Design, Synthesis, Anticancer Properties and In Silico Evaluation of C(4) N ‐Heteroaryl 4 H ‐Chromenes

The C(4) N‐heteroaryl 2‐amino‐3‐nitro‐4 H ‐chromenes are podophyllotoxin (POD) mimics as they possess the pharmacophore features of the anticancer natural product. We have achieved a facile synthesis of several such 4 H ‐chromenes by substitution of C(4) SMe in N ‐alkyl 4‐(methylthio)‐3‐nitro‐4 H ‐chromen‐2‐amines with heteroaromatic amines like 2‐aminopyridines and 2‐aminopyrimidines. Resulting 4 H ‐chromenes were evaluated for anticancer activity against prostate and lung cancer cell lines. Two of the 4 H ‐chromenes showed significant anti‐cancer activity, even better than POD. Both of them were non‐toxic towards normal cell‐lines. In silico ADMET studies revealed drug‐likeliness of all the 4 H ‐chromenes. Molecular docking studies with αβ tubulin concurred with in vivo results and revealed that the 4 H ‐chromenes bind to the active site of POD. Molecular dynamics simulation studies on the complexes of αβ tubulin with the two best 4 H ‐chromenes revealed high stability. Overall, our studies revealed that the two 4 H ‐chromenes could act as lead compounds for further development of potent anticancer drugs.