Synthesis, bioevaluation and molecular docking study of new piperazine and amide linked dimeric 1,2,3-triazoles

Abstract

In search of more potent new antitubercular agents, a library of novel piperazine tethered dimeric 1,2,3-triazoles were designed by assembling 1,2,3-triazoles and piperazine in a single molecular architectural framework. The titled compounds (3a–m) were synthesized by 1,3-dipolar cycloaddition of 1,4-di(prop-2-yn-1-yl)piperazine (1) and various azides (2a–m) using click chemistry approach with good yields. All the synthesized compounds (3a–m) have been screened for their in vitro antitubercular, antifungal and antioxidant activities against their respective strains. Among them, 3b, 3d, and 3i have revealed promising antitubercular activity against Mycobacterium tuberculosis (Mtb) H37Rv with MIC 12.5 µg/mL. Molecular docking results provided well-clustered solutions to the mode of binding for these molecules into the active site of Mtb enoyl reductase (InhA). In addition to this, most of synthesized compounds were found to have potential antifungal as well as antioxidant activity.

Graphical Abstract

Keywords:

• Antifungal activity
• antioxidant activity
• antitubercular activity
• dimeric 1,2,3-triazoles
• molecular docking study

Experimental

Materials and methods

All the chemicals were of laboratory grade, purchased from commercial suppliers Spectrochem, Avra, Alfa Aesar and Sigma Aldrich and were used without further purification. Purity and completion of reaction time of all synthesized compounds were monitored by thin layer chromatography (TLC) using silica gel 60-F₂₅₄ precoated on aluminum sheets as an adsorbent, Merck, Germany and visualization was accomplished by iodine/ultraviolet light. Melting points of all the synthesized compounds were determined in an open capillary tube method and are uncorrected. ¹H NMR spectra were recorded on a Brukar DRX-400 and 400 MHz NMR spectrometer using tetramethylsilane (TMS) as an internal standard and chemical shifts are in δ(ppm). The splitting pattern abbreviations are designed as singlet (s); doublet (d); double doublet (dd); triplet (t); quartet (q) and multiplet (m). ¹³C NMR spectra were recorded on a Brukar DRX-75 and 100 MHz NMR in DMSO-d₆. High-resolution mass spectra (HRMS) were obtained using HRMS-ESI-Q-Time of flight LC/MS instrument.

General procedure for the synthesis of piperazine incorporated dimeric 1,2,3-triazoles (3a–m)

In a round bottom flask 1,4-di(prop-2-yn-1-yl)piperazine 1 (0.01 mol) and the newly synthesized azides 2a–m (0.02 mol) were allowed to react in the presence of aqueous solution of CuSO₄.5H₂O and sodium ascorbate t-BuOH/H₂O (1:2) at room temperature for 8 h. The same experimental procedure of click reaction we have used in our earlier research work.^[58,59] The progress of the reaction was monitored by TLC using ethyl acetate: hexane (3:7) as a solvent system. After completion of the reaction, the reaction mixture was poured on crushed ice. The obtained solid products (3a–m) were filtered, dried and crystallised in ethanol-DMF.

Synthesis of 2,2′-(4,4′-(piperazine-1,4-diylbis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis (N-phenylacetamide) (3b)

The compound (3b) was obtained by Cu (I)-catalyzed 1,3-dipolar cycloaddition reaction between 1,4-di(prop-2-yn-1-yl)piperazine (1) and azide (2b) as dark greenish solid; Yield: 94%; Mp: >270 °C; ¹H NMR (400 MHz, DMSO-d₆, δ_H ppm) 2.95 (s, 4H, piperazinyl-H), 3.02 (s, 4H, piperazinyl-H), 4.78 (s, 4H, piperazinyl N–CH₂), 5.38 (s, 4H, triazolyl N–CH₂), 7.14–7.63 (m, 10H, Ar–H), 8.68 (s, 2H, triazolyl–H), 10.58 (s, 2H, amido N–H); ¹³C NMR (100 MHz, DMSO-d₆, δ_C ppm) 24.5, 70.2, 72.8, 116.9, 119.3, 133.1, 133.5, 135.1, 138.5, 162.0; HRMS (ESI) calcd. for C₂₆H₃₁N₁₀O₂ M + H⁺: 515.2632; found 515.2636.

Acknowledgments

One of the author T.R.D. is very much grateful to Dr. Babasaheb Ambedkar Marathwada University, Aurangabad for the award of University Scholars Fellowship. Authors are also thankful to the Head, Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad-431 004, India for providing laboratory facility. We are also grateful to Schrodinger Inc. for GLIDE software to perform the molecular docking studies.

Disclosure statement

The authors declare no competing interest.