8H-Chromeno[2′,3′:4,5]imidazo[2,1-a]isoquinoline

The title compound, C18H12N2O, comprises two aromatic fragments, viz., imidazo[2,1-a]isoquinoline and benzene, linked by oxygen and methyl­ene bridges. Despite the absence of a common conjugative system within the mol­ecule, it adopts an essentially planar conformation with an r.m.s. deviation of 0. 036 Å. In the crystal, due to this structure, mol­ecules form stacks along the b axis by π⋯π stacking inter­actions, with shortest C⋯C distances in the range 3.340 (4)–3.510 (4) Å. The mol­ecules are bound by inter­molecular C—H⋯O inter­actions within the stacks and C—H⋯π inter­actions between the stacks

Synthesis of Novel Benzo[<i>b</i>][1,6]naphthyridine Derivatives and Investigation of Their Potential as Scaffolds of MAO Inhibitors

In this work, 2-alkyl-10-chloro-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridines were obtained and their reactivity was studied. Novel derivatives of the tricyclic scaffold, including 1-phenylethynyl (5), 1-indol-3-yl (8), and azocino[4,5-b]quinoline (10) derivatives, were synthesized and characterized herein for the first time. Among the newly synthesized derivatives, 5c–h proved to be MAO B inhibitors with potency in the low micromolar range. In particular, the 1-(2-(4-fluorophenyl)ethynyl) analog 5g achieved an IC50 of 1.35 μM, a value close to that of the well-known MAO B inhibitor pargyline

In-vitro and in-silico studies of annelated 1,4,7,8-tetrahydroazocine ester derivatives as nanomolar selective inhibitors of human butyrylcholinesterase

Based on previous finding showing 2,3,6,11-tetrahydro-1H-azocino[4,5-b]indole as suitable scaffold of novel inhibitors of acetylcholinesterase (AChE), a main target of drugs for the treatment of Alzheimer's disease and related dementias, herein we investigated diverse newly and previously synthesized beta-enamino esters (and ke-tones) derivatives of 1,4,7,8-tetrahydroazocines (and some azonines) fused with benzene, 1H-indole, 4H-chro-men-4-one and pyrimidin-4(3H)-one. Twenty derivatives of diversely annelated eight-to-nine-membered azaheterocyclic ring, prepared through domino reaction of the respective tetrahydropyridine and azepine with activated alkynes, were assayed for the inhibitory activity against AChE and butyrylcholinesterase (BChE). As a major outcome, compound 7c, an alkylamino derivative of tetrahydropyrimido[4,5-d]azocine, was found to be a highly potent BChE-selective inhibitor, which showed a noncompetitive/mixed-type inhibition mechanism against human BChE with single digit nanomolar inhibition constant (Ki = 7.8 +/- 0.2 nM). The four-order magnitude BChE-selectivity of 7c clearly reflects the effect of lipophilicity upon binding to the BChE binding cavity. The ChEs' inhibition data, interpreted by chemoinformatic tools and an in-depth in-silico study (mo-lecular docking combined with molecular dynamics calculations), not only highlighted key structural factors enhancing inhibition potency and selectivity toward BChE, but also shed light on subtle differences dis-tinguishing the binding sites of equine BChE from the recombinant human BChE. Compound 7c inhibited P-glycoprotein with IC50 of 0.27 mu M, which may support its ability to permeate blood-brain barrier, and proved to be no cytotoxic in human liver cancer cell line (HepG2) at the BChE bioactive concentrations. Overall, the biological profile allows us to envision 7c as a promising template to improve design and development of BChE-selective ligands of pharmaceutical interest, including inhibitors and fluorogenic probes

Chemical and Biological Evaluation of Novel 1<i>H</i>-Chromeno[3,2-<i>c</i>]pyridine Derivatives as MAO Inhibitors Endowed with Potential Anticancer Activity

About twenty molecules sharing 1H-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 1H-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-1H-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 (IC50 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 (IC50 0.51 μM) and moderate inhibitor of both ChEs (IC50s 7–8 μM); (iii) the 1H-indol-3-yl fragment at C10 slightly increases the MAO B inhibition potency, with the analog 6c achieving MAO B IC50 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 IC50s in the range 4.83–11.3 μM

Auto-deconvolution and molecular networking of gas chromatography-mass spectrometry data.

We engineered a machine learning approach, MSHub, to enable auto-deconvolution of gas chromatography-mass spectrometry (GC-MS) data. We then designed workflows to enable the community to store, process, share, annotate, compare and perform molecular networking of GC-MS data within the Global Natural Product Social (GNPS) Molecular Networking analysis platform. MSHub/GNPS performs auto-deconvolution of compound fragmentation patterns via unsupervised non-negative matrix factorization and quantifies the reproducibility of fragmentation patterns across samples