Contilistat, a New Multitarget Small Polyfunctionalized Indole Derivative

Abstract

We describe the design, synthesis, and in vitro biological evaluation of contilistat, a novel polyfunctionalized indole derivative designed as a hybrid of contilisant and vorinostat containing key pharmacophoric groups of both parent ligands.

Key words

docking analysis - medicinal chemistry - multitarget drugs - indoles - contilistat

Publication History

Received: 05 September 2024

Accepted after revision: 29 October 2024

Article published online:
22 November 2024

• References and Notes

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• 25 Contilistat TFA (0.3 mL, 3.65 mmol) and Et₃SH (0.5 mL, 3.04 mmol) were added to a solution of diamide 8 (267 mg, 0.30 mmol) in anhyd CH₂Cl₂ (6 mL), and the mixture was kept at r.t. for 2 h. The solvent was then removed and the crude product was purified by column chromatography [Biotage Sfär KP-Amino D, (CH₂Cl₂–5% MeOH)] to give a solid product; yield: 110 mg (58%); mp 83–85 °C. IR (KBr): 285 (O–H), 3227 (N–H), 1651 (C=O), 1462 (O=S=O), 1161 (C–O–C) cm^–1. ¹H NMR (400 MHz, DMSO-d ₆ + D₂O, 100 °C): δ = 7.86 (d, J = 9.1 Hz, 1 H), 7.74 (dm, J = 7.3 Hz, 2 H), 7.65 (tm, J = 8.5 Hz, 1 H), 7.54 (ddm, J = 8.5, 7.3 Hz, 1 H), 7.00 (d, J = 2.6 Hz, 1 H), 6.89 (dd, J = 9.1, 2.6 Hz, 1 H), 6.45 (s, 1 H), 4.91 (d, J = 1.5 Hz, 2 H), 4.20 (d, J = 2.1 Hz, 2 H), 3.98 (t, J = 6.7 Hz, 2 H), 2.37 (t, J = 6.7 Hz, 2 H), 2.32 (t, J = 5.4 Hz, 4 H), 2.02–1.94 (m, 2 H), 1.82 (p, J = 6.7 Hz, 2 H), 1.56–1.43 (m, 10 H), 1.36 (ptm, J = 5.7 Hz, 2 H), 1.30–1.17 (m, 4 H). ¹³C NMR (101 MHz, DMSO-d ₆ + D₂O, 100 °C): δ = 172.6 (2 C), 155.8, 137.6 (2 C), 134.3, 131.3, 130.4, 129.6 (2 C), 125.8 (2 C), 114.8, 113.7, 109.8, 104.9, 66.6, 54.9, 53.9 (2 C), 31.9, 28.1, 26.3, 25.3 (3 C), 24.5, 24.2, 23.9. (Some of the ¹H and ¹³C NMR peaks were masked or could not be located; for details and the assignments of peaks, see the SI). HRMS (ESI): m/z [M + H]⁺ calcd for C₃₄H₄₄N₄O₆S: 637.3045; found: 637.3045.