Novel isoxazoline‐linked 1,3,4‐thiadiazole hybrids as anticancer agents: Design, synthesis, biological evaluation, molecular docking, and molecular dynamics simulation

Abstract

In the current study, natural (R)‐carvone was utilized as a starting material for the efficient synthesis of two series of isoxazoline derivatives bearing the 1,3,4‐thiadiazole moiety. The new compounds were obtained in good yields and were characterized by 1H and 13C NMR and HRMS analysis. The newly synthesized monoterpenic isoxazoline 1,3,4‐thiadiazole and their thiosemicarbazone intermediate derivatives were evaluated for their anticancer activity in four cancer cell lines (HT‐1080, A‐549, MCF‐7, and MDA‐MB‐231). Most of the synthesized compounds exhibited moderate to high anticancer effects. Compound 13c showed the highest anticancer activity with IC50 values ranging from 19.33 ± 1.81 to 34.81 ± 3.03 µM. Further investigation revealed that compounds 12e and 13c could inhibit the cell growth of HT‐1080 and MCF‐7 cells by inducing apoptosis through caspase‐3/7 activation. The apoptotic effect was accompanied by an S phase and G2/M cell cycle arrest for 13c and 12e, respectively. Compounds 12e and 13c were assessed in silico using molecular docking and molecular dynamics. We found that compound 13c is moderately active against the caspase‐3 protein, which triggers apoptosis via intrinsic and extrinsic routes, making compound 13c a promising candidate to activate the proapoptotic protein (caspase‐3).

Design, Synthesis, Cytotoxic Effect Evaluation and Molecular Docking of (R)‐Camphor‐Based Thiazolidinone‐Isoxazole and Thiazolidinone‐1,2,3‐triazole Hybrids“

“…Cell culture was realized in a manner analogous to [35–37] . The human fibrosarcoma cell line HT‐1080 (CCL 121) was purchased from Sigma Aldrich (ECACC collection, Saint Quentin Fallavier, France).…”

“…Cell culture was realized in a manner analogous to. [35][36][37] The human fibrosarcoma cell line HT-1080 (CCL 121) was purchased from Sigma Aldrich (ECACC collection, Saint Quentin Fallavier, France). The human breast adenocarcinoma MCF-7 (HTB-22) and lung carcinoma A-549 (CCL-185) cell lines were purchased from the American Type Culture Collection (ATCC).…”

Nitrile Oxide, Alkenes, Dipolar Cycloaddition, Isomerization and Metathesis Involved in the Syntheses of 2-Isoxazolines

“…Natural ( R )-carvone was used by Oubella as a dipolarophile for the efficient syntheses of 3,5,5-trisubstituted 2-isoxazoline bearing the carvone-1,3,4-thiadiazole-deriving moiety in position 3— Scheme 254 [ 270 ].…”

“… Syntheses of trisubstituted isoxazolines via 1,3-DP cycloaddition of R 1 -PhCNO to ( R )-carvone [ 270 ]. a = CH 2 Cl 2 , NaOCl; b = NH 2 CSNHNH 2, H 2 SO 4 , EtOH, rfx., 3 h, then diarylnitrilimines, EtOH, rfx., 3 h; R 1 , R 2 , R 3 = H, COOEt, Me; Me, COOEt, Me; o -MeO, COOEt, p -O 2 N; o -MeO, p -ClC 6 H 4 , H and others; up to 81% yield (final products).…”