Fakher Chabchoub

Synthesis, biological assessment, and molecular modeling of racemic 7-aryl-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-8-amines as potential drugs for the treatment of Alzheimer's disease

The synthesis, pharmacological analysis and molecular modeling of the readily available racemic tacrine analogs 21-30, bearing the 7-aryl-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-8-amine heterocyclic ring system (II), prepared by Friedländer reaction of 2-amino-4-aryl-4H-benzo[h]chromene-3-carbonitriles (11-20) with cyclohexanone, are described in this paper. Molecules 21-30 are potent and selective inhibitors of hAChE, in the low micromolar range, one of the most potent inhibitors, 4-(8-amino-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-7-yl)-2-methoxyphenol (25), showing a IC(50) (hAChE) = 0.33 ± 0.04 μM. Kinetic studies of compound 25 proved that this compound is a mixed type inhibitor for EeAChE (K(i) = 81 nM). Accordingly, molecular modeling of inhibitor 25 showed that both enantiomers have two major predicted binding modes at the active and at the peripheral anionic sites of AChE. Inhibitor 25 has an excellent antioxidant profile as determined in the ORAC experiment (1.47 ± 0.10 Trolox equiv). Inhibitors 26-28 and 30 are permeable to BBB as determined in the PAMPA assay. Compared to tacrine, selected compounds 26-28 and 30 showed less hepatic toxicity in HepG2 cells. Moreover, cell viability-related studies in cortical neurons in primary cultures show that compounds 26-28 and 30 (0.1-50 μM) have significant neuroprotective effects against mitochondrial chain blockers-induced cell death, and, unlike tacrine, are not neurotoxic at concentrations lower than 50 μM. It is worth highlighting that compound 27 has the best neuroprotective properties out of all assayed compounds and shows no neurotoxicity. To sum up, these tacrine analogs can be considered as attractive multipotent therapeutic molecules on pharmacological receptors playing key roles in the progress of Alzheimers disease.

Synthesis of aminocyanopyrazoles via a multi-component reaction and anti-carbonic anhydrase inhibitory activity of their sulfamide derivatives against cytosolic and transmembrane isoforms.

A convenient protocol for the multicomponent reaction (MCRs) between malononitrile with an orthoester and hydrazine derivatives, under acid catalyst is described. A series of aminocyanopyrazoles 4 was prepared, isolated and characterized. These pyrazoles reacted with sodium nitrite followed by secondary amine reagent and with formic acid to lead pyrazolotriazines 6 and pyrazolopyrimidinones 7. Some of the aminopyrazoles were converted to the corresponding sulfamides by reaction with sulfamoyl chloride. The aminopyrazoles incorporating phenyl and tosyl moieties were tested as inhibitors of four carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the human (h) hCA I, II, IX and XII. Many of them showed low micromolar or submicromolar inhibition of these enzymes. The corresponding sulfamides were low nanomolar CA inhibitors.

Nontoxic and Neuroprotective β‑Naphthotacrines for Alzheimer's Disease

The synthesis, toxicity, neuroprotection, and human acetylcholinesterase (hAChE)/ human butyrylcholinesterase (hBuChE) inhibition properties of β-naphthotacrines1-14 as new drugs for Alzheimers disease (AD) potential treatment, are reported. β-Naphthotacrines1-14 showed lower toxicity than tacrine; moreover, at the highest concentration assayed (300 μM) compounds 7, 10 and 11 displayed 2.25-2.01-fold higher cell viability than tacrine in HepG2 cells. A neuroprotective effect was observed for compounds 10 and 11 in a neuronal cortical culture exposed to a combination of oligomycin A/rotenone. An efficient and selective inhibition of hAChE, was only observed for the β-naphthotacrines bearing electron-donating substituents at the aromatic ring, β-naphthotacrine10 being the most potent (hAChE: IC50 = 0.083 ± 0.024 μM). Kinetic inhibition analysis clearly demonstrated that β-naphthotacrine10 behaves as a mixed-type inhibitor (Ki2= 0.72 ± 0.06 μM) at high substrate concentrations (0.5-10 μM), while at low concentrations (0.01-0.1 μM) it behaves as a hAChE competitive inhibitor (Ki1= 0.007 ± 0.001 μM). These findings identified β-naphthotacrine10 as a potent and selective hAChE inhibitor in a nanomolar range, with toxicity lower than that of tacrine both in human hepatocytes and rat cortical neurons, with a potent neuroprotective activity and, consequently, an attractive multipotent active molecule of potential application in AD treatment.

Synthesis, biological assessment and molecular modeling of 14-aryl-10,11,12,14-tetrahydro-9H-benzo[5,6]chromeno[2,3-b]quinolin-13-amines

The synthesis and pharmacological evaluation of racemic 14-aryl-10,11,12,14-tetrahydro-9H-benzo[5,6]chromeno[2,3-b]quinolin-13-amines (19-28), prepared by Friedländer reaction of 3-amino-1-aryl-1H-benzo[f]chromene-2-carbonitriles (10-18) with suitable cycloalkanones is described. These molecules are potent, in the nanomolar range [IC(50) (EeAChE)=7-101 nM], and selective inhibitors of acetylcholinesterase (AChE). The most potent inhibitor, 4-(13-amino-10,11,12,14-tetrahydro-9H-benzo[5,6]chromeno[2,3-b]quinolin-14-yl)phenol (20) [IC(50) (EeAChE)=7±2 nM] is four-fold more active than tacrine. Kinetic studies on compound 20 showed that this is a mixed-type inhibitor of EeAChE with a K(i) of 5.00 nM. However, racemic 20 was unable to displace propidium iodide, suggesting that the inhibitor does not strongly bind to the peripheral anionic site (PAS) of AChE. Docking, molecular dynamics stimulations, and MM-GBSA calculations agree well with this behavior.

ACTION OF PRIMARY AMINES AND HYDROXYLAMINE ON ETHOXYMETHYLENEAMINONAPHTOPYRANES: SYNTHESIS OF NEW NAPHTOPYRANO [2,3-d] PYRIMIDINES DERIVATIVES

A variety of naphtopyrans 1 has been prepared by reaction of 2-naphtol with aryl (or alkyl) idenemalononitriles. The reaction of the naphtopyrans with triethylorthoformiate and then with primary amines and hydroxylamine, leads to new naphtopyrano [2, 3-d] pyrimidines 3 and 4, whose structures were confirmed by IR and NMR spectroscopy.

Synthesis and Biological Assessment of Racemic Benzochromenopyrimidinimines as Antioxidant, Cholinesterase, and Aβ1−42 Aggregation Inhibitors for Alzheimer's Disease Therapy

Given the complex nature of Alzheimer′s disease (AD), compounds that are able to simultaneously address two or more AD‐associated targets show greater promise for development into drugs for AD therapy. Herein we report an efficient two‐step synthesis and biological evaluation of new racemic benzochromene derivatives as antioxidants, inhibitors of cholinesterase and β‐amyloid (Aβ1−42) aggregation. Based on the results of the primary screening, we identified 15‐(3‐methoxyphenyl)‐9,11,12,15‐tetrahydro‐10H,14H‐benzo[5,6]chromeno[2,3‐d]pyrido[1,2‐a]pyrimidin‐14‐imine (3 e) and 16‐(3‐methoxyphenyl)‐9,10,11,12,13,16‐hexahydro‐15H‐benzo[5′,6′]chromeno[2′,3′:4,5]pyrimido[1,2‐a]azepin‐15‐imine (3 f) as new potential multitarget‐directed ligands for AD therapy. Further in‐depth biological analysis showed that compound 3 f is a good human acetylcholinesterase inhibitor [IC50=(0.36±0.02) μm], has strong antioxidant activity (3.61 μmol Trolox equivalents), and moderate Aβ1−42 antiaggregating power (40.3 %).

Action du Disulfure de Carbone et du Phenylthioisocyanate sur des Derives Naphtopyraniques: Obtention des Naphtopyranopyrimidodithiones et des Naphtopyranopyrimidothiones

Naphtopyranes 1 react with carbon disulfide and phenylthioisocyanate to give the naphtopyranopyrimidodithiones 3 and the naphtopyranopyrimido-thiones 4 respectively. The structure of products 3 and 4 is confirmed by IR, NMR, and for some of the compounds by elemental analysis and LC/MS.

Synthese et Reactivité des Pyranopyrimidines Tosyles vis a vis du Chlorure de Thionyle: Obtention des 1,2,3,5-Thiatriazolopyrimidines

Iminoethers 1 react with phenylhydrazine to give naphtopyranes 2′ or with tosylhydrazine to yield the pyranopyrimidines 2. The condensation of these pyranopyrimidines with thionylchloride forms a new synthetic method for accessing to 1,2,3,5-thiatriazolopyrimidine-1-oxyde derivatives 3.

Heterocyclization of Imidates with 3‐Alkyl‐5‐amino‐1‐phenyl‐1,2,4‐triazoles: Synthesis of New Triazolotriazines

Abstract Some novel triazolo[4,3‐a]triazines derivatives were synthesized by reaction of N‐cyanoimidates and N‐ethoxycarbonylimidates with 3‐alkyl‐5‐amino‐1‐phenyl‐1,2,4‐triazoles.

Synthesis of 6-Amino-5-cyano-1,4-disubstituted-2(1H)- Pyrimidinones via Copper-(I)-catalyzed Alkyne-azide 'Click Chemistry' and Their Reactivity

In this paper we present the room temperature synthesis of a novel serie of 1,4-disubstituted-1,2,3-triazoles 4a-l by employing the (3+2) cycloaddition reaction of pyrimidinones containing alkyne functions with different model azides in the presence of copper sulphate and sodium ascorbate. To obtain the final triazoles, we also synthesized the major precursors 6-amino-5-cyano-1,4-disubstituted-2(1H)-pyrimidinones 3a-r from ethyl 2,2-dicyanovinylcarbamate derivatives 2a-c and various primary aromatic amines containing an alkyne group. The triazoles were prepared in good to very good yields.