Synthesis of 6-exomethylenepenams as β-lactamase inhibitors

The 6,6-dibromopenam (6) was treated with CH3MgBr and carbaldehyde 5 to afford the hydroxy compound 7, which was reacted with acetic anhydride to give acetoxy compound 8. The deacetobromination of 8 with zinc and acetic acid gave 6-exomethylenepenams, E-isomer 10 and Z-isomer 9, which was oxidized to sulfone 11 by m-CPBA. The p-methoxybenzyl compounds were deprotected by AlCl3 and neutralized to give the sodium salts 12, 13 and 14.     

Synthesis of 5-chloro-3-[4-(3-diethylaminopropoxy)benzoyl]-2-(4-methoxyphenyl)benzofuran as a β-amyloid aggregation Inhibitor

An efficient synthesis of 5-chloro-3-[4-(3-diethylaminopropoxy)benzoyl]-2-(4-methoxyphenyl)benzofuran (8), a potent beta-amyloid aggregation inhibitor, is described. 5-Chloro-2-(4-methoxyphenyl)benzofuran (3) was obtained by the one-pot synthesis of 4-chlorophenol with omega-(methylsulfinyl)-p-methoxyacetophenone (1) under Pummerer reaction conditions, and it was followed by the desulfurization of the resultant 5-chloro-3-methylthio-2-(4-methoxyphenyl)benzofuran (2e). Acylation of benzofuran 3 with 4-(3-bromopropoxy)benzoyl chloride (6) gave the ketone 7, which was converted into compound 8 by the treatment of diethylamine.     

Synthesis of 6-[2-(Benzoxazol-2-ylmethylamino)ethoxy]-1-Alkyl-1H-lndole-2-Carboxylic acid and inhibitory activity on β-Amyloid aggregation

6-[2-(benzoxazol-2-ylmethylamino)ethoxy]-1-alkyl-1H-indole-2-carboxylic acids were designed and synthesized as beta-amyloid (Abeta) fibril assembly inhibitors. Their inhibitory activity on Abeta, aggregation was evaluated by thioflavin T assay although their activities were insignificant.     

Synthesis and anti-HIV-1 screening of novel N′-(1-(aryl)ethylidene)-2-(5,5-dioxido-3-phenylbenzo[e]pyrazolo[4,3-c][1,2]thiazin-4(1H)-yl)acetohydrazides

A novel series of N′-(1-(aryl)ethylidene)-2-(5,5-dioxido-3-phenylbenzo[e]pyrazolo[4,3-c][1,2]thiazin-4(1H)-yl)acetohydrazides was synthesized. The synthesis was carried out by thermal method as well as ultrasonic bath to reduce reaction time and to enhance product yields. The synthesized compounds were characterized by spectroscopic techniques like NMR, infrared and EIMS. The structure of compound 5w was elucidated by X-ray crystallography. The titled compounds were evaluated for anti-human immunodeficiency virus type 1 (anti-HIV-1) and cytotoxic activities. Biological studies indicated that amongst these compounds, 5a, b, j, h and i showed the activity with median effective concentration (EC₅₀) values less than 20 μM. Compound 5i exhibited the most potent anti-HIV-1 activity (EC₅₀ = 3.2 μM) while 5h showed anti-HIV-1 activity (EC₅₀ = 3.8 μM) with no toxicity at all in primary human lymphocytes, CEM and VERO cells.     

Synthesis and preliminary pharmacological investigation of new N-substituted-N-[ω-(ω-phenoxy-alkylpiperazin-1-yl)alkyl]guanidines as non-imidazole histamine H(3) antagonists

Novel, potent non‐imidazole histamine H₃ receptor antagonists were prepared. Detailed structure–activity studies revealed that N‐(4‐trifluoromethylbenzyl)‐N‐[4‐(7‐phenoxyheptylpiperazin‐1‐yl)butyl]guanidine (pA₂ = 8.49 ± 0.05), 1h , and N‐(4‐nitrobenzyl)‐N‐[4‐(7‐phenoxyheptylpiperazin‐1‐yl)butyl]guanidine (pA₂ = 8.43 ± 0.05), 1l , exhibit high affinity for the H₃ histamine receptor. The most potent antagonists in this series, 1e , 1h , and 1l , were also in vitro tested as H₁ receptor antagonists, showing weak H₁‐antagonistic activity with pA₂ = 6.70 ± 0.09, pA₂ = 6.46 ± 0.09, and pA₂ = 6.65 ± 0.11, respectively.     

Synthesis and biochemical evaluation of δ(2)-isoxazoline derivatives as DNA methyltransferase 1 inhibitors

A series of Δ(2)-isoxazoline constrained analogues of procaine/procainamide (7a-k and 8a-k) were prepared and their inhibitory activity against DNA methyltransferase 1 (DNMT1) was tested. Among them, derivative 7b is far more potent in vitro (IC(50) = 150 μM) than other non-nucleoside inhibitors and also exhibits a strong and dose-dependent antiproliferative effect against HCT116 human colon carcinoma cells. The binding mode of 7b with the enzyme was also investigated by means of a simple competition assay as well as of docking simulations conducted using the recently published crystallographic structure of human DNMT1. On the basis of the findings, we assessed that the mode of inhibition of 7b is consistent with a competition with the cofactor and propose it as a novel lead compound for the development of non-nucleoside DNMT inhibitors.     

Discovery of a novel glucagon receptor antagonist N-[(4-{(1S)-1-[3-(3, 5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the treatment of type II diabetes

A potent, selective glucagon receptor antagonist 9m, N-[(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive antagonist with high binding affinity (IC(50) of 6.6 nM) and functional cAMP activity (IC(50) of 15.7 nM). It is selective for glucagon receptor relative to other family B GPCRs, showing IC(50) values of 1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1, and VPAC2. Compound 9m blunted glucagon-induced glucose elevation in hGCGR mice and rhesus monkeys. It also lowered ambient glucose levels in both acute and chronic mouse models: in hGCGR ob/ob mice it reduced glucose (AUC 0-6 h) by 32% and 39% at 3 and 10 mpk single doses, respectively. In hGCGR mice on a high fat diet, compound 9m at 3, and 10 mpk po in feed lowered blood glucose levels by 89% and 94% at day 10, respectively, relative to the difference between the vehicle control and lean hGCGR mice. On the basis of its favorable biological and DMPK properties, compound 9m (MK-0893) was selected for further preclinical and clinical evaluations.     

Synthesis of 3-(5-bromo-2,3-dimethoxy-phenyl)-[1, 2, 4] oxadiazole analogues and their evaluation as anti-Parkinson′s agents

A series of 3-(5-bromo-2,3-dimethoxy-phenyl)-[1, 2, 4] oxadiazole derivatives was prepared and their evaluation for anti-Parkinson’s activity was measured in vivo using albino rats. The result of the biological activity studies indicated that some of the synthesized compounds have good agonistic activity on the dopamine receptors and a few of them were also found to be free from neurotoxicity. Thus these compounds might be useful ligands for studying the functional role of dopamine receptors in vivo. The high log P value of the compounds indicates that they should easily cross the blood-brain barrier (log P > 2.6).      

Synthesis of novel 2-(3′-aryl-sydnon-4′-ylidene)-5′-substituted-[1,3,4]-thiadiazolylamines and [1,3,4]-thiadiazol-2′-yl-3-oxo-[1,2,4]-triazoles as antimicrobial agents

The title compounds (3g–n) and (6g–n) were synthesized using 3-arylsydnones as synthons, and the structures were confirmed by IR, ¹H NMR, FAB mass and CHN analysis. These compounds were evaluated for their antibacterial and the antifungal activities in terms of minimum inhibitory concentrations (MICs) against the bacterial strains E. coli, B. cereus, and the fungal strains A. niger, C. albicans. Some of the compounds have shown significant activities.     

Structure-guided design of β-secretase (BACE-1) inhibitors

β-secretase (BACE-1) is a membrane-tethered aspartyl protease that serves as the rate-limiting enzyme in processing the amyloid precursor protein (APP) and, thus, is believed to play a central role in the neurodegenerative disorder, Alzheimer's disease. Due to the availability of X-ray crystal structures for the soluble domain of BACE-1, structure-based methods have been widely employed in the design of BACE-1 inhibitors. A variety of computational methods have been used, ranging from quantum mechanical studies to molecular dynamics calculations and scoring methods, all aimed at understanding the unique chemical features of the BACE-1 active site. However, BACE-1 has proven to be a difficult target due to its extended active site, its intrinsic flexibility and the requirement for brain penetration.     

Synthesis and Structure–Activity Relationship Study of 1-Phenyl-1-(quinazolin-4-yl)ethanols as Anticancer Agents

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Synthesis and investigation of Nα-[3-di(2-chloroethyl)amino-4-methylbenzoyl]amino acids

Pharmaceutical Chemistry Journal -     

Synthesis and antifungal activity of 9-aryl-8-(2-thienyl)-4,9-dihydrotetrazolo-[1′,5′-1,2]pyrimido[4,5-d]pyridazin-5(6 h)-ones

A series of 9-aryl-8-(2-thienyl)-4,9-dihydrotetrazolo[1′,5′-1,2]pyrimido[4,5-d]pyridazin-5(6H)-ones have been obtained by reaction of equivalent amounts of methyl esters of 7-aryl-6-(2-thienyl)-4,7-dihydrotetrazolo[1, 5-a]pyrimidine-5-carboxylic acids and hydrazine hydrate at 180–190°C in the absence of solvents. The structures of the synthesized compounds have been determined based on spectral data (PMR, IR, high-resolution mass spectrometry). The synthesized compounds were tested for antimicrobial activity.     

Synthesis and biological evaluation of (6- and 7-phenyl) coumarin derivatives as selective nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is an enzyme that catalyzes NADPH-dependent reduction of the weak estrogen, estrone, into the most potent estrogen, estradiol, which exerts proliferative effects via the estrogen receptors. Overexpression of 17β-HSD1 in estrogen-responsive tissues is related to the development of hormone-dependent diseases, such as breast cancer and endometriosis; thus, 17β-HSD1 represents an attractive target for the development of new therapies. We have discovered that simple coumarines 1 and 2 significantly inhibit 17β-HSD1 in a recombinant enzyme assay, with high selectivity against 17β-HSD2. We postulated that the introduction of various p-substituted phenyl moieties to position 6 or 7 of the coumarin core using the Suzuki-Miyaura cross-coupling reaction would provide mimetics of steroidal structures with improved inhibition of 17β-HSD1. The best inhibitor in the series proved to be 6a, with an IC(50) of 270 nM, and with exceptional selectivity for 17β-HSD1 over 17β-HSD2 and against the α and β estrogen receptors.     

Synthesis and Pharmacokinetics of 2-(4-amino-3,5-dichlorophenyl)-2-(alkylamino)ethanols - Structural Isomers of β2 Agonists Clenproperol and Clenpenterol

Pharmaceutical Chemistry Journal - Methods for the synthesis of 2-(4-amino-3,5-dichlorophenyl)-2-(isopropylamino)ethanol and 2-(4-amino-3,5-dichlorophenyl)-2-(tert-amylamino)ethanol, which are...