has the potential to unravel insights that can contribute to the development of novel therapeutic interventions and preventive measures. • Synthesis, experimental and theoretical investigation of new class of 1,3,4-thiadiazole-based pyrazolo[3,4- d ]pyrimidines. • The experimental results show that the 7a-7 l compounds achieves good performance. • Compounds 7b , 7f , and 7 l showed better antiproliferative activity against the Caco-2 cell line • Docking on colorectal carcinoma and lung carcinoma enzymatic interactions mainly agree with the experimental results. • In silico research using ADME-T profiling validated their favorable oral bioavailability.