Synthesis and Evaluation of Bakuchiol-Tethered Triazoles as Cytotoxic Agents

Neha Sengar; Joydeep Chatterjee; Raj Kumar; Inder Pal Singh

doi:10.1055/a-2531-7183

Synlett, Table of Contents

Synlett 2025; 36(16): 2643-2646
DOI: 10.1055/a-2531-7183

letter

Small Molecules in Medicinal Chemistry

Synthesis and Evaluation of Bakuchiol-Tethered Triazoles as Cytotoxic Agents

Authors

Neha Sengar

^aDepartment of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, 160062, India
Joydeep Chatterjee

^bDepartment of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
Raj Kumar∗

^bDepartment of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
Inder Pal Singh∗

^aDepartment of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, 160062, India

Abstract

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Abstract

A novel series of bakuchiol-tethered triazole compounds was synthesized by reaction of azido bakuchiol with different substituted alkynes. The anticancer activity of all synthesized compounds was evaluated against A549 (lung), MCF-7, and MDA-MB-231 (breast) human tumor cells. Cytotoxicity screening showed that several compounds displayed notable cytotoxic effects against tumor cells compared to the parent molecule bakuchiol. The prominent effects were produced by compounds with IC₅₀ values of 8.9 μM and 8.2 μM against the MCF-7 and A-549 cells, respectively.

Key words

anticancer - bakuchiol - triazole - click chemistry - semisynthetic - cancer

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References

References and Notes
1 Mandal R, Basu P. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2018; 61: 1505
2 Sathishkumar K, Chaturvedi M, Das P, Stephen S, Mathur P. Indian. J. Med. Res. 2022; 156: 598
3 Tanwar AK, Sengar N, Mase N, Singh IP. Expert Opin. Ther. Pat. 2024; 34: 873
4 Tanwar AK, Dhiman N, Kumar A, Jaitak V. Eur. J. Med. Chem. 2021; 213: 113037
5 Zhong L, Li Y, Xion L, Wang W, Wu M, Yaun T, Yang W, Tian C, Miao Z, Wang T, Yang S. Signal Transduct. Target Ther. 2021; 6: 248
6 Demain LA, Vaishnav P. Microb. Biotechnol. 2011; 4: 687
7 Newman DJ, Cragg GM. J. Nat. Prod. 2020; 83: 770
8 Newman DJ, Cragg GM. J. Nat. Prod. 2012; 75: 311
9 Mehta G, Nayak UR, Dev S. Tetrahedron 1972; 29: 1119
10 Jafernik K, Halina E, Ercisli S, Szopa A. Nat. Prod. Res. 2020; 35: 5828
11 Chen Z, Jin K, Gao L, Lou G, Jin Y, Yu Y, Lou Y. Eur. J. Pharmacol. 2010; 643: 170
12 Katsura H, Tsukiyama RI, Suzuki A, Kobayashi M. Antimicrob. Agents Chemother. 2001; 45: 3009
13 Choi SY, Lee S, Choi WH, Lee Y, Jo YO, Ha TY. J. Med. Food 2010; 13: 1019
14 Lau KM, Wong JH, Wu YO, Cheng L, Wong CW, To MH, Lau CP, Yew DT. W, Leung PC, Fung KP, Hui M, Ng TB, Lau CB. S. Phytomedicine 2014; 21: 942
15 Adhikari S, Joshi R, Patro BS, Ghanty TK, Chintalwar GJ, Sharma A, Chattopadhay S, Mukherjee T. Chem. Res. Toxicol. 2003; 16: 1062
16 Mao H, Wang H, Ma S, Xu Y, Zhang H, Wang Y, Niu Z, Fan G, Zhu Y, Gao XM. Toxicol. Appl. Pharmacol. 2014; 274: 180
17 Li L, Chen X, Liu CC, Lee LS, Man C, Cheng SH. Front. Pharmacol. 2016; 7: 1
18 Gupta N, Sharma S, Raina A, Bhushan S, Mailk FA, Sangwan PL. ChemistrySelect 2017; 2: 5196
19 Gupta N, Sharma S, Raina A, Dangroo NA, Bhushan S, Sangwan PL. RSC Adv. 2016; 6: 106150
20 Gautam LK, Ling T, Lang W, Rivas F. Eur. J. Med. Chem. 2016; 113: 75
21 Majeed R, Reddy MV, Chinthankindi PK, Sangwan PL, Hamid A, Chashoo G, Saxena AK, Koul S. Eur. J. Med. Chem. 2012; 49: 55
22 Xu Z, Zhao SJ, Liu Y. Eur. J. Med. Chem. 2019; 183: 111700
23 Kumar A, Yadav AK, Mishra V, Kumar D. SynOpen 2023; 7: 186
24 Hou W, Luo Z, Zhang G, Cao D, Li D, Ruan H, Ruan BH, Su L, Xu H. Eur. J. Med. Chem. 2017; 138: 1042
25 Matin MM, Matin P, Rahman MR, Hadda BT, Almalki FA, Mahmud S, Ghoneim MM, Alruwaily M, Alshehri S. Front. Mol. Biosci. 2022; 9: 864286
26 Kim KA, Shim SH, Ahn HR, Jung SH. Toxicol. Appl. Pharmacol. 2013; 269: 109
27 Carreiro EP, Sena AM, Puerta A, Padron JM, Burke AJ. Synlett 2020; 31: 615
28 Ma Q, Bian M, Gong G, Bia C, Liu C, Wei C, Quan Z, Du H. J. Nat. Prod. 2022; 85: 15
29 Gautam LN, Ling T, Lang W, Rivas F. Eur. J. Med. Chem. 2016; 113: 75
30 Guo HY, Chen ZA, Shen QK, Quan ZS. J. Enzyme Inhib. Med. Chem. 2021; 36: 1115
31 Cot A, Ozgeris FB, Sahin I, Cesme M, Onur S, Tumer F. J. Mol. Struct. 2022; 1269: 133763. Typical Procedure for the Synthesis of Bakuchiol Triazole (S,E)-4-(3,7-Dimethyl-3-vinylocta-1,6-dien-1-yl)-2-[4-(4-nitrophenyl)-1H-1,2,3-triazol-1-yl]phenol (17) A round-bottom flask (RBF) was charged with bakuchiol (1, 256 mg, 1 mmol) and t-BuONO (0.48 mL, 4 mmol) in THF. The mixture was stirred at 30 °C for 4 h. After monitoring by thin-layer chromatography, the reaction mixture was purified using a silica gel bed, affording nitro-bakuchiol (2) in an isolated yield of 83%. Next, the FeO-OH catalyst for the reduction of nitro-bakuchiol was prepared by mixing FeCl₃ (1 g) with 2 M NaOH (10 mL) to create an alkaline solution. The mixture was filtered, dried at 60 °C for 12 h, and pulverized into a fine powder. For the reduction, a methanolic solution of 2 (301 mg, 1 mmol) was combined with the prepared FeO-OH catalyst (40 mg) and N₂H₄·H₂O (188 μL, 2 mmol). The mixture was refluxed for 12 h. After evaporation of the solvent using a rotavapor, the residue was purified over a silica gel column to yield 3 with an excellent isolated yield of 92%. Subsequently, the diazonium salt of 3 (271 mg, 1 mmol) was prepared in situ by mixing with hydrochloric acid and water (1:1) at 5–10 °C for 20–25 min. This mixture was treated dropwise with sodium azide (260 mg, 4 mmol) over 10 min, maintaining the temperature at 5–10°C. After addition, the temperature was raised to 30 °C, and the reaction was stirred for an additional 2 h, affording 3-azido-bakuchiol (4) in an isolated yield of 90%. Finally, the RBF was charged with 4 (296 mg, 1 mmol), 1-ethynyl nitrobenzene (147 mg, 1 mmol), and sodium ascorbate (80 mg, 20 mol%) in THF. Aqueous CuSO₄·5H₂O (25 mg, 5 mol%) was added to the reaction mixture, which was stirred for 24 h at 30 °C. The reaction mixture was purified over a silica gel column, yielding a triazole product 17 with an isolated yield of 65% and 95% purity (qNMR). Yellow solid (65%); mp 188–189 °C. IR (neat): ν_max = 2967, 2917, 2854, 1604, 1518, 1467, 1412, 1338, 1240, 1111, 1093, 967 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 9.42 (s, 1 H), 8.48 (s, 1 H), 8.36 (d, J = 8.7 Hz, 2 H), 8.12 (d, J = 8.9 Hz, 2 H), 7.45 (d, J = 1.9 Hz, 1 H), 7.38 (dd, J = 8.6, 2.0 Hz, 1 H), 7.16 (d, J = 8.7 Hz, 1 H), 6.31 (d, J = 16.1 Hz, 1 H), 6.17 (d, J = 16.1 Hz, 1 H), 5.90 (dd, J = 17.5, 10.7 Hz, 1 H), 5.13–5.04 (m, 3 H), 1.99–1.95 (m, 2 H), 1.68 (s, 3 H), 1.61 (s, 3 H), 1.55–1.52 (m, 2 H), 1.24 (s, 3 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 148.11, 147.83, 145.57, 145.42, 138.11, 135.76, 131.56, 131.09, 127.78, 126.52, 125.34, 124.57, 124.50, 122.44, 119.71, 118.91, 117.20, 112.38, 42.73, 41.18, 25.71, 23.23, 17.68 ppm. LRMS (ESI+): m/z calcd for C₂₆H₂₉N₄O₃ [M + H]⁺: 445.54; found: 445.41

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