Design, synthesis and evaluation of novel 1,2,4-triazole derivatives as promising anticancer agents

Abstract

Herein, we reported the synthesis of nineteen novel 1,2,4-triazole derivatives including 1,3-diphenyl-2-(1H-1,2,4-triazol-1-yl) propan-1-ones (7a-e), 1-(1,3-diphenylpropan-2-yl)-1H-1,2,4-triazole (8a-c) and 1,4-diphenyl-2-(1H-1,2,4-triazol-1-yl) butane-1,4-diones (10a-k). The structures of these derivatives were confirmed by spectroscopic techniques like IR, ¹H-NMR, Mass spectroscopy and Elemental analysis. The cytotoxic activities of the synthesized compounds were evaluated against three human cancer cell lines including MCF-7, Hela and A549 using MTT assay. Compounds 7d, 7e, 10a and 10d showed a promising cytotoxic activity lower than 12 μM against Hela cell line. The safety of these compounds was also, evaluated on MRC-5 as a normal cell line and relieved that most of the synthesized compounds have proper selectivity against normal and cytotoxic cancerous cell lines. Finally, molecular docking studies were also, done to understand the mechanism and binding modes of these derivatives in the binding pocket of aromatase enzyme as a possible target.

Keywords: 1,2,4-Triazole; ADME; Anticancer; MTT assay; Molecular docking.

Fig. 1

Chemical structures of 1,2,4-triazole-based drugs

Fig. 2

Structure of 1,2,4-triazole derivatives with anticancer activity

Fig. 3

Design of new 1,2,4-triazole derivatives

Fig. 4

Synthesis of target compounds 7a-e, 8a-c and 10a-k. Reagents and conditions: a) AlCl₃, dichloromethane, r.t., 24 h, b) NaHCO₃, toluene, reflux, 20 h, c) NaH, CH₃CN, reflux, 24 h, d) N₂H₄.H₂O, KOH, Ethylene glycol,170 ˚C, 4 h, e) NaH, CH₃CN, reflux, 24 h

Fig. 5

Cytotoxic effect of compounds 7a-e, 8a-c and 10a-k on MCF-7, Hela and A549 cell lines Taken to gather, regarding the cytotoxic evaluations on 7a-e and 8a-c derivatives, it can be realizing that 7e was the most potent derivative against all three tested cell lines. The structure activity relationship disclosed that electronegative substitution such as Cl and Br at para position of phenyl ring (X₁) and also, the presence of phenyl ring at R position could increase the inhibitory activity significantly in a 7a-e series. Also, the presence of one-carbonyl group showed necessary for pharmacological effect. In addition, propane-1-yl-derivatives (8a-c) had least effect on cytotoxic activity. In the case of 10a-k, replacement of H with Ph moiety at R position led to decreased cytotoxic activity (10f-k) and also, no substituted analogue (10a) had favorable pharmacological effect on MCF-7 and Hela cell lines. The cytotoxicity of all synthesized compounds were shown in Table 1.

Fig. 6

2D interaction diagrams representing the docked conformation of compounds 10a and 10d in the human placental aromatase (3EQM). (Van der waals: green, dark pink: π-π, light pink: π-alkyl, purple: π-sigma, orange: π-cation, blue: halogen bond)

Fig. 7

2D interaction diagrams representing the docked conformation of compounds 7c and 8c in the human placental aromatase (3EQM). (Van der waals: green, dark pink: π-π, light pink: π-alkyl, purple: π-sigma, orange: π-cation, blue: halogen bond)