Design, synthesis, anticancer activity and docking studies of theophylline containing 1,2,3-triazoles with variant amide derivatives

Abstract

A new series of theophylline analogues containing 1,2,3-triazoles with different amide groups (22-41) has been designed and synthesized, and their biological activities have been evaluated as potential anticancer agents. The anticancer activities of the synthesized compounds were studied in four cancer cell lines viz. lung (A549), colon (HT-29), breast (MCF-7) and melanoma (A375). Furthermore, these compounds were screened for computational ADME and Lipinski's analysis followed by molecular docking and binding energy calculations against the various therapeutic targets involved in cell proliferation. The in vitro results demonstrate that compounds 22, 27, 36 and 40 have pivotal anticancer activity. Among these, compounds 22 and 27 have significant cytotoxic activity in all three cell lines; the in silico docking studies also reveal that compounds 22, 27 and 36 have good dock scores, binding affinities and binding energies towards human epidermal growth factor receptor 2. This is the first report to demonstrate theophylline hybrids containing 1,2,3-triazoles as potential anticancer agents.

Fig. 1. Bioactive theophylline and 1,2,3-triazole moieties.

Fig. 2. Molecular and LIGPLOT interactions of compounds 22 (A) and 41 (B) with the tyrosine kinase domain of human epidermal growth factor receptor 2 (HER2).

Scheme 1. Synthesis of biphenyl amine compounds 5, 7, 12 and 15. Reagents and conditions: (a) K₃PO₄, Pd(dppf)Cl₂·CH₂Cl₂, 1,4-dioxane : H₂O, 100 °C, 10–16 h.

Scheme 2. Synthesis of aliphatic cyclic amide and biphenyl amide compounds 22–31 and 32–41. Reagents and conditions: (a) (i) K₂CO₃, DMF, 85 °C, 12 h; (ii) TPP, DIAD, THF, rt, 5 h; (b) LiOH·H₂O, THF : H₂O, rt, 2 h; (c) DCC, DMAP, DCM, rt, 16 h; (d and e) CuSO₄·5H₂O, sodium ascorbate, t-BuOH : H₂O, rt, 16 h; (f, g and h) HATU, DIPEA, DCM, rt, 16 h.