Synthesis of new isoxazoline derivatives from harmine and evaluation of their anti-Alzheimer, anti-cancer and anti-inflammatory activities

Abstract

In our study, a series of new harmine derivatives has been prepared by cycloaddition reaction using various arylnitrile oxides and evaluated in vitro against acetylcholinesterase and 5-lipoxygenase enzymes, MCF7 and HCT116 cancer cell lines. Some of these molecules have been shown to be potent inhibitors of acetylcholinesterase and MCF7 cell line. The greatest activity against acetylcholinesterase (IC50 = 10.4 µM) was obtained for harmine 1 and cytotoxic activities (IC50 = 0.2 µM) for compound 3a. Two derivatives 3e and 3f with the thiophene and furan systems, respectively, showed good activity against 5- lipoxygenase enzyme (IC50 = 29.2 and 55.5 µM, respectively).

Synthesis of new anticancer and anti-inflammatory isoxazolines and aziridines from the natural (-)-deltoin

“…The prepared derivatives have been shown to be inactive to moderately active and the noted per cent inhibitions of most of them ranged from 3.3 ± 1.2% (compound 2e ′) to 53.1 ± 4.8% (mixture 2f+f ′) at 200 μ m . These results were in agreement with one of our earlier works that described the anti‐5‐lipoxygenase activity of certain isoxazolines prepared from harmine . The results of the above work have shown that cycloadducts with isoxazolines bearing a phenyl, a 4‐methylphenyl, a 4‐methoxyphenyl and a 4‐chlorophenyl have been found to be inactive .…”

“…These results were in agreement with one of our earlier works that described the anti-5-lipoxygenase activity of certain isoxazolines prepared from harmine. [25] The results of the above work have shown that cycloadducts with isoxazolines bearing a phenyl, a 4-methylphenyl, a 4-methoxyphenyl and Table 1 5-lipoxygenase inhibition capacity (per cent inhibition (%)) and cytotoxicity (HCT-116, IGROV-1 and OVCAR-3 cells lines) (IC 50 (lM)) of (-)-deltoin 1 and its derivatives 2a,a 0 -f,f 0 and 3a,a 0 -e,e 0 The aziridine derivatives, except 3c,c 0 , have shown a moderate cytotoxic activity against the ovary cell lines IGROV-1 and OVCAR-3 with IC 50 values ranging from 31.0 AE 2.0 to 71.0 AE 2.6 lM. This difference is due to the selectivity of the products tested against these cancer cell lines.…”

“…However, the manner of attachment of this ring in the molecule certainly affects the cytotoxic activity. [26][27][28] The absence of any significant improvement in activity of (-)-deltoin 1 by incorporating an isoxazoline system bearing an aromatic ring at C-6″ with a chlorine, a methyl, a methoxy and a butoxy all in para-position has shown the importance of the nature of the aromatic moiety used, [25] in addition to the stereochemistry of the asymmetric centres introduced.…”

Benzofuran and Indole: Promising Scaffolds for Drug Development in Alzheimer's Disease

“…discuss the inhibitory activity of harmine and its isoxazoline derivatives (Figure ) against AChE. Harmine and its isoxazoline derivatives show inhibition of AChE, and harmine shows the best inhibitory activity with an IC 50 value of 10.4 μ m …”

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

“…From ancient times, this alkaloid drew increasing interest due to its diverse pharmacological and biological activities 11 . It is known to be anti-acetylcholinesterase, antimicrobial, antifungal and cytotoxic 12 . The latest research showed that harmine can inhibit the breast cancer protein BCRP so it was used as resistance to anticancer drugs 13 .…”