Chemical and Biological Evaluation of Novel 1 H -Chromeno[3,2- c ]pyridine Derivatives as MAO Inhibitors Endowed with Potential Anticancer Activity.
Larisa N KulikovaRosa PurgatorioAndrey A BeloglazkinViktor A TafeenkoRaesi Gh RezaDaria D LevickayaSabina SblanoAngelina BoccarelliModesto de CandiaMarco CattoLeonid G VoskressenskyCosimo Damiano AltomarePublished in: International journal of molecular sciences (2023)
About twenty molecules sharing 1 H -chromeno[3,2- c ]pyridine as the scaffold and differing in the degree of saturation of the pyridine ring, oxidation at C10, 1-phenylethynyl at C1 and 1 H -indol-3-yl fragments at C10, as well as a few small substituents at C6 and C8, were synthesized starting from 1,2,3,4-tetrahydro-2-methylchromeno[3,2- c ]pyridin-10-ones (1,2,3,4-THCP-10-ones, 1 ) or 2,3-dihydro-2-methyl-1 H -chromeno[3,2- c ]pyridines (2,3-DHPCs, 2 ). The newly synthesized compounds were tested as inhibitors of the human isoforms of monoamine oxidase (MAO A and B) and cholinesterase (AChE and BChE), and the following main SARs were inferred: (i) The 2,3-DHCP derivatives 2 inhibit MAO A (IC 50 about 1 μM) preferentially; (ii) the 1,2,3,4-THCP-10-one 3a , bearing the phenylethynyl fragment at C1, returned as a potent MAO B inhibitor (IC 50 0.51 μM) and moderate inhibitor of both ChEs (IC 50 s 7-8 μM); (iii) the 1 H -indol-3-yl fragment at C10 slightly increases the MAO B inhibition potency, with the analog 6c achieving MAO B IC 50 of 3.51 μM. The MAO B inhibitor 3a deserves further pharmacological studies as a remedy in the symptomatic treatment of Parkinson's disease and neuroprotectant for Alzheimer's disease. Besides the established neuroprotective effects of MAO inhibitors, the role of MAOs in tumor insurgence and progression has been recently reported. Herein, antiproliferative assays with breast (MCF-7), colon (HCT116) and cisplatin-resistant ovarian (SK-OV-3) tumor cells revealed that the 10-indolyl-bearing 2,3,4,10-THCP analog 6c exerts anti-tumor activity with IC 50 s in the range 4.83-11.3 μM.