Synthesis, ADMET prediction and reverse screening study of 3,4,5-trimethoxy phenyl ring pendant sulfur‐containing cyanopyrimidine derivatives as promising apoptosis inducing anticancer agents.

• Alginic acid, a natural carbohydrate is explored as a green bifunctional heterogeneous, biopolymeric organocatalyst for the expeditious synthesis of dihydropyrimidines (DHPMs). • A mild reaction protocol with high to quantitative yields (82–96%). • The catalyst was characterized through X-ray diffraction, thermogravimetric analysis, scanning electron microscopy and infrared spectroscopic techniques. • Reusability of the catalyst was assessed up to five consecutive cycles. Cancer remains considered as one of the leading global health problems either due to meagre and suboptimal therapeutic response of chemotherapeutic agents or due to the emergence of spontaneous complex multidrug resistance in cancer cells. This created a persistent need for the development of new anticancer agents. Enthralled by the high success rate for natural product-based drug discovery and current research scenario, we synthesized a new series of 3,4,5-trimethoxy phenyl ring pendant sulfur‐containing cyanopyrimidine derivatives clubbed with different amines intending to search an anticancer lead compound. To probe the anti-proliferative spectrum of the synthesized derivatives, an in-vitro evaluation was piloted against a panel of 60 cancer cell lines at the National Cancer Institute (NCI) representing major types of cancer diseases. Most of the derivatives showed good to moderate anti-proliferative activity. The results revealed that compound 4e displayed the most promising broad-spectrum anticancer activity with high growth inhibition of various cell lines representing multiple cancers diseases. Mechanistic investigation of compound 4e in human breast cancer MDA-MB-231 cells showed that compound 4e triggers cell death through the induction of apoptosis. ADMET studies and reverse screening were also performed to identify the potential targets of designed molecules. It was concluded that 3,4,5-trimethoxy phenyl ring pendant sulfur‐containing cyanopyrimidine derivative 4e could act as a promising hit molecule for further development of novel anticancer therapeutics. [ABSTRACT FROM AUTHOR]