Synthesis,characterization and preliminary screening of regioisomeric 1-(3-pyridazinyl)-3-arylpyrazole and 1-(3-pyridazinyl)-5-arylpyrazole derivatives towards cyclooxygenase inhibition

In a search for novel compounds with analgesic and anti-inflammatory activity, a series of regioisomeric 1-(3-pyridazinyl)-3-arylpyrazole (5a–f, 6a–f) and 1-(3-pyridazinyl)-5-arylpyrazole (7a–f, 8a–f) derivatives were synthesized. The structure of these regioisomers was confirmed by spectral techniques. The compounds were preliminarily screened at 8 μM concentration for their inhibitory activity against cyclooxygenase enzymes, COX-1 and COX-2, using a human whole blood test. The tested derivatives showed inhibitory activity for both enzymes and are worthy of further investigation for developing better leads.     

Inhibitory effects of isatin Mannich bases on carbonic anhydrases,acetylcholinesterase, and butyrylcholinesterase

The effects of isatin Mannich bases incorporating (1-[piperidin-1-yl (P1)/morpholin-4-yl (P2)/N-methylpiperazin-1-yl (P3)]methyl)-1H-indole-2,3-dione) moieties against human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoenzymes hCA I and hCA II, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzymes were evaluated. P1–P3 demonstrated impressive inhibition profiles against AChE and BChE and also inhibited both CAs at nanomolar level. These inhibitory effects were more powerful in all cases than the reference compounds used for all these enzymes. This study suggests that isatin Mannich bases P1–P3 are good candidate compounds especially for the development of new cholinesterase inhibitors since they were 2.2–5.9 times better inhibitors than clinically used drug Tacrine.     

Synthesis,antiviral activity and structure–activity relationship of 1-(1-aryl-4,5-dihydro-1H-imidazoline)-3-chlorosulfonylureas and products of their cyclization

Novel 1-(1-aryl-4,5dihydro-1H-imidazoline)-3-chlorosulfonylourea derivatives 3a–3f were synthesized in the reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with chlorosulfonyl isocyanate. The second series of compounds 4a–4f was prepared from the respective 1-(1-aryl-4,5-dihydro-1H-imidazoline)-3-chlorsulfonylureas 3a–3f and 1,1′-carbonyldiimidazole (CDI). The selected compounds were tested for their activity against Herpes simplex virus and coxsackievirus B3 (CVB3). It was determined that three derivatives, i.e 3d, 4a and 4d are active against Herpes simplex virus (HSV-1). Compounds 3d and 4c are active against CVB3. Their favorable activity can be primarily attributed to their low lipophilicity values. Moreover, the lack of substituent in the phenyl moiety or 4-methoxy substitution can be considered as the most beneficial for the antiviral activity.     

New quinoxalinone inhibitors targeting secreted phospholipase A2 and α-glucosidase

Elevated blood glucose and increased activities of secreted phospholipase A2 (sPLA2) are strongly linked to coronary heart disease. In this report, our goal was to develop small heterocyclic compound that inhibit sPLA2. The title compounds were also tested against α-glucosidase and α-amylase. This array of enzymes was selected due to their implication in blood glucose regulation and diabetic cardiovascular complications. Therefore, two distinct series of quinoxalinone derivatives were synthesised; 3-[N′-(substituted-benzylidene)-hydrazino]-1H-quinoxalin-2-ones 3a–f and 1-(substituted-phenyl)-5H-[1,2,4]triazolo[4,3-a]quinoxalin-4-ones 4a–f. Four compounds showed promising enzyme inhibitory effect, compounds 3f and 4b–d potently inhibited the catalytic activities of all of the studied proinflammatory sPLA2. Compound 3e inhibited α-glucosidase (IC₅₀?=?9.99?±?0.18 µM); which is comparable to quercetin (IC₅₀?=?9.93?±?0.66 µM), a known inhibitor of this enzyme. Unfortunately, all compounds showed weak activity against α-amylase (IC₅₀?>?200 µM). Structure-based molecular modelling tools were utilised to rationalise the SAR compared to co-crystal structures with sPLA2-GX as well as α-glucosidase. This report introduces novel compounds with dual activities on biochemically unrelated enzymes mutually involved in diabetes and its complications.     

Synthesis of 3′-Deoxy-3′-[4-(pyrimidin-1-yl)methyl-1,2,3-triazol-1-yl]thymidine via 1,3-Dipolar Cycloaddition

Abstract

The synthesis of new 3′-deoxy-3′-[4-(pyrimidin-1-yl)methyl-1,2,3-triazol-1-yl]thymidine 6a–f, from 3′-azido-3′-deoxy-5′-O-monomethoxytrityl-thymidine is described. The key step is the 1,3-dipolar cycloaddition between the azido group of the protected AZT 3 and N-1-propargylpyrimidine derivatives 2a–f. All new derivatives 6a–f were evaluated for their inhibitory effects against the replication of HIV-1 (IIIB), HIV-2 (ROD). No marked activity was found.     

Synthesis and Antiviral Activities of New Pyrazolo[4,3‐c]quinolin‐3‐ones and Their Ribonucleoside Derivatives

Several new pyrazolo[4,3‐c]quinolin‐3‐one ribonucleosides (5a–g) and their corresponding heterocycle moieties (3a–g) were synthesized and evaluated against vaccinia virus (VV) and herpes simplex virus type 1 (HSV‐1). The derivatives 3c and 3d showed modest inhibitory activity against vaccinia virus reaching 70% at a concentration of 100 µM. All heterocyclic compounds (3a–f) showed a modest inhibition against HSV‐1, reaching the maximal inhibitory effect around 20–30%. The antiviral effects of most of the pyrazolo[4,3‐c]quinolin‐3‐one ribonucleosides (5a–f) on VV and HSV were not impressive.     

Novel N-quinonyl amino acids and their transformation to 3-substituted p-isoxazinones

Summary. Quinonyl amino acids are building blocks in the preparation of peptides which target the quinonic drug to cancer damaged area. Novel N-(3-chloro-1,4-dihydro-1,4-dioxonaphthalen-2-yl)-α-amino acids 1a–f were prepared by direct substitution of 2,3-dichloro-1,4-naphthoquinone. The quinonic moiety was reduced by NaBH₄ to yield the corresponding hydroquinones 2a–f, which in acidic conditions underwent internal cyclization to yield the 3,4-dihydro-2H-naphth[1,2-b]-1,4-oxazine-2-ones (six-membered azlactones) 3a–f. Received February 2, 2000 Accepted March 29, 2000     

SYNTHESIS AND ANTIVIRAL EVALUATION OF N-GLYCOSIDES DERIVED FROM 6-AMINO-3-ARYL-2-METHYL-4-(3H)-QUINAZOLINONES

Reaction of monosaccharides (D-glucose, D-galactose, D-xylose or L-arabinose) with 6-amino-3-aryl-2-methyl-4-(3H) quinazolinones (1a–c) in boiling methanol yielded the corresponding N-glycopyranosides 3a–c, 4a–c, 5a,b and 6a,b. The N-glycopyranosides 3a–c, 4a–c, 5a,b and 6a,b were acetylated with acetic anhydride and pyridine to give the corresponding acetate derivatives 7a–c, 8a–c, 9a,b and 10a,b. The structures of all these glycosides were assessed by elemental analysis, IR, NMR and mass spectra. Some of these products were tested for anticancer and anti-AIDS activity.     

Insights into biological activity of ureidoamides with primaquine and amino acid moieties

Primaquine (PQ) ureidoamides 5a–f were screened for antimicrobial, biofilm eradication and antioxidative activities. Susceptibility of the tested microbial species towards tested compounds showed species- and compound-dependent activity. N-(diphenylmethyl)-2-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]-4-methylpentanamide (5a) and 2-(4-chlorophenyl)-N-(diphenylmethyl)-2-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]acetamide (5d) showed antibacterial activity against S. aureus strains (MIC?=?6.5?µg/ml). Further, compounds 5c and 5d had weak antibacterial activity against Escherichia coli and Pseudomonas aeruginosa. None of the tested compounds showed a wide spectrum of antifungal activity. In contrast, most of the compounds exerted strong activity in a biofilm eradication assay against E. coli, P. aeruginosa and Candida albicans, comparable to or even higher than gentamycin, amphotericin B or parent PQ. The most active compounds were 5a and 5b. Tested compounds were inactive against biofilm formation by C. parapsylosis, Enterococcus faecalis, C. tropicalis and C. krusei. Compounds 5b–f significantly inhibited lipid peroxidation (80–99%), whereas compound 5c presented interesting LOX inhibition.     

Synthesis,antimicrobial activity and molecular modeling study of substituted 5-aryl-pyrimido[5,4-c]quinoline-2,4-diones

A series of pyrimido[5,4-c]quinoline-2,4-dione derivatives 5a–k were synthesized in moderate yields via a thermolysis reaction of equimolar ratio of 5-arylidine-1,3-dimethylbarbituric acid derivatives 3a–d with aniline derivatives 4a–d at 150–180 °C for 1–2?h. Eight of the synthesized compounds were chosen for a primary in vitro one-dose anticancer assay performed using the full NCI 60 cell panel. Only compound 5b showed moderate GI% at the used dose (10 μM) against four of the tested cell lines corresponding to leukemia SR (GI%: 51), non small-cell lung cancer HOP-92 (GI%: 63), melanoma UACC-62 (GI%: 53) and renal cancer UO-31 (GI%: 69). On the other hand, antimicrobial screening of the whole set of the synthesized compounds was performed against three Gram +ve and two Gram ?ve bacterial strains. Results of the antimicrobial screening showed that compounds 5d, 5e, 5f, 5h and 5k have broad-spectrum antibacterial efficacy being moderately active against all the tested Gram +ve and two Gram ?ve bacteria. Also, compound 5a showed interesting results being only active against Streptococcus faecalis and both tested Gram ?ve strains viz. E. coli and P. aeruginosa. In order to compare the binding mode of the most active compounds 5e and 5f along with the inactive compound 5c we docked these compounds into the empty binding site of topoisomerase II DNA gyrase (PDB ID: 1KZN), and results were compared with the bound inhibitor Clorobiocin.     

Compressed images for affinity prediction-2 (CIFAP-2): an improved machine learning methodology on protein–ligand interactions based on a study on caspase 3 inhibitors

Abstract

The aim of this study is to propose an improved computational methodology, which is called Compressed Images for Affinity Prediction-2 (CIFAP-2) to predict binding affinities of structurally related protein–ligand complexes. CIFAP-2 method is established based on a protein–ligand model from which computational affinity information is obtained by utilizing 2D electrostatic potential images determined for the binding site of protein–ligand complexes. The quality of the prediction of the CIFAP-2 algorithm was tested using partial least squares regression (PLSR) as well as support vector regression (SVR) and adaptive neuro-fuzzy ?nference system (ANFIS), which are highly promising prediction methods in drug design. CIFAP-2 was applied on a protein–ligand complex system involving Caspase 3 (CASP3) and its 35 inhibitors possessing a common isatin sulfonamide pharmacophore. As a result, PLSR affinity prediction for the CASP3–ligand complexes gave rise to the most consistent information with reported empirical binding affinities (pIC₅₀) of the CASP3 inhibitors.     

Synthesis of 3-aroyl-4-aryl-1-isopropylamino-4-piperidinols and evaluation of the cytotoxicities of the compounds against human hepatoma and breast cancer cell lines

Abstract

Some 4-piperidinol derivatives were synthesized and their cytotoxicity was tested against human hepatoma (Huh7) and breast cancer (T47D) cells. Aryl part was changed as phenyl in 2a, 4-methylphenyl in 2b, 4-methoxyphenyl in 2c, 4-chlorophenyl in 2d, 4-fluorophenyl in 2e, 4-bromophenyl in 2f, 4-nitrophenyl in 2g and 2-thienyl in 3. Compounds were synthesized and reported for the first time by this study except 2a and 2d. Chemical structures were confirmed by ¹H NMR, ¹³C NMR, IR, MS and elemental analyses. Compounds 2a (3.1 times), 2c (3.8 times), 2f (4.6 times), 2g (1.3 times) and 3 (3.2 times) had 1.3–4.6 times higher cytotoxic potency than the reference compound 5-FU against Huh7 cell line while all the compounds synthesized had shown lower activities against T47D cell line than 5-FU. In the light of these results, compounds 2a, 2c, 2f, 2g and 3 may serve as model compounds for further studies.     

Synthesis,antitumor activity,and cytotoxicity of 4-substituted 1-benzyl-5-diphenylstibano-1H-1,2,3-triazoles

Trisubstituted 5-organostibano-1H-1,2,3-triazoles (3a–f) were synthesized by the Cu-catalyzed azide-alkyne cycloaddition of various ethynylstibanes (1) with benzylazide (2) in the presence of CuBr (5 mol%) under aerobic conditions. The reaction of 5-stibanotriazoles with HCl afforded C5-unsubstituted 1,2,3-triazoles (4a–f). The antitumor activity of trisubstituted 5-organostibano-1H-1,2,3-triazoles (3a–f) and their 5-unsubstituted 1,2,3-triazoles (4a–f) were evaluated in several tumor cell lines. All 5-stibanotriazoles (3a–f) exerted an excellent antitumor activity. On the contrary, 5-unsubstituted 1,2,3-triazoles (4a–f) without a diphenylantimony group in the molecule exhibited very low antitumor activity compared with 5-stibanotriazoles (3a–f). In compounds of both the series, the substituted 4-butyl group appeared to decrease antitumor activity. However, results suggested that organometal (antimony) in the molecule was required for greater antitumor activity. In addition, all 5-stibanotriazoles (3a–f), but not all 5-unsubstituted 1,2,3-triazoles (4a–f), exhibited cytotoxicity in normal vascular endothelial cells derived from bovine aorta. Among the compounds (3b–e) that exhibited excellent antitumor activity, those with 4-methylphenyl (3b) and 1-cyclohexenyl (3e) showed relatively low cytotoxicity to vascular endothelial cells. Together, these results suggest that trisubstituted 5-organostibano-1H-1,2,3-triazoles, including compounds 3b and 3e, may serve as potential anticancer therapeutic drugs in the future.     

An Improved Synthesis of 1-β-D-Arabinofuranosylcytosine 5′-Phosphate-L-1,2-diacylglycerols

Abstract

5′-O-MMTr-cytosine arabinoside was prepared on a large scale from 5′-O-MMTr-cytidine with diphenyl carbonate via 5′-protected cytidine-2′,3′-carbonate-aracytidine-2′,2-anhydro derivative at a 67 % yield. The synthesis of 1,2-L-dipalmitoyl-snglycerol, 1,2-L-distearoyl-sn-glycerol and 1,2-L-dioleoyl-sn-glycerol described here using 9-fluorenylmethoxycarbonyl (FMOC) group for protection of 3-position of glycerol which can be selectively removed by Et₃N treatment on the overall 60–70 % yield based on 1.2,-isopropilidene-sn-glycerol. These glycerols were phosphorylated first with 2-chlorophenyl-phosphoro-bis-triazolide quantitatively¹ in order to avoid acyl migration, then the glycerophosphate intermediates were condensed with 2′,3′,N⁴-trileulinyl-l-β-D-arabinofuranosylcytosine in the presence of 2-mesytilenesulphonyl chloride (MsCl) and 1 -methylimidazole (Melm)-which was used in the coupling of nucleotides²-^? in an 85–95 % yield compared with the low yielding diester method of Ryu³. Deblocking was carried out in two steps with tetrabutylammonium fluoride (TBAF) and hydrazine hydrate, producing target compouns (14a, 14b, 14c) at a 50 % yield.     

Synthesis and antibacterial properties of new N4-acetylated hexahydro-2,7-dioxopyrido[2,3-f]quinoxaline-8-carboxylic acids

Direct interaction between 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and primary α-amino acids (exemplified by glycine, alanine, and l-valine) in aqueous ethanolic NaHCO₃ at 70–80°C for 24–72?h produced the respective N-(4-oxoquinolin-7-yl)-α-amino acids (6a–c). The latter derivatives underwent reductive lactamization upon treatment with Na₂S₂O₄ in aqueous ethanol to afford moderate yields of the corresponding pyrido[2,3-f]quinoxaline-8-carboxylic acids (8a–c). Acetylation of 8a–c using acetyl chloride afforded N₄-acetylated hexahydro-2,7-dioxopyrido[2,3-f]quinoxaline-8-carboxylic acids (9a–c). The structures, assigned to these new heterocyclic products, are supported by analytical and spectral data. The synthesized compounds (6a–c/9a–c) showed appreciable antibacterial activity as compared with ciprofloxacin.     

Stereoselective reduction of 2-azido-1-phenylethanone derivatives by whole cells of marine-derived fungi applied to synthesis of enantioenriched β-hydroxy-1,2,3-triazoles

Several marine-derived fungi were evaluated by the bioreduction of 2-azido-1-phenylethanone 1, and the strains A. sydowii CBMAI 935 and M. racemosus CBMAI 847 were selected for the reduction of 2-azido-1-phenylethanone derivatives 2–4. Whole cells of A. sydowii CBMAI 935 promoted the reduction of 2-azido-1-phenylethanones 1–4 with high selectivities to yield the (S)-2-azido-1-phenylethanols 1a–4a. Bioreduction of compounds 1–4 by M. racemosus CBMAI 847 led to (R)-2-azido-1-phenylethanols for 1, 2 and 4 and (S)-2-azido-1-phenylethanol 3. Enantiomerically enriched 2-azido-1-phenylethanols 1a–4a and phenylacetylene 5 were applied in the synthesis of β-hydroxy-1,2,3-triazoles using CuSO₄ and sodium ascorbate leading to regioselective formation of enantioenriched 1,4-disubstituted 1,2,3-triazole compounds 1b–4b.     

In vitro antimicrobial studies of new benzimidazolium salts and silver N-heterocyclic carbene complexes

A series of new benzimidazolium salts (1a–g) were synthesized from the reaction of 1-(4-vinylbenzyl)benzimidazole with various alkyl halides. These salts were used to synthesize silver N-heterocyclic carbene (Ag-NHC) complexes (2a–f). The thirteen compounds were characterized by FT-IR, NMR (¹H and ¹³C) spectroscopic methods and an elemental analysis technique. These selected candidates were tested for their in vitro antimicrobial activities. Antibacterial and antifungal results indicated that the new salts, and particularly their silver complexes, were found to be strongly effective against seven Gram (?) bacterial strains, three Gram (+) bacterial strains and one yeast (Candida albicans).     

The Pharmacological effects of novel 5-fluoro-N-(9,10-dihydro-9,10-dioxoanthracen-8-yl)-1H-indole-2-carboxamide derivatives on plasma lipid profile of Triton-WR-1339-induced Wistar rats

A novel series of 5-fluoro-N-(9,10-dihydro-9,10-dioxoanthracen-8-yl)-1H-indole-2-carboxamides (3c–3g) were synthesized. The present study was undertaken to investigate the possible antihyperlipidemic effect of these novel compounds on hyperlipidemic rats. Hyperlipidemia was induced by a single intraperitoneal injection of Triton WR-1339 (300 mg/kg). The tested animals were divided into normal control (NCG), hyperlipidemic control (HCG), compounds 3c-, 3d-, 3e-, 3f-, 3g- and bezafibrate (BF)-treated groups. At a dose of 15 mg/kg, compounds 3c–3g and BF (100 mg/kg) significantly (p < 0.0001) reduced elevated plasma triglycerides levels after 12 and 24 h compared to the hyperlipidemic control group. However, only compounds 3e and 3g obviously showed a significant (p < 0.0001) reduction in plasma total cholesterol levels after 12 and 24 h. Moreover, high-density lipoprotein cholesterol levels were significantly increased in all treated groups. The current study demonstrates that 5-fluoro-N-(9,10-dihydro-9,10-dioxoanthracen-8-yl)-1H-indole-2-carboxamides (3c–3g) have a definite antihyperlipidemic potential and these beneficial activities may contribute to their cardioprotective and antiatherosclerotic role.     

3-Methyl-2-phenyl-1-substituted-indole derivatives as indomethacin analogs: design,synthesis and biological evaluation as potential anti-inflammatory and analgesic agents

In a new group of 3-methyl-2-phenyl-1-substituted-indole derivatives (10a–f), the indomethacin analogs were prepared via the Fisher indole synthesis reaction of propiophenone with appropriately substituted phenylhydrazine hydrochloride. This is followed by the insertion of the appropriate benzyl or benzoyl fragment. All the synthesized compounds were evaluated for their anti-inflammatory (in vitro and in vivo) and analgesic activities. The methanesulphonyl derivatives 10d, e and f showed the highest anti-inflammatory (in vitro and in vivo) and analgesic activities. In addition, molecular docking studies were performed on compounds 10a–f and the results were in agreement with that obtained from the in vitro COX inhibition assays. The significant anti-inflammatory and analgesic activities exhibited by 10d and 10e warrant continued preclinical development as potential anti-inflammatory and analgesic agents.