Microbial and xanthine dehydrogenase inhibitory activity of some flavones

Xanthine dehydrogenase (XDH) is responsible for the pathological condition called Gout. In the present study different flavones synthesized from chalcone were evaluated in vitro for their inhibitory activity. Inhibitory activity of flavones on XDH was determined in terms of inhibition of uric acid synthesis from Xanthine. The enzymatic activity was found maximum at pH 7.5 and temperature 40 degrees C. The flavones 6-chloro-2-[3-(4-hydroxy-phenyl)-1-phenyl-1-H-pyrazol-4-yl]-chromen-4-one (F(1)) and 6-chloro-7methyl-2-[3-(4-chloro-phenyl)-1-phenyl-1-H-pyrazol-4-yl]-chromen-4-one(F(2)),were noncompetitive and competitive inhibitor with Ki values 1.1 and 0.22 respectively. The flavones (F(1)), (F(2)), 6-chloro-2-[3-(4-chloro-phenyl)-1phenyl-1-H-pyrazol-4-yl]-chromen-4-one(F(3)), 8-bromo-6-chloro-2-[3-(4-chloro-phenyl)-1-phenyl-1-H-pyrazol-4-yl]-chromen-4-one (F(4)), 2-[3-(4-hydroxy-phenyl)-1-phenyl-1-H-pyrazol-4-yl]-chromen-4-one (F(5)) and 6-methyl-2-[3-(4-hydroxy-phenyl)-1-phenyl-1-H-pyrazol-4-yl]-chromen-4-one (F(6)) were also screened for their antimicrobial activity, measured in terms of zone of inhibition. A broad spectrum antifungal activity was obtained against Trichoderma viridae, Candida albicans, Microsporum cannis, Penicillium chrysogenum and Fusarium moniliformae. In case of Aspergillus niger and Aspergillus flavous only spore formation was affected, while antibacterial activity was observed against Staphylococcus aureus, Bacillus subtilis and Serratia marsecens only. The flavones were further analyzed for quantitative structural activity relationship study (QSAR) by using PASS, online software to determine their Pa value. Toxicity and drug relevant properties were revealed by PALLAS software in terms of their molecular weight. Log P values were also studied. The result showed both the F(1) and F(2) flavones as antigout and therefore supports the development of novel drugs for the treatment of gout.     

Synthesis and antibacterial activity of a new series of 3-[3-(substituted phenyl)-1-phenyl-1H-pyrazol-5-yl]-2H-chromen-2-one derivatives

A series of 3-[3-(substituted phenyl)-1-phenyl-1H-pyrazol-5-yl]-2H-chromen-2-one (4a–k) were synthesized by reaction of 3-[2,3-dibromo-3-(substituted phenyl)propanoyl]-2H-chromen-2-one (3 a-k) with phenyl hydrazine in presence of triethylamine in absolute ethanol, characterized by spectral data and screened for their in vitro antibacterial activity against gram-positive and gram-negative bacteria. Among the series, compounds 4d, 4h and 4i displayed an encouraging antibacterial activity profile as compared to reference standard drug ciprofloxacin against tested bacterial strains.     

Synthesis of new heterocyclic hybrids based on pyrazole and thiazolidinone scaffolds as potent inhibitors of tyrosinase

As a part of ongoing studies in developing new Tyrosinase inhibitors, a class of structurally novel 2-(2,4-dimethoxy phenylamino)-5 methylene-4-thiazolinone derivatives were synthesized by incorporating 2-(2,4-dimethoxy-phenylamino)-thiazol-4-one with various 1-(1-methyl-buta-1,3-dienyl)-3-phenyl-1H-pyrazole-4-carbaldehyde. The results showed that some of the synthesized compounds exhibited significant inhibitory activities. Especially, 5-[3-(2-chloro-phenyl)-1-phenyl-1H-pyrazol-4-ylmethylene]-2-(2,4-dimethoxy-phenylamino)-thiazol-4-one (5h) and 5-[3-(3-chloro-phenyl)-1-phenyl-1H-pyrazol-4-ylmethylene]-2-(2,4-dimethoxy-phenylamino)-thiazol-4-one (5g) possessing 2-chloro-phenyl and 3-chloro-phenyl group exhibited the most potent tyrosinase inhibitory activity with an IC₅₀ value of 34.12 and 52.62 μM, respectively. The inhibition mechanism analysis of 5h and 5g thiazolidinone derivatives demonstrated that the inhibitory effects of the compounds on tyrosinase were reversible and competitive. Preliminary structure–activity relationships (SAR) analysis suggested that further development of such compounds might be of interest, as it manifests simple reversible slow binding inhibition against monophenolase and diphenolase.     

Benzimidazol-1-yl-1-phenylpropanone Analogs as Potent Antimicrobial Agents: Rational Design and Synthesis

Designed, synthesized a sequence of novel benzimidazol-1-yl-1-phenylpropanone hybrids and assessed for in vitro antimicrobial potential counter to several bacterial strains. Computational Methodology was carried out for designing of the target molecules and structures were confirmed by spectroscopic analysis. Amid the 12 integrated derivatives, (3-(2-((3-fluorobenzylidene)amino)-1H-benzo[d]imidazol-1-yl)-1-phenylpropan-1-one ( 6g ) and 3-(2-((4-fluorobenzylidene)amino)-1H-benzo[d]imidazol-1-yl)-1-phenylpropan-1-one ( 6k ) were found to acquire excellent antibacterial activity against all bacterial strains (Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus), whereas derivative 3-(2-((2-fluorobenzylidene)amino)-1H-benzo[d]imidazol-1-yl)-1-phenylpropan-1-one ( 6c ), was potent against Escherichia coli, Bacillus subtilis, Staphylococcus aureus and displayed moderate action against P. aeruginosa. Derivatives with NO₂ substituent at 3^rd and 4^th position, 3-(2-((3-nitroobenzylidene)amino)-1H-benzo[d]imidazol-1-yl)-1-phenylpropan-1-one ( 6h ) and 3-(2-((4-nitroobenzylidene)amino)-1H-benzo[d]imidazol-1-yl)-1-phenylpropan-1-one ( 6 l ) respectively declared good to moderate results against all bacterial strains. Further, 3-(2-((3-chlorobenzylidene)amino)-1H-benzo[d]imidazol-1-yl)-1-phenylpropan-1-one ( 6f ) and 3-(2-((4-chlorobenzylidene)amino)-1H-benzo[d]imidazol-1-yl)-1-phenylpropan-1-one ( 6j ) were found to be more competent against both fungal strains (C. albicans, A. niger). Serial two-fold dilution method was used for the entire study and standard drugs utilized were ciprofloxacin and clotrimazole. MIC values (μg/ml) of novel synthesized analogs were reported in comparison to standard drugs for antibacterial and antifungal actions. Molecular docking studies showed that designed molecules dynamically bound with effective area of the receptor (DNA gyrase B, Clotrimazole complex of cytochrome P 45046A1) and in vitro results were in accord with in silico studies.     

Design,Synthesis and Antibacterial Activity of Novel Pyrimidine-Containing 4H-Chromen-4-One Derivatives**

A series of pyrimidine-containing 4H-chromen-4-one derivatives were designed and synthesized by combining bioactive substructures. Preliminary biological activity results showed that most of the compounds displayed significant inhibitory activities in vitro against Xanthomonas axonopodis pv. Citri (X. axonopodis), Xanthomonas oryzae pv. oryzae (X. oryzae) and Ralstonia solanacearum (R. solanacearum). In particular, compound 2-[(3-{[5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-1-benzopyran-3-yl]oxy}propyl)sulfanyl]-4-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile ( 4c ) demonstrated a good inhibitory effect against X. axonopodis and X. oryzae, with the half-maximal effective concentration (EC₅₀) values of 15.5 and 14.9 μg/mL, respectively, and compound 2-[(3-{[5,7-Dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-1-benzopyran-3-yl]oxy}propyl)sulfanyl]-4-(3-fluorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile ( 4h ) showed the best antibacterial activity against R. solanacearum with an EC₅₀ value of 14.7 μg/mL. These results were better than commercial reagents bismerthiazol (BT, 51.7, 70.1 and 52.7 μg/mL, respectively) and thiodiazole copper (TC, 77.9, 95.8 and 72.1 μg/mL, respectively). In vivo antibacterial activity results indicated that compound 4c displayed better curative (42.4 %) and protective (49.2 %) activities for rice bacterial leaf blight than BT (35.2, 39.1 %) and TC (30.8, 27.3 %). The mechanism of compound 4c against X. oryzae was analyzed through scanning electron microscopy (SEM). These results indicated that pyrimidine-containing 4H-chromen-4-one derivatives have important value in the research of new agrochemicals.     

Synthesis,Molecular Docking and Preliminary Antileukemic Activity of 4-Methoxybenzyl Derivatives Bearing Imidazo[2,1-b][1,3,4]thiadiazole

In this study, we synthesized 22 compounds in a series with various substitution on imidazo[2,1-b][1,3,4]thiadiazole. The potential cytotoxic activity of these compounds investigated in leukemia cell lines by Differential Nuclear Staining (DNS). Our results identified two compounds, 2-(4-methoxybenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl thiocyanate and 6-(4-chlorophenyl)-2-(4-methoxybenzyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde, exhibited the most cytotoxic effect against murine leukemia cells (L1210), human T-lymphocyte cells (CEM) and human cervix carcinoma cells (HeLa) with IC₅₀ values ranging between 0.79 and 1.6 μM. The results indicate that 2-(4-methoxybenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl thiocyanate is inducing phosphatidylserine externalization and caspase-3 activation which are both a hallmark of apoptosis. Docking studies showed that 2-(4-methoxybenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl thiocyanate binds within the active sites of transforming growth factor beta (TGF-β) type I receptor kinase domain by strong hydrogen binding and hydrophobic interactions.     

Design,synthesis and biological evaluation of 5-amino-4-(1H-benzoimidazol-2-yl)-phenyl-1,2-dihydro-pyrrol-3-ones as inhibitors of protein kinase FGFR1

Fibroblast growth factor receptor 1 (FGFR1) plays an important role in tumorigenesis and is therefore an attractive target for anticancer therapy. Using molecular docking approach we have identified inhibitor of FGFR1 belonging to 5-amino-4-(1H-benzoimidazol-2-yl)-phenyl-1,2-dihydro-pyrrol-3-ones with IC₅₀ value of 3.5 μM. A series of derivatives of this chemical scaffold has been synthesized and evaluated for inhibition of FGFR1 kinase activity. It was revealed that the most promising compounds 5-amino-1-(3-hydroxy-phenyl)-4-(6-methyl-1H-benzoimidazol-2-yl)-1,2-dihydro-pyrrol-3-one and 5-amino-4-(1H-benzoimidazol-2-yl)-1-(3-hydroxy-phenyl)-1,2-dihydro-pyrrol-3-one inhibit FGFR1 with IC₅₀ values of 0.63 and 0.32 μM, respectively, and posses antiproliferative activity against KG1 myeloma cell line with IC₅₀ values of 5.6 and 9.3 μM. Structure–activity relationships have been studied and binding mode of this chemical class has been proposed.     

Microwave assisted synthesis and antimicrobial activity of 2-quinoxalinone-3-hydrazone derivatives

A simple and efficient method has been developed for the synthesis of various 2-quinoxalinone-3-hydrazone derivatives using microwave irradiation technique. The series of 2-quinoxalinone-3-hydrazone derivatives synthesized, were structurally confirmed by analytical and spectral data and evaluated for their antimicrobial activities. The results showed that this skeletal framework exhibited marked potency as antimicrobial agents. The most active antibacterial agent was 3-{2-[1-(6-chloro-2-oxo-2H-chromen-3-yl)ethylidene]hydrazinyl}quinoxalin-2(1H)-one, 7 while 3-[2-(propan-2-ylidene)hydrazinyl]quinoxalin-2(1H)-one, 2 appeared to be the most active antifungal agent.     

In Vitro antifungal activity of 2-(4-substituted phenyl)-3(2H)-isothiazolones

The in vitro antifungal activity of several N2-phenyl-3(2H)-isothiazolones substituted at C4 of the phenyl moiety with heterocyclic nucleus or groups of different physico-chemical properties against four human pathogenic fungi was determined by broth macrodilution method; results were compared with those obtained with itraconazole and ketoconazole. These isothiazolones showed moderate to high activity against some or all tested strains and in comparison with the reference drugs, 5-chloro-2-(4-nitrophenyl)isothiazol-3-one (1g), 5-chloro-2-phenylisothiazol-3-one (1c), 4-[4-(5-chloro-3-oxo-3H-isothiazol-2-yl)phenyl]-1,4-dihydrotriazol-5-one (1s) and 2-(4-nitrophenyl)isothiazol-3-one (2g) against Aspergillus niger, 5-chloro-2-(4-nitrophenyl)isothiazol-3-one (1g) and 4-[4-(5-chloro-3-oxo-3H-isothiazol-2-yl)phenyl]piperazine-1-carboxamide (1q) against Trichophyton mentagrophytes had comparable activity, compounds 1g and 2g showing higher activity against Microsporum canis. Antifungal activity was favored by the presence of chlorine at C5 of the isothiazolone and/or the presence of nitro group or heterocyclic nucleus at C4 of the phenyl ring and proper hydrophilicity of the molecule.     

Synthesis and in vitro anti-HIV activity of N-1,3-benzo[d]thiazol-2-yl-2-(2-oxo-2H-chromen-4-yl)acetamide derivatives using MTT method

A series of novel N-1,3-benzo[d]thiazol-2-yl-2-(2-oxo-2H-chromen-4-yl)acetamide derivatives has been synthesized. All the newly synthesized compounds were evaluated for their anti-HIV activity using MTT method. Most of these compounds showed moderate to potent activity against wild-type HIV-1 with an EC₅₀ ranging from >7 EC₅₀ [μg/ml] to <100 EC₅₀ [μg/ml]. Among them, N-1,3-benzo[d]thiazol-2-yl-2-(2-oxo-2H-chromen-4-yl)acetamide 6v was identified as the most promising compound (EC₅₀ = <7 μg/ml). Among all the compounds, three compounds 6m, 6v and 6u have been exhibits potent anti-HIV activity against MT-4 cells.     

Synthesis and biological evaluation of 2,5-disubstituted 1,3,4-oxadiazole derivatives with both COX and LOX inhibitory activity

Dual cyclooxygenase/lipoxygenase (COX/LOX) inhibitors constitute a valuable alternative to classical nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors for the treatment of inflammatory diseases. A series of 3-(5-phenyl/phenylamino-[1,3,4]oxadiazol-2-yl)-chromen-2-one and N-[5-(2-oxo-2H-chromen-3-yl)-[1,3,4]oxadiazol-2-yl]-benzamide derivatives were synthesized and screened for anti-inflammatory, analgesic activity. All the derivatives prepared are active in inhibiting oedema induced by carrageenan. Compound 4e was found more potent with 89% of inhibition followed by compound 4b (86%). Compounds with >70% of anti-inflammatory activity were tested for analgesic, ulcerogenic, and lipid peroxidation profile. Selected compounds were also evaluated for inhibition of COXs (COX-1 and COX-2) and LOXs (LOX-5, LOX-12, and LOX-15). Compound 4e was comparatively selective for COX-2, LOX-5, and LOX-15. Study revealed that these derivatives were more effective than ibuprofen with reduced side effects. It can be suggested that these derivatives could be used to develop more potent and safer NSAIDs.     

Pro-fluorescent probe with morpholine moiety and its reactivity towards selected biological oxidants

Biological oxidants participate in many processes in the human body. Their excessive production causes organelle damage, which may result in the accumulation of cytotoxic mediators and cell degradation and may manifest itself in various diseases. Peroxynitrite (ONOO⁻), hypochlorous acid (HOCl), hydrogen peroxide (H₂O₂), and peroxymonocarbonate (HOOCO₂⁻) are important oxidants in biology, toxicology, and various pathologies. Derivatives of coumarin, containing an oxidant-sensitive boronate group, have been recently developed for the fluorescent detection of inflammatory oxidants. Here, we report the synthesis and characterization of 4-[2-(morpholin-4-yl)-2-oxoethyl]-2-oxo-2H-chromen-7-yl boronic acid ( MpC-BA ) as a fluorescent probe for the detection of oxidants, with better solubility in water, high stability and fast response time toward peroxynitrite and hypochlorous acid. The effectiveness of the MpC-BA probe for the detection of peroxynitrite was measured by adding bolus ONOO⁻ or using the co-generating superoxide and nitrogen oxide system. MpC-BA is oxidized by ONOO⁻ to 7-hydroxy-4-[2-(morpholin-4-yl)-2-oxoethyl]-2H-chromen-2-one ( MpC-OH ). However, peroxynitrite-specific product ( MpC-H ) is formed in the minor reaction pathway. MpC-OH is also yielded in the reaction of MpC-BA with HOCl, and the subsequent formation of a chlorinated MpC-OH gives a specific product for HOCl ( MpC-OHCl ). H₂O₂ slowly oxidizes MpC-BA . However, the addition of NaHCO₃ increased the MpC-OH formation rate. We conclude that MpC-BA is potentially an improved fluorescent probe detecting peroxynitrite and hypochlorite in biological settings. Complementation of the fluorescence measurements by HPLC-based identification of chlorinated and reduced coumarin(s) will help identify the oxidants detected.     

Synthesis and SAR studies of bis-chromenone derivatives for anti-proliferative activity against human cancer cells

A novel family of 3-((4-oxo-4H-chromen-3-yl)methyl)-4H-chromen-4-one (bis-chromone) derivatives were designed, synthesized and studied for their anti-cancer activity using the XTT assay for the growth inhibition against various human cancer cells. Among them, 3-((5-(cyclohexylmethoxy)-4-oxo-4H-chromen-3-yl)methyl)-7-methoxy-4H-chromen-4-one and 3-((5-(cyclohexylmethoxy)-4-oxo-4H-chromen-3-yl)methyl)-7-hydroxy-4H-chromen-4-one showed micromolar level of in vitro anti-proliferative activity against human cancer cell lines. The SAR studies indicated bis-chromone as a basic scaffold to design anticancer agents. The 5-cyclohexylmethoxy on the first chromenone ring and electron donating group such as CH₃, OCH₃ or hydrogen bonding group (OH) on the other chromenone ring of bis-chromone increased the activity. However, saturation of one of chromenone to chromanone in bis-chromones decreased the activity.     

Synthesis and anti-rhinovirus activity of novel 3-[2-(pyridinyl)vinyl]substituted -2H-chromenes and -4H-chromen-4-ones

Human rhinoviruses (HRVs) are the most common cause of viral respiratory infections and their complications. So far, no anti-viral agent has been approved for prevention or treatment of HRV infections. Pursuing our researches on small molecules with anti-rhinovirus activity, in this paper we describe the synthesis and in vitro anti-HRV 1B and 14 properties of new [2-(2H-chromen-3-yl)vinyl]pyridines and 3-[2-(pyridinyl)vinyl]-4H-chromen-4-ones. Generally, the synthesized compounds interfered with the replication of both serotypes at the micromolar or submicromolar concentrations. Preliminary results on their mechanism of action, performed on selected (E)-2-[2-(2H-chromen-3-yl)vinyl]pyridine, indicate an interference with the early step(s) of HRV 1B and 14 replication, probably at the uncoating level.     

Isolation of a 2-Pyrone Compound as an Antioxidant from a Fungus and Its New Reaction Product with 1,1-Diphenyl-2-picrylhydrazyl Radical

The indophenol-reducing compound, 4-hydroxy-3,6-dimethyl-2H-pyrane-2-one (I), was isolated from the culture filtrate of an unidentified fungus. I also reacted with the DPPH radical to form a reaction product IV which was determined to be 1-[4-(3,4-dihydro-3,6-dimethyl-2,4-dioxo- 2H-pyran-3-yl)phenyl]-1-phenyl-2-picrylhydrazine. This is the first report describing the formation of an adduct of the DPPH radical and its scavenger.     

Chromones from the stems of Cassia fistula and their anti-tobacco mosaic virus activities

Three new chromones, 5-methoxy-2,2-dimethyl-7-(2-oxopropyl)-2,3-dihydrochromen-4-one (1), 5-methoxy-2,2-dimethyl-8-(2-oxopropyl)-2,3-dihydrochromen-4-one (2), and 1-(3,4-dihydro-5-methoxy-2,2-dimethyl-2H-chromen-7-yl)propan-2-one (3), together with four known chromones (4–7) were isolated from the stems of Cassia fistula. Their structures were elucidated by spectroscopic methods, including extensive 1D- and 2D-NMR techniques. Compounds 1–5 were evaluated for their anti-tobacco mosaic virus (anti-TMV) activities. The results showed that compound 5 exhibited high anti-TMV activity with inhibition rate of 30.8% at a concentration of 20 μM. The other compounds also exhibited potential anti-TMV activities with inhibition rates in the range of 15.6–22.1% at the same concentration.     

柯拉斯那沉香的生物活性成分研究

为了解柯拉斯那(Aquilaria crassna)的化学成分,从其所产沉香中分离得到10个化合物,经波谱分析分别鉴定为:6,8-羟基-2-(2-苯乙基)色酮(1),6,8-二羟基-2-[2-(4-甲氧基苯)乙基]色酮(2),rel-(1a R,2R,3R,7b S)-1a,2,3,7b-tetrahydro-2,3-dihydroxy-5-(2-phenylethyl)-7H-oxireno[f][1]benzopyran-7-one(3),rel-(1a R,2R,3R,7b S)-1a,2,3,7b-tetrahydro-2,3-dihydroxy-[2-(4-methoxyphenyl)-ethyl]-7H-oxireno[f][1]benzopyran-7-one(4),rel-(1a R,2R,3R,7b S)-1a,2,3,7b-tetrahydro-2,3-dihydroxy-5-[2-(3-hydroxy-4-methoxyphenyl)-ethyl]-7H-oxireno[f][1]benzopyran-7-one(5),oxidoagarochromone B(6),oxidoagarochromone C(7),(5S,6R,7S,8R)-2-[2-(3′-hydroxy-4′-methoxyphenyl)ethyl]-5,6,7,8-tetrahydroxy-5,6,7,8-tetrahydrochromone(8),6,7-cis-dihydroxy-2-(2-phenylethyl)-5,6,7,8-tetrahydrochromone(9),N-trans-feruloyltyramine(10)。化合物3~5和8~10为首次从柯拉斯那沉香中分离得到。化合物1,3,6,7,9和10对乙酰胆碱酯酶具有一定的抑制活性,化合物4对人慢性髓原白血病细胞株K-562和人胃癌细胞株SGC-7901均具有较小的抑制作用,化合物1和3对人肝癌细胞株BEL-7402也有抑制活性。     

2-Chloro-1,4-naphthoquinone derivative of quercetin as an inhibitor of aldose reductase and anti-inflammatory agent

Abstract

The ability of flavonoids to affect multiple key pathways of glucose toxicity, as well as to attenuate inflammation has been well documented. In this study, the inhibition of rat lens aldose reductase by 3,7-di-hydroxy-2-[4-(2-chloro-1,4-naphthoquinone-3-yloxy)-3-hydroxy-phenyl]-5-hydroxy-chromen-4-one (compound 1), was studied in greater detail in comparison with the parent quercetin (compound 2). The inhibition activity of 1, characterized by IC₅₀ in low micromolar range, surpassed that of 2. Selectivity in relation to the closely related rat kidney aldehyde reductase was evaluated. At organ level in isolated rat lenses incubated in the presence of high glucose, compound 1 significantly inhibited accumulation of sorbitol in a concentration-dependent manner, which indicated that 1 was readily taken up by the eye lens cells and interfered with cytosolic aldose reductase. In addition, compound 1 provided macroscopic protection of colonic mucosa in experimental colitis in rats. At pharmacologically active concentrations, compound 1 and one of its potential metabolite 2-chloro-3-hydroxy-[1,4]-naphthoquinone (compound 3) did not affect osmotic fragility of red blood cells.     

A new therapeutic approach in Parkinson’s disease: Some novel quinazoline derivatives as dual selective phosphodiesterase 1 inhibitors and anti-inflammatory agents

The increasing life expectancy in our population makes Parkinson’s disease (PD) a growing public health problem. There is a great need to find a way to prevent and delay the disease. It was shown that selective phosphodiesterase 1 (PDE1) inhibitors and anti-inflammatory agents might be effective in treating PD. Therefore, a novel 1,2,9,11-tetrasubstituted-7H-thieno[2′,3′:4,5]pyrimido[6,1-b]-quinazolin-7-one (1–15) and 1,3,10,12-tetrasubstituted-8H-pyrido[2′,3′:4,5]pyrimido[6,1-b]quinazolin-8-one (16–36) derivatives were synthesized by reported method and investigated for their ability to inhibit PDE1. Most of the synthesized compounds have shown good activity against PDE1 and were less effective than 3-isobutyl-1-methylxanthine. All the compounds were also tested for their in vitro anti-inflammatory activity by carrageenan-induced oedema in rats. In addition, ulcerogenic activity was determined. The combined anti-inflammatory data from in vitro animal model showed that compounds, 9,11-dibromo-1-(2-furyl)-3-(4-tolyl)-8H-pyrido[2′,3′:4,5]pyrimido[6,1-b]quinazolin-8-one 23, 9,11-dibromo-1-(4-methoxy-phenyl)-3-phenyl-8H-pyrido[2′,3′:4,5]pyrimido[6,1-b]quinazolin-8-one 24, 9,11-dibromo-1-(4-chloro-phenyl)-3-(4-tolyl)-8H-pyrido[2′,3′:4,5]pyrimido[6,1-b]quinazolin-8-one 29 and 9-bromo-1-(4-chloro-phenyl)-3-(4-tolyl)-8H-pyrido[2′,3′:4,5]pyrimido[6,1-b]quinazolin-8-one 36 exhibited even more potent anti-inflammatory activity and low gastric ulceration incidence compare to reference standard Indomethacin. Since compound 23, 24, 29 and 36 exhibits both anti-inflammatory activity and PDE1 inhibition, it needs further detailed studies.     

Studies on the 1,1-Diphenyl-2-picrylhydrazyl Radical Scavenging Mechanism for a 2-Pyrone Compound

The radical scavenging mechanisms for the 2-pyrone compound, 4-hydroxy-3,6-dimethyl-2H-pyrane-2-one (1), and the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical (4) in several solvent systems were evaluated by the quantitative change in compounds detected at 270 nm and subsequent HPLC analyses. The HPLC profile for each condition suggested that the reaction proceeded by a different mechanism in each solvent system. In organic solvents (CHCl₃, iso-propanol, and EtOH), 1- [4-(3,4-dihydro-3,6-dimethyl-2,4-dioxo-2H-pyran-3-yl) phenyl]-1-phenyl-2-picrylhydrazine (2) was produced as an adduct of the DPPH radical and 1. On the other hand, the reaction in a buffer solution (an acetate buffer at pH 5.5) gave several degradation products with 1-[4-(2,3-dihydro-2,5-dimethyl-3-oxo-fur-2-yl) phenyl]-1-phenyl-2-picrylhydrazine (5), this being structurally elucidated by spectroscopic analyses. The decrease of the DPPH radical in each reaction system suggests that compound 1 could scavenge about 1.5-1.8 equivalents of the radical in organic solvents and about 3.5-3.9 in the buffer solution.