ABSTRACT
Alzheimer's disease (AD) is a multifactorial neurodegenerative disease that has a heavy social and economic impact on all societies and for which there is still no cure. Multitarget-directed ligands (MTDLs) seem to be a promising therapeutic strategy for finding an effective treatment for this disease. For this purpose, new MTDLs were designed and synthesized in three steps by simple and cost-efficient procedures targeting calcium channel blockade, cholinesterase inhibition, and antioxidant activity. The biological and physicochemical results collected in this study allowed us the identification two sulfonamide-dihydropyridine hybrids showing simultaneous cholinesterase inhibition, calcium channel blockade, antioxidant capacity and Nrf2-ARE activating effect, that deserve to be further investigated for AD therapy.
Subject(s)
Alzheimer Disease , Dihydropyridines , Neurodegenerative Diseases , Humans , Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/therapeutic use , Ligands , Neurodegenerative Diseases/drug therapy , Dihydropyridines/pharmacology , Dihydropyridines/therapeutic use , Calcium Channels , Cholinesterases/metabolism , Acetylcholinesterase/metabolismABSTRACT
A series of new [1,2,4]triazolo[4,3-a]pyrimidine derivatives was prepared using a one-pot three-component synthesis from 5-amino-1-phenyl-1H-1,2,4-triazoles, aromatic aldehydes and ethyl acetoacetate. The compound structures were confirmed by IR, 1H-NMR, 13C-NMR, HRMS and X-ray analyses. The biological activity of these compounds as antitumor agents was evaluated. Their antitumor activities against cancer cell lines (MDA-MB-231 and MCF-7) were tested by the MTT in vitro method. Among them, compounds 4c and 4j displayed the best antitumor activity with IC50 values of 17.83 µM and 19.73 µM against MDA-MB-231 and MCF-7 cell lines, respectively, compared to the Cisplatin reference.
Subject(s)
Antineoplastic Agents , Pyrimidines , Humans , Pyrimidines/chemistry , Antineoplastic Agents/chemistry , Cisplatin/pharmacology , MCF-7 Cells , Magnetic Resonance Spectroscopy , Drug Screening Assays, Antitumor , Structure-Activity Relationship , Cell Proliferation , Cell Line, Tumor , Molecular StructureABSTRACT
Ten new differently substituted 3-benzyl-5-aryl-3,5-dihydro-4H-benzo[6,7]chromeno[2,3-d]pyrimidin-4,6,11-triones 3 were synthesized by a simple and cost-efficient procedure in a one-pot, three-component reaction from readily available ethyl 2-amino-4-aryl-5,10-dioxo-5,10-dihydro-4H-benzo[g]chromene-3-carboxylates, benzylamine and triethyl orthoformate under solvent- and catalyst-free conditions. All the new compounds were screened for their antiproliferative activity against two colorectal-cancer-cell lines. The results showed that the compounds 3-benzyl-5-phenyl-3,5-dihydro-4H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11-trione (3a) and 3-benzyl-5-(3-hydroxyphenyl)-3,5-dihydro-4H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11-trione (3g) exhibited the most potent balanced inhibitory activity against human LoVo and HCT-116 cancer cells.
Subject(s)
Colorectal Neoplasms , Pyrimidines , Humans , Pyrimidines/chemistry , HCT116 Cells , Benzopyrans/chemistry , Colorectal Neoplasms/drug therapyABSTRACT
Novel multitarget-directed ligands BIGI 4a-d and BIGI 5a-d were designed and synthesized with a simple and cost-efficient procedure via a one-pot three-component Biginelli reaction targeting acetyl-/butyrylcholinesterases inhibition, calcium channel antagonism, and antioxidant ability. Among these multitarget-directed ligands, BIGI 4b, BIGI 4d, and BIGI 5b were identified as promising new hit compounds showing in vitro balanced activities toward the recognized AD targets. In addition, these compounds showed suitable physicochemical properties and a good druglikeness score predicted by Data Warrior software.
Subject(s)
Alzheimer Disease , Antioxidants , Calcium Channel Blockers , Cholinesterase Inhibitors , Molecular Targeted Therapy , NF-E2-Related Factor 2 , Humans , Alzheimer Disease/drug therapy , Antioxidants/chemical synthesis , Cholinesterase Inhibitors/chemical synthesis , Ligands , NF-E2-Related Factor 2/metabolism , Structure-Activity Relationship , Calcium Channel Blockers/chemical synthesisABSTRACT
Multidrug resistance constitutes a serious obstacle of the treatment success of cancer by chemotherapy. Mostly it is driven by expression of ABC transport proteins that actively efflux the anticancer agents out of the cell. This work describes the design and synthesis of 12 new pyrimidopyrimidines, as well as their inhibition of ABCG2 a transporter referred also to as breast cancer resistance protein, the selectivity versus ABCB1 (P-glycoprotein/P-gp) and ABCC1 as well as the investigation of their accumulation in single cells. From these results, N-(3,5-dimethoxyphenyl)-2-methyl-7-phenyl-5-(p-tolyl)pyrimido[4,5-d]pyrimidin-4-amine 7 h was identified as promising hit that deserves further investigation showing a selective and effective inhibition of ABCG2 with IC50 equal to 0.493 µM only 2-fold less active than Ko143.
Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Neoplasm Proteins/antagonists & inhibitors , Pyrimidines/pharmacology , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Humans , Molecular Structure , Neoplasm Proteins/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Herein we have reviewed our recent developments for the identification of new tacrine analogues for Alzheimer's disease (AD) therapy. Tacrine, the first cholinesterase inhibitor approved for AD treatment, did not stop the progression of AD, producing only some cognitive improvements, but exhibited secondary effects mainly due to its hepatotoxicity. Thus, the drug was withdrawn from the clinics administration. Since then, many publications have described non-hepatotoxic tacrines, and in addition, important efforts have been made to design multitarget tacrines by combining their cholinesterase inhibition profile with the modulation of other biological targets involved in AD.
Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/pharmacology , Neuroprotective Agents/pharmacology , Tacrine/analogs & derivatives , Tacrine/pharmacology , Acetylcholinesterase/metabolism , Cell Line, Tumor , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/metabolism , Humans , Molecular Docking Simulation , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/metabolism , Protein Binding , Tacrine/metabolismABSTRACT
Alzheimer's disease (AD) is multifactorial disease characterized by the accumulation of abnormal extracellular deposits of amyloid-beta (Aß) peptide, and intracellular neurofibrillary tangles (NFTs), along with dramatic neuronal death and decreased levels of choline acetyltransferase. Given the limited therapeutic success of available drugs, it is urgent to explore all the opportunities available to combat this illness. Among them, the discovery of new heterocyclic scaffolds binding different receptors involved in AD should offer structural diversity and new therapeutic solutions. In this context, this work describes new triazolopyridopyrimidine easily prepared in good yields showing anticholinesterase inhibition and strong antioxidant power, particularly the most balanced: 6-amino-5-(4-methoxyphenyl)-2-phenyl-[1,2,4]triazolo[1',5':1,6] pyrido[2,3-d]pyrimidine-4-carbonitrile(3c) with IC50 equal to 1.32 µM against AChE and oxygen radical absorbance capacity (ORAC) value equal to 4.01 Trolox equivalents (TE); thus representing a new and very promising hit-triazolopyridopyrimidine for AD therapy.
Subject(s)
Antioxidants/chemical synthesis , Cholinesterase Inhibitors/chemical synthesis , Quinoxalines/chemical synthesis , Alzheimer Disease/drug therapy , Drug Discovery , HumansABSTRACT
New tritarget small molecules combining Ca2+ channels blockade, cholinesterase, and H3 receptor inhibition were obtained by multicomponent synthesis. Compound 3p has been identified as a very promising lead, showing good Ca2+ channels blockade activity (IC50 = 21 ± 1 µM), potent affinity against hH3R (Ki = 565 ± 62 nM), a moderate but selective hBuChE inhibition (IC50 = 7.83 ± 0.10 µM), strong antioxidant power (3.6 TE), and ability to restore cognitive impairment induced by lipopolysaccharide.
Subject(s)
Alzheimer Disease/drug therapy , Calcium Channel Blockers/pharmacology , Cholinesterase Inhibitors/pharmacology , Neuroprotective Agents/pharmacology , Receptors, Histamine H3/chemistry , Small Molecule Libraries/pharmacology , Vasodilator Agents/pharmacology , Alzheimer Disease/metabolism , Animals , Calcium Channel Blockers/chemistry , Cholinesterase Inhibitors/chemistry , Humans , Memory Disorders/drug therapy , Memory Disorders/metabolism , Mice , Neuroblastoma/drug therapy , Neuroblastoma/metabolism , Neuroprotective Agents/chemistry , Small Molecule Libraries/chemistry , Tumor Cells, Cultured , Vasodilator Agents/chemistryABSTRACT
In this work we describe the synthesis, Ca+2 channel blockade capacity and antioxidant power of N3,N5-bis(2-(5-methoxy-1H-indol-3-yl)ethyl)-2,6-dimethyl-4-aryl-1,4-dihydropyridine-3,5-dicarboxamides 1-9, a number of multi-target small 1,4-dihydropyridines (DHP), designed by juxtaposition of melatonin and nimodipine. As a result, we have identified antioxidant DHP 7 (Ca2+ channel blockade: 55%, and 8.78 Trolox/Equivalents), the most balanced DHP analyzed here, for potential Alzheimer's disease therapy.
Subject(s)
Alzheimer Disease/drug therapy , Antioxidants/pharmacology , Calcium Channel Blockers/pharmacology , Calcium Channels/chemistry , Calcium/metabolism , Dihydropyridines/pharmacology , Neuroblastoma/drug therapy , Humans , Melatonin/pharmacology , Neuroblastoma/pathology , Nimodipine/pharmacology , Tumor Cells, CulturedABSTRACT
In view of the multifactorial nature of Alzheimer's disease (AD), multitarget small molecules (MTSM) represent the most potent and attractive therapeutic strategy to design new drugs for Alzheimer's disease therapy. The new MTSM KojoTacrines (KTs) were designed and synthesized by juxtaposition of selected pharmacophoric motifs from kojic acid and tacrine. Among them, 11-amino-2-(hydroxymethyl)-12-(3-methoxyphenyl)-7,9,10,12-tetrahydropyrano [2',3':5,6] pyrano[2,3-b]quinolin-4(8H)-one (KT2d) was identified as less-hepatotoxic than tacrine, at higher concentration, a moderate, but selective human acetylcholinesterase inhibitor (IC50 = 4.52 ± 0.24 µM), as well as an antioxidant agent (TE = 4.79) showing significant neuroprotection against Aß1-40 at 3 µM and 10 µM concentrations. Consequently, KT2d is a potential new hit-ligand for AD therapy for further biological exploration.
Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/pharmacology , Neuroprotective Agents/pharmacology , Tacrine/pharmacology , Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Drug Design , Humans , Models, Molecular , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Structure-Activity Relationship , Tacrine/chemical synthesis , Tacrine/chemistryABSTRACT
In this study, the enzymatic synthesis of phenylacetoyl glycerol ester was carried out as a response to the increasing consumer demand for natural compounds. 1,3-dihydroxyphenylacetoyl-sn-Glycerol (1,3-di-HPA-Gly), labeled as "natural" compound with interesting biological properties, has been successfully synthesized for the first time in good yield by a direct esterification of glycerol (Gly) with p-hydroxyphenylacetic acid (p-HPA) using immobilized Candida antarctica lipase as a biocatalyst. Spectroscopic analyses of purified esters showed that the glycerol was mono- or di-esterified on the primary hydroxyl group. These compounds were evaluated for their antioxidant activity using two different tests. The glycerol di-esters (1,3-di-HPA-Gly) showed a higher antiradical capacity than that of the butyl hydroxytoluene. Furthermore, compared to the p-HPA, synthesized ester (1,3-di-HPA-Gly) exhibited the most antibacterial effect mainly against Gramâ¯+â¯bacteria. Among synthesized esters the 1,3-di-HPA-Gly was most effective as antioxidant and antibacterial compound. These findings could be the basis for a further exploitation of the new compound, 1,3-di-HPA-Gly, as antioxidant and antibacterial active ingredient in the cosmetic and pharmaceutical fields.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Antioxidants/chemical synthesis , Candida/enzymology , Fungal Proteins/chemistry , Glycerol/chemical synthesis , Lipase/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antioxidants/chemistry , Chromatography, High Pressure Liquid , Enzymes, Immobilized/chemistry , Enzymes, Immobilized/metabolism , Fungal Proteins/metabolism , Glycerol/analogs & derivatives , Glycerol/chemistry , Glycerol/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Lipase/metabolism , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Spectroscopy, Fourier Transform Infrared , Tandem Mass SpectrometryABSTRACT
AIM: Due to the complex nature of Alzheimer's disease, there is a renewed search for multitarget directed drugs. RESULTS: This paper describes the synthesis and in vitro biological evaluation of six racemic 13-aryl-2,3,4,13-tetrahydro-1H,12H-benzo[6,7]chromeno[2,3-d]pyrido[1,2-a]pyrimidine-7,12,14-triones (1a-6a), and six racemic 15-aryl-8,9,10,11,12,15-hexahydro-14H-benzo[6',7']chromeno[2',3:4,5] pyr-imido [1,2-a]azepine-5,14,16-triones (1b-6b), showing antioxidant and cholinesterase inhibitory capacity. Among these compounds, 13-phenyl-2,3,4,13-tetrahydro-1H,12H-benzo[6,7]chromeno[2,3-d]pyrido[1,2-a]pyrimidine-7,12,14-trione (1a) is a nonhepatotoxic at 300 µmol/l dose concentration, and a selective EeAChE inhibitor showing good antioxidant power. CONCLUSION: A new family of racemic benzochromenopyrimidinetriones has been investigated for their potential use in the treatment of Alzheimer's disease.
Subject(s)
Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Antioxidants/pharmacology , Cholinesterase Inhibitors/pharmacology , Heterocyclic Compounds, 4 or More Rings/pharmacology , Naphthoquinones/pharmacology , Alzheimer Disease/metabolism , Antioxidants/chemical synthesis , Antioxidants/chemistry , Cell Survival/drug effects , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Hep G2 Cells , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Humans , Molecular Structure , Naphthoquinones/chemical synthesis , Naphthoquinones/chemistry , Structure-Activity RelationshipABSTRACT
Herein we report an efficient two step synthesis and biological assessment of 12 racemic tetrahydropyranodiquinolin-8-amines derivatives as antioxidant, cholinesterase inhibitors and non-hepatotoxic agents. Based on the results of the primary screening, we identified 7-(3-methoxyphenyl)-9,10,11,12-tetrahydro-7H-pyrano[2,3-b:5,6-h']diquinolin-8-amine (2h) as a particularly interesting non-hepatotoxic compound that shows moderate antioxidant activity (1.83 equiv Trolox in the ORAC assay), a non competitive inhibition of hAChE (IC50 = 0.75 ± 0.01 µM), and brain permeable as determined by the PAMPA-Blood Brain Barrier assay.
Subject(s)
Aminoquinolines/pharmacology , Antioxidants/pharmacology , Cholinesterase Inhibitors/pharmacology , Acetylcholinesterase , Alzheimer Disease/drug therapy , Aminoquinolines/chemical synthesis , Antioxidants/chemistry , Blood-Brain Barrier/metabolism , Chemical and Drug Induced Liver Injury , Cholinesterase Inhibitors/chemistry , GPI-Linked Proteins/antagonists & inhibitors , HumansABSTRACT
We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 µM), good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.
Subject(s)
Alzheimer Disease/prevention & control , Antioxidants/chemical synthesis , Antioxidants/pharmacology , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Liver/drug effects , Spectrum AnalysisABSTRACT
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 ß-amyloid (Aß1-42 ) 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)â µm], has strong antioxidant activity (3.61â µmol Trolox equivalents), and moderate Aß1-42 antiaggregating power (40.3 %).
Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Antioxidants/chemical synthesis , Cholinesterase Inhibitors/therapeutic use , Cholinesterases/metabolism , Imines/chemistry , Peptide Fragments/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Antioxidants/chemistry , Antioxidants/therapeutic use , Binding Sites , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Cholinesterases/chemistry , Humans , Imines/chemical synthesis , Imines/therapeutic use , Ligands , Molecular Docking Simulation , Peptide Fragments/antagonists & inhibitors , Protein Structure, TertiaryABSTRACT
BACKGROUND: Owing to the complex nature of Alzheimer's disease, there is a renewed and growing search for multitarget non-toxic tacrines as simple, easily available drugs in order to stop the progress and development of the disease. RESULTS: This paper describes our preliminary results on the synthesis, in vitro biochemical evaluation and molecular modeling of isoxazolotacrines as potential drugs for the treatment of Alzheimer's disease. Novel 3-phenyl-5,6,7,8-tetrahydroisoxazolo[5,4-b]quinolin-4-amine (OC41) is a promising, 31% less toxic than tacrine in HepG2 cells, and selective reversible human butyrylcholinesterase inhibitor (IC50 = 5.08 ± 1.12 µM), also showing good drug-like properties according to the absorption, Distribution, Metabolism, Excretion, Toxicity analysis. CONCLUSION: A new family of non-hepatotoxic permeable tacrine analogs, showing selective butyrylcholinesterase inhibition, have been discovered for the potential treatment of Alzheimer's disease.
Subject(s)
Cholinesterase Inhibitors/chemistry , Isoxazoles/chemistry , Tacrine/chemistry , Acetylcholinesterase/chemistry , Acetylcholinesterase/genetics , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Butyrylcholinesterase/chemistry , Butyrylcholinesterase/genetics , Butyrylcholinesterase/metabolism , Cell Survival/drug effects , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/pharmacology , HEK293 Cells , Hep G2 Cells , Humans , Molecular Docking Simulation , Protein Binding , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Tacrine/pharmacology , Tacrine/therapeutic useABSTRACT
We report the synthesis of new anti-inflammatory 1,7-dihydropyrazolo[3',4':4,5]pyrimido[1,6-a]pyrimidine 5 from aminocyanopyrazole. All compounds were characterized by physical, chemical and spectral studies. Preliminary pharmacological evaluation of the resulting products showed that compounds 5a, b, f (50-100 mg/kg, i.p) are active anti-inflammatory agents in carrageenan-induced rat paw oedema assay, and their effects are comparable to that of acetylsalicylic-lysine (300 mg/kg, i.p.), used as a reference drug. The nature of substituent (Y, R3) had a pronounced effect on the anti-inflammatory activity. Studies of structure-activity relationships have led to selection of compound ethyl-3,5-dimethyl-7-imino-N1-phenyl-1,7-dihydropyrazolo[3',4':4,5]pyrimido[1,6-a]pyrimidine-6-carboxylate, 5f which exhibited the most potent anti-inflammatory activity. In addition, the compounds 5a, b, f showed a significant gastroprotective effect against HCl/EtOH-induced gastric ulcer.
ABSTRACT
The synthesis, toxicity, neuroprotection, and human acetylcholinesterase (hAChE)/ human butyrylcholinesterase (hBuChE) inhibition properties of ß-naphthotacrines1-14 as new drugs for Alzheimer's disease (AD) potential treatment, are reported. ß-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 ß-naphthotacrines bearing electron-donating substituents at the aromatic ring, ß-naphthotacrine10 being the most potent (hAChE: IC50 = 0.083 ± 0.024 µM). Kinetic inhibition analysis clearly demonstrated that ß-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 ß-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.
Subject(s)
Alzheimer Disease/drug therapy , Cerebral Cortex/drug effects , Cholinesterase Inhibitors/pharmacology , Neurons/drug effects , Neuroprotective Agents/pharmacology , Tacrine/analogs & derivatives , Acetylcholinesterase/metabolism , Butyrylcholinesterase/metabolism , Cell Survival/drug effects , Cerebral Cortex/pathology , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Hep G2 Cells , Humans , Molecular Structure , Neurons/pathology , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Structure-Activity Relationship , Tacrine/chemical synthesis , Tacrine/chemistry , Tacrine/pharmacologyABSTRACT
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.
Subject(s)
Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrases/metabolism , Cytosol/enzymology , Pyrazoles/pharmacology , Sulfonamides/pharmacology , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrases/isolation & purification , Dose-Response Relationship, Drug , Humans , Molecular Structure , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/isolation & purification , Protein Isoforms/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistryABSTRACT
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 Alzheimer's disease.