Modular Synthesis and Antiproliferative Activity of New Dihydro-1H-pyrazolo[1,3-b]pyridine Embelin Derivatives

Abstract

A set of new dihydro-1H-pyrazolo[1,3-b]pyridine and pyrazolo[1,3-b]pyridine embelin derivatives was synthesized through a multicomponent reaction from natural embelin, 3-substituted-5-aminopyrazoles and aldehydes. The synthesized compounds were evaluated against three hematologic tumor cell lines, HEL (acute erythroid leukemia), K-562 (chronic myeloid leukemia) and HL-60 (acute myeloid leukemia), and five breast cancer cell lines (SKBR3, MCF-7, MDA-MB-231, BT-549, HS-578T). The primate non-malignant kidney Vero cell line was used as the control of cytotoxicity. From the obtained results, some structure–activity relationships were outlined. Furthermore, in silico prediction of physicochemical properties and ADME parameters were determined for the derivatives with the best antiproliferative values.

Synthesis of Quinoline and Dihydroquinoline Embelin Derivatives as Cardioprotective Agents

“…2-Hydroxy-9-(4-nitrophenyl)-3-undecylacridine-1,4-dione (6a). Yield: 14.4 mg (72%) of compound 6a, as an orange oil; UV (EtOH) λ max 291, 297, 344 nm; IR (film) ν max 3373, 2989, 2307, 1703, 1155, 1073, 827 cm −1 ; 1 H NMR (500 MHz, CDCl 3 ): 0.87 (t, J = 7.2 Hz, 3H), 1.25 (bs, 16H), 1.39 (m, 2H), 2.71 (t, J = 7.7 Hz, 2H), 7.41 (d, J = 8.9 Hz, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.64 (t, J = 7.5 Hz, 2H), 7.95 (d, J = 7.7 Hz, 2H), 8.46 (d, J = 8.5 Hz, 2H), 8.51 (d, J = 8.4 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ 14.1 (CH 3 ), 22.7 (CH 2 ), 23.8 (CH 2 ), 28.1 (CH 2 ), 29.3 (CH 2 ), 29.4 (CH 2 ), 29.5 (CH 2 ), 29.6 (CH 2 ), 29.7 (CH 2 × 2), 31.9 (CH 2 ), 114.7 (C), 123.9 (CH × 2), 127.3 (CH), 127.6 (C), 127.9 (C), 129.2 (CH × 2), 130.1 (CH), 132.0 (CH), 133.5 (CH), 143.1 (C), 147.6 (C), 147.9 (C), 149.2 (C), 149.4 (C), 154.3 (C), 180.4 (C), 182.2 (C); EIMS m/z (%) 500 ([M + ], 100), 472 (10), 372 (21) (39), 335 (46), 304 (20) 7-Bromo-2-hydroxy-9-(4-nitrophenyl)-3-undecylacridine-1,4dione (6m). Yield: 5.4 mg (72%) of compound 6m, as an orange oil; UV (EtOH) λ max 291, 297, 350 nm; IR (film) ν max 3054, 2989, 2926, 2855, 2307, 1662, 1520, 1423, 1267, 895 cm −1 ; 1 H NMR (500 MHz, CDCl 3 ) 0.87 (t, J = 7.1 Hz, 3H), 1.25 (bs, 16H), 1.39 (m, 2H), 2.71 (t, J = 7.7 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 1.9 Hz, 1H), 8.01 (dd, J = 2.1, 8.9 Hz, 1H), 8.37 (d, J = 8.9 Hz, 1H), 8.48 (d, J = 8.5 Hz, 2H); 13 79 Br [M + ] 578.1416).…”

“…43−45 Our research group improved selectivity and potency of this natural product by increasing its complexity and structural diversification, using a domino Knoevenagel−Michael addition−intramolecular cyclization sequence developed by us. 46,47 Aiming to extend the chemical diversity around nitrogencontaining heterocycles fused to this natural benzoquinone, we decided to carry out the synthesis of embelin derivatives fused to dihydroquinoline and quinoline structures.…”