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Tumor suppressor protein p53 is one of the most appealing targets for targeted anticancer therapy, due to its significant role in cancer prevention and abundant mutation in human cancers. A novel series of 4‐phenyl‐5‐(thiophen‐2‐yl)‐4H‐1,2,4‐triazole‐3‐thiols having ability to liberate p53 function by interrupting p53‐MDM2 interaction were successfully discovered by structure‐based designing approach and the principle of bioisosterism. In silico modules predicted that these small molecule inhibitors comprising 1,2,4‐triazole‐3‐thiol scaffold have draggability and ability to mimic critical binding residues of p53. To verify this hypothesis, we have synthesized and evaluated all designed compounds for their in vitro antiproliferative activity against A549, U87 and HL60 cell lines. Fourteen out of fifteen compounds exhibited good in vitro inhibitory activity in lower micromolar values. Particularly, compound F10 …