Synthesis, cytotoxic, anti-lipoxygenase and anti-acetylcholinesterase capacities of novel derivatives from harmine

Abstract

We synthesized two series of new hydrazide harmine derivatives. The reaction of harmine 1 with ethyl acetate chloride afforded the corresponding ethyl ester 2. The treatment of 2 with hydrazine hydrate gave the hydrazide 3 which further converted into hydrazones 4a-j and dihydrazides 5a-c. A series of new triazoles 7a-f has also been prepared from the suitable propargyl harmine 6. The synthesized derivatives were characterized by 1 H-NMR, 13 C-NMR, and HRMS and evaluated for their activities against MCF7, HCT116 OVCAR-3, acetylcholinesterase and 5-lipoxygenase. The most hydrazones derivatives 4a-j have a good cytotoxic activity against all cell lines, when 4a, 4d, 4f and 4 g are more active than 1 (against OVCAR-3 IC 50 16.7-2.5 mM). The compound 6 was the most active (IC 50 ¼ 1.9 mM) against acetylcholinesterase. Some compounds exhibited significant activity against 5-lipoxygenase (IC 50 ¼ 30.9-63.1 mM).

Synthesis and Biological Evaluation of Harmirins, Novel Harmine–Coumarin Hybrids as Potential Anticancer Agents

“…Twenty novel hybrid compounds comprising two distinct pharmacophores-harmine/ β-carboline and coumarin, connected via triazole linker-were synthesized using CuAAC from harmine-based azides and coumarin alkynes (4 and 5) and coumarin azides and harmine-based alkynes (11)(12)(13), respectively. The evaluation of their antiproliferative activity in vitro against a panel of human cell lines revealed that seven harmirins display activities in the single-digit micromolar range against MCF-7 and HCT116.…”

“…In general, β-carbolines possess a wide range of biological activities, such as anticancer, anti-inflammatory, antiviral, antiparasitic, hallucinogenic, etc. [3,5,[10][11][12][13]. Today, the abundance of research in this field focuses on their anticancer properties.…”

Structure‐Based Design and Synthesis of Harmine Derivatives with Different Selectivity Profiles in Kinase versus Monoamine Oxidase Inhibition

“…(7‐Methoxy‐1‐methyl‐β‐carbolin‐9‐yl)acetic acid ethyl ester (10) : Using ethyl 2‐chloroacetate as the alkylating agent, we obtained 10 (338 mg, 1.13 mmol, 80 %) as an off‐white solid. 1 H NMR (500 MHz, [D 6 ]DMSO): δ =1.22 (t, J= 7.0 Hz, 3 H), 2.82 (s, 1 H), 3.88 (s, 1 H), 4.20 (q, J= 7.0 Hz, 2 H), 5.51 (s, 2 H), 6.89 (dd, J= 1.8, 8.6 Hz, 1 H), 7.28 (d, J= 1.8 Hz, 1 H), 7.88 (d, J= 5.2 Hz, 1 H), 8.09 (d, J= 8.6 Hz, 1 H), 8.18 ppm (d, J= 5.2 Hz, 1 H); 13 C NMR (125 MHz, [D 6 ]DMSO): δ =14.4, 22.8, 46.7, 56.1, 61.6, 94.2, 110.0, 112.7, 114.6, 122.7, 129.1, 135.4, 138.8, 141.0, 143.8, 161.1, 170.0 ppm; HRMS: m / z : calcd for C 17 H 18 N 2 O 3 +H + : 299.1395 [ M +H] + ; found: 299.1391 (Δ f =0.33 ppm).…”

β-Carboline as a Privileged Scaffold for Multitarget Strategies in Alzheimer’s Disease Therapy

“…If isoxazoline derivatives were associated with a 10-fold drop of inhibition potency (IC 50 = 11 μM for the most active analogue 12), 12 a large series of triazoles and hydrazides were found completely inactive against AChE (IC 50 > 100 μM). 13 Natural βcarbolines bearing a 9-methoxy group were also marginally active. 23 Globally, the functionalization of positions 1 and 7 only provided a limited impact (e.g., IC 50 > 10 μM for 1, 9a, and 9b).…”