Design, Synthesis, Crystal Structure and Anticancer Evaluation of Novel Chiral 1,3,4‐Oxadiazole Derivatives Mimicking Paclitaxel Pharmacophore

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1,3,4‐Oxadiazole heterocycles exhibit versatile pharmacological activities and have emerged as privileged scaffolds for developing antiviral and anticancer drug candidates in pharmaceutical chemistry. To improve the antitumor potency of oxadiazole‐based small molecules, a series of novel chiral derivatives were rationally designed by incorporating chiral pharmacophoric fragments into the parent 1,3,4‐oxadiazole skeleton. Herein, 11 chiral 1,3,4‐oxadiazole hybrids, including 4a–4f , 5a , 5e , 6a , 6b , and 6e , were synthesized via a concise three‐step route starting from commercially available para‐substituted ethyl benzoates. The aminolysis and alcoholysis reactions of ethyl 5‐(4‐substituted phenyl)‐1,3,4‐oxadiazole‐2‐carboxylate served as the key synthetic transformation in this work. All target compounds were obtained with yields ranging from 52% to 72%, and their chemical structures were fully characterized by 1 H NMR, 13 C NMR, and electrospray ionization mass spectrometry (ESI‐MS). Furthermore, the single‐crystal structures of compounds 4b and 4d were unambiguously determined by X‐ray diffraction analysis. All synthetic derivatives were evaluated for in vitro antiproliferative activity against five human cancer cell lines (MDA‐MB‐231, A549, SPC‐A1, EC109, and MCF‐7) with docetaxel as the positive control. Most compounds displayed moderate to potent cytotoxicity against the tested tumor cell lines. Notably, compound 4b exerted the strongest antiproliferative activity among all candidates and showed higher cytotoxic potency than docetaxel against A549 and SPC‐A1 cells. Subsequent structure–activity relationship (SAR) studies verified that para‐position electron‐withdrawing substituents (fluoro, chloro, and nitro groups) on the phenyl ring could significantly enhance antitumor activity, whereas electron‐donating substituents (methyl and methoxy groups) reduced cytotoxic potency. The overall findings demonstrate that these chiral 1,3,4‐oxadiazole analogs are promising lead compounds for novel anticancer drug discovery, and further structural optimization and pharmacological mechanism research are worthy of continued investigation.