Synthesis and evaluation of a new class of tertiary alcohol based BACE-1 inhibitors

BACE-1 has emerged as one of the best characterized targets for future Alzheimer therapy. In accordance with the successful identification of masked inhibitors of HIV-1 protease, we envisioned that tert-alcohol containing transition-state mimicking structures would also be worthwhile evaluating as BACE-1 inhibitors. Twelve novel inhibitors were prepared via synthetic routes using epoxyalcohol derivates as key intermediates. The best synthesized tert-hydroxy inhibitor exhibited a BACE-1 IC₅₀ value of 0.38 μM.     

Synthesis,Characterization, and Spectroscopic Properties of Hexa(4-Bromo-2-Formyl-Phenoxy)Cyclotriphosphazene and Hexa(4-Chloro-2-Formyl-Phenoxy)Cyclotriphosphazene and Fully Substituted Cyclotriphosphazene Derivatives Bearing a Schiff Base at Room Temperature

Abstract

Hexa(4-bromo-2-formyl-phenoxy)cyclotriphosphazene (2) and hexa(4-chloro-2- formyl-phenoxy)cyclotriphosphazene (3) were obtained from the reactions of hexachloro- cyclotriphosphazene (1) with 5-bromosalicylaldehyde and 5-chlorosalicylaldehyde in the presence of (C₂H₅)₃N and K₂CO₃ at room temperature, respectively. The new two organocyclotriphosphazenes bearing formyl groups were reacted with 4-cyano aniline, 2-phenyl aniline, 4-aceto aniline, 5-chloro-2-hydroxy aniline, 2-hydroxy aniline, 4-hydroxy aniline, 2-(4-morpholino)ethyl amine, 4-carboxy aniline, 4-carbomoyl aniline, 2-mercapto aniline, and 5-amino isoquonoline to prepare cyclotriphosphazene derivatives containing a Schiff base at room temperature. However, fully phenoxy-substituted cyclotriphosphazenes containing a Schiff base were isolated from the reactions of the compound 2 and 3 with 5-chloro-2-hydroxy aniline, 2-hydroxy aniline, 4-hydroxy aniline, and 2-(4-morpholino)ethyl amine. The structures of the synthesized compounds were characterized by elemental analysis, IR, and NMR (¹H, ¹³C, ³¹P) spectroscopy. According to the results of the analysis, all synthesized compounds were found to be fully substituted organocyclotriphosphazenes, such as hexa[4-bromo-2-(5-chloro-2-hydroxy-pheyliminomethyl)phenoxy]cyclotriphosphaze (2a). All cyclotriphosphazene derivatives synthesized gave fluorescence emission peaks in range between 300 nm and 410 nm.     

Synthesis and Antimicrobial Evaluation of Novel N-Substituted β-Hydroxy Benzimidazole Sulfone Fluoroquinolones by Selective Oxidation Using Ticl4-H2O2

Abstract

The synthesis of N-substituted β-hydroxy benzimidazole sulfones containing 8-methoxy fluoroquinolone has been described and they were evaluated for antimicrobial activities. The compounds of N-substituted β-hydroxy benzimidazole sulfides (4a–e) and N-substituted β-hydroxy benzimidazole sulfones (5a–e) at C-7 of fluoroquinoline exhibited superior activity in vitro. 8-Methoxy fluoroquinolone carboxylic acid (1), reaction with piperizine in acetonitrile in presence of triethylamine under reflux gives 7-piperazinyl-8-methoxyfluoroquinolone (2). The latter is reacted with epichlorohydrine in presence of NaOH in acetone yielded N-substituted epoxide (3), which on treatment with 5-substituted-2-mercaptobenzimidazoles gives N-substituted β-hydroxy benzimidazole sulfides (4). Further, 4 on treatment with TiCl₄-H₂O₂ and in DCM yielded the corresponding N-substituted β-hydroxy benzimidazole sulfone (5).     

Computational design of novel cyclic urea as HIV-1 protease inhibitor

A series of novel cyclic urea molecules 5,6-dihydroxy-1,3-diazepane-2,4,7-trione as HIV-1 protease inhibitors were designed using computational techniques. The designed molecules were compared with the known cyclic urea molecules by performing docking studies, calculating their ADME (Absorption, Distribution, Metabolism, and Excretion) properties and protein ligand interaction energy. These novel molecules were designed by substituting the P ₁/P′ ₁ positions (4 ^th and 7 ^th position of 1, 3-diazepan-2-one) with double bonded oxygens. This reduces the molecular weight and increases the bioavailability, indicating better ADME properties. The docking studies showed good binding affinity towards HIV-1 protease. The biological activity of these inhibitors were predicted by a model equation generated by the regression analysis between biological activity (log 1/K ⁱ ) of known inhibitors and their protein ligand interaction energy. The synthetic studies are in progress.      

An efficient method for the synthesis of 9-β-D-2′-deoxyribofuranosyl-6-methylpurine

A new method for the preparation of 9-β-D-2′-deoxyribofuranosyl-6-methylpurine from inosine (1) is described. Inosine was converted to 6-chloropurinenucleoside (4) via acetylation, chlorination, and deacetylation. Compound 4 was transformed to the key intermediate 6-methylpurinenucleoside (7) via protection of the 2′,3′,5′-hydroxy groups of 4 with 3,4-dihydropyran to give compound 5, then methylation at the 6-position of 5 with dimethyl copper lithium gave compound 6; depyranylation of 6 led to the subsequent selective protection of the 3′,5′-hydroxy groups of 7 with O[Si(I-Pr)₂Cl]₂ followed by reaction with phenyl chlorothionoformate to give compound 9. Compound 9 was then converted to the target compound 11 via 2′-deoxidation and 3′, 5′-desilylation. The structures of these products were identified by Mass Spectrum (MS), ¹H-NMR (Nuclear Magnetic Resonance) spectra and elemental analysis. Translated from Chinese Journal of Organic Chemistry, 2006, 26(10): 1394–1397 (in Chinese)     

Structural and electronic properties of new fullerene derivatives and their possible application as HIV-1 protease inhibitors

Density functional theory (DFT) calculations have been carried out at the hybrid Becke 3-Lee–Yang–Parr; B3LYP/3-21G** level of theory to study two series of hydroxy-chalca-acetic acid-(4-pyrrolidin-1-yl-phenyl) ester [C₆₀-C₂H₄N-(4-XCOCH₂OH)C₆H₄] and hydroxy-chalcoacetic acid-[2-(2-hydroxy-acetylchalcanyl)-4-pyrrolidin-1-yl-phenyl] ester[C₆₀-C₂H₄N-(3,4-XCOCH₂OH)C₆H₄]. The X atom is O, S or Se for the two series. The vibrational spectra, physical, chemical, thermodynamics and Quantitative Structure Activity Relationship (QSAR) properties of the studied molecules are calculated and discussed. We have evaluated these molecules as HIV-1 protease inhibitors based on the hydrogenation interaction between the hydroxymethylcarbonyl (HMC) groups and the two aspartic acid of the HIV-1 protease active site. Results show that some of the investigated fullerene-based derivatives can be considered promising as HIV-1 protease inhibitors.     

Automated Docking and the Search for HIV Protease Inhibitors

Abstract

This article will discuss the motivations, technologies, and future directions of computational automated docking in the context of the structure-based rational design of HIV-1 protease inhibitors. Docking simulations are widely used for screening of compound libraries to identify new drug leads, employing a simple model for rapid testing of thousands of compounds. Docking simulations are also useful for lead enhancement, using more detailed models to analyze the atomic interactions between inhibitors and target macromolecules. Major advances have been reported in the development of empirical force fields, which now allow assessment of relative binding strength and drug specificity, and extensions of automated docking techniques allow de novo drug design.     

FILO (Field Interaction Ligand Optimization): A simplex strategy for searching the optimal ligand interaction field in drug design

A method (FILO, Field Interaction Ligand Optimization) for obtaining the optimal molecular interaction field was developed on the basis of the Simplex optimization procedure applied to a matrix of interaction energies obtained by performing a GRID computation on a suitable data set. The FILO procedure was tested on a set of nine HIV-1 protease inhibitors with known crystal structures. The results of FILO consist of the optimal molecular interaction field of a putative new ligand with optimal binding affinity. The final FILO model yields R ² and R ² _CV values of 0.993 and 0.936, respectively, and finds eight negative and four positive interaction nodes for the OH probe taken as an example. The eight H bonding interactions pointed out by FILO identified well the binding site AA-residues Gly A27, Asp A29, water 501, Gly B48 and Asp A25 of HIV-1 protease.     

Preparation of Some Derivatives of N‐tert‐Butyldecahydro‐3‐isoquinoline Carboxamide

N‐tert‐Butyldecahydro‐3‐isoquinoline carboxamide (1) is a key structural fragment present in a variety of medicinally important HIV protease inhibitors. Derivatives of this carboxamide were prepared by alkylation with either 2‐iodoethanol, allyl bromide, or bromoacetaldehyde dimethylacetal. The corresponding aldehyde of the dimethylacetal derivative was prepared by reaction with BBr₃ in CH₂Cl₂.     

Synthesis and Conformational Studies of Unnatural Pyrimidine Nucleosides

ABSTRACT

Starting from 3,4-di-O-acetyl-L-rhamnal (6) and thymine (7) the unsaturated nucleosides 1-(2′,3′,6′-trideoxy-4′-O-acetyl-α- and β-L-erythro-hex-2′-enopyranosyl)-thymine (8a and 8b) were prepared in anomerically pure form. In solution 8a was shown to be present in the ⁵ H _o and ⁰ H ₅ conformations, whereas the predominant conformation of 8b was ⁵ H _o. Chemical transformation of 8a and 8b led to the saturated nucleosides 1-(2′,3′,6′-trideoxy-α- and β-L-erythro-hexopyranosyl)thymine (10a and 10b, respectively), which were converted into 1-(4′-azido-2′,3′,4′,6′-tetradeoxy-α- and β-L-threo-hexopyranosyl)thymine (12a and 12b). Preliminary biological studies showed that 9b was inactive against the HIV-1 and HIV-2 viruses.     

Molecular modeling studies of human immunodeficiency virus type 1 protease inhibitors using three‐dimensional quantitative structure‐activity relationship,virtual screening,and docking simulations

In this paper, two 3‐dimensional quantitative structure‐activity relationship models for 60 human immunodeficiency virus (HIV)‐1 protease inhibitors were established using random sampling analysis on molecular surface and translocation comparative molecular field vector analysis (Topomer CoMFA). The non–cross‐validation (r²), cross‐validation (q²), correlation coefficient of external validation (Q²_ext), and F of 2 models were 0.94, 0.80, 0.79, and 198.84 and 0.94, 0.72, 0.75, and 208.53, respectively. The results indicated that 2 models were reasonable and had good prediction ability. Topomer Search was used to search R groups in the ZINC database, 20 new compounds were designed, and the Topomer CoMFA model was used to predicate the biological activity. The results showed that 18 new compounds were more active than the template molecule. So the Topomer Search is effective in screening and can guide the design of new HIV/AIDS drugs. The mechanism of action was studied by molecular docking, and it showed that the protease inhibitors and Ile50, Asp25, and Arg8 sites of HIV‐1 protease have interactions. These results have provided an insight for the design of new potent inhibitors of HIV‐1 protease.     

Structure-Toxicity Relationships for Aminoalkanols: A Comparison with Alkanols and Alkanamines

Abstract

The relative toxicity (logIGC^?1 ₅₀) of 49 selected aliphatic amines and aminoalkanols was evaluated in the static Tetrahymena pyriformis population growth impairment assay. Excess toxicity, indicated by potency greater than predicted for non-polar narcotic alkanols, was associated with both classes of test chemicals. Moreover, the aminoalkanols were found to be more toxic than the corresponding alkanamines. A high quality 1-octanol/water partition coefficient (log K _ow) dependent quantitative structure-activity relationship (QSAR), logIGC^?1 ₅₀ = 0.78 (log K _ow)-1.42; r ² = 0.934, was developed for alkanamines. This QSAR represented the amine narcosis mechanism of toxic action. No quality QSAR was developed for the aminoalkanols. However, several structure-toxicity features were observed for this class of chemicals. Two-amino-1-hydroxy derivatives being more toxic than the corresponding derivatives, where the amino and hydroxy moieties were separated by methylene groups. Hydrocarbon branching next to the amino moiety resulted in decreased toxicity. Aminoalkanol alters lipid metabolism in T. pyriformis.     

THE SYNTHESIS OF DISODIUM O-n-ALKYLTHIOPHOSPHATES

Abstract

The disodium O-alkylthiophosphates were synthesized by reaction of PSCl₃ with the corresponding alcohols to the O-alkylphosphorodichloridothioates (1), which were hydrolyzed in aqueous triethylamin–sodium acetate solution.¹ The O-alkylthiophosphates (2) were isolated as barium salts and converted to the disodium salts by Na₂SO₄.

Because the barium salts of O-ethyl- and O-n-propyl-thiophosphate were soluble in water, the corresponding dichlorido compounds were hydrolyzed directly to the disodium salts in aqueous sodium hydroxide plus dioxane according to Gray and Hamer.²

Further purification was achieved by column chromatography on Sephadex LH20 using water as an eluant. Pure products, which were not contaminated by either inorganic thiophosphate or O-alkylphosphates, were thus obtained.     

Synthesis and characterization of two binuclear nickel(II) complexes of thiophenol-based “end-off” compartmental ligands and their application as catalysts for selective oxidation of sulfides

Reaction of the binucleating S-protected ligand precursors 2-(N,N-dimethylthiocarbamato)-5-methylisophthalaldehyde di-2′-hydroxy anil (I) and 2-(N,N-dimethylthiocarbamato)-5-methylisophthalaldehyde di-2′-hydroxy 5′-methyl anil (II) with nickel(II) acetate tetrahydrate in the presence of pyrazole afforded the binuclear nickel(II) complexes [L^INi₂(pz)] (1) and [L^IINi₂(pz)] (2), respectively. The complexes have been characterized by routine physicochemical studies as well as by X-ray single crystal structure analysis. In both complexes, Ni(II) ions are doubly bridged by the thiophenolic sulfur of the pentadentate Schiff base ligand and a pyrazolate group. Efficient protocols for the oxidation of sulfides to sulfoxides with high selectivities, catalyzed by binuclear μ-thiophenolato-μ-pyrazolatonickel(II) in the presence of urea hydrogen peroxide (UHP) were explored. We obtained predominantly the monooxygenated product. The resulting products are obtained in good to excellent yields within a reasonable time.     

New Synthesis of Acetaminophen Derivatives Containing a Phosphorus Atom

Two derivatives of acetaminophen have been efficiently prepared from 4-aminophenol via a two-step procedure involving acetylation of OH and NH ₂ groups and then the reaction of the acetylated compounds with diakyl acetylenedicarboxylate in the presence of triphenylphosphine. The products were obtained in good yields.     

Synthesis of Novel 3-(5-(Alkyl/arylthio)-1,3,4-Oxadiazol-2-yl)-8-Phenylquinolin-4(1H)-One Derivatives as Anti-HIV Agents

Novel quinolone derivatives featuring an 1,3,4-oxadiazole ring as a metal-chelating component and a benzyl group base on HIV-1 integrase inhibitors pharmacophore were designed and synthesized. An antiviral assay revealed that most analogues inhibited HIV-1 replication in the cell culture. Our results showed that compounds bearing small alkyl groups as R group were inactive in anti-HIV-1 assay, whereas compounds possessing benzyl or substituted benzyl at the same position showed good anti-HIV activity with the range of 20–57% at 100 μM concentration. Among them, 3-(5-((2-fluorobenzyl)thio)-1,3,4-oxadiazol-2-yl)-8-phenylquinolin-4-(1H)-one (compound 13) showed reasonable cell-based antiviral activity (EC₅₀ = 50 μM) with no considerable cytotoxicity (CC₅₀ > 100 μM) in the cell viability assay, suggesting that it may be amenable to further development for identifying new anti-HIV-1 agents. Docking studies using the later crystallographic data available for PFV integrase corroborate favorable binding to the active site of HIV integrase, providing a basis for the design of more potent analogues.     

Asymmetric Synthesis of Some Chiral Aryl and Hetero Aryl-Substituted β-, γ-, δ-Hydroxy Esters

Sixteen chiral β-, γ-, and δ-hydroxy esters with aryl, substituted aryl, and heteroaryl groups 2a–2s were synthesized by the asymmetric reduction of their corresponding keto esters 1a–1s as chiral pure reference compounds and starting materials. The asymmetric reduction was achieved by (R)-Me-CBS-oxazaborolidine. Ten new chiral γ- and δ-hydroxy esters 2d, 2e, and 2j–2s were obtained with high ee values and characterized by infrared, NMR (¹H and ¹³C), mass spectrometry, chiral high-performance liquid chromatography, and specific rotation.     

Synthesis of novel HIV-1 protease inhibitors based on carbohydrate scaffolds

The synthesis of peptidomimetic inhibitors of HIV-1 protease based on 6-deoxy-6-amino-β-d-glucopyranoside and 6-deoxy-6-amino-β-d-mannopyranoside scaffolds has been achieved. The inhibitors had IC₅₀ values in the micromolar range. The results provide a platform for the development of more potent carbohydrate based inhibitors of HIV-1 and other aspartic proteases.     

PHOSPHORORGANISCHE VERBINDUNGEN 851 SYNTHESE UND ANWENDUNG OPTISCH AKTIVER TERTIÄRER PHOSPHINE ALS CO-KATALYSATOREN DER HOMOGENHYDRIERUNG MIT RHODIUM-PHOSPHIN-KOMPLEXEN

Abstract

Die Darstellung der optisch aktiven Methyl-n-propyl(bzw.-isopropyl)arylphosphine 1 bis 8 wird beschrieben. Hierbei ist Aryl: p-Methoxyphenyl (1 und 2), p-Dimethylaminophenyl (3 und 4), o-Methoxyphenyl (5 und 6), o-Dimethyl-aminophenyl (7) und o-Aminophenyl (8).

Die Phosphine 1 bis 8 werden als optisch aktive Co-Katalysatoren bei der Homogenhydrierung von α- und ß-Methylzimtsäureethylester, der α-Acetaminoacrylsäure und der α-Acetaminozimtsäure mit Rhodium-Phosphinkomplexen eingesetzt und jeweils die optische Induktion bestimmt. Folgende Ergebnisse (Vgl. die Tabellen 1 bis 4) wurden erhalten:

1) Die CH₃O-Gruppe und N(CH₃)₂-Gruppe verändern unabhängig von ihrer Stellung die optische Induktion bei der Homogenhydrierung von α- und ß-Methylzimtsäureethylester nur unwesentlich im Vergleich zu den entsprechenden Methyl-n-propyl (bzw.-isopropyl)-phenylphosphinen.

2) Bei der Homogenhy drierung von α-Acetaminoacrylsäure und α-Acetaminozimtsäure üben para-ständige OCH₃- und (CH₃)₂N-Gruppen in den optisch aktiven Co-Katalysatoren (Verbindungen 1 bis 4) keinen Einfluß auf die Höhe der optischen Induktion aus.

3) In ortho-Stellung verknüpfte OCH₃- und (CH₃)₂N-Gruppen (Verbindungen 5 bis 7) führen jedoch bei der Homogenhydrierung von α-Acetaminoacrylsäure und α-Acetaminozimtsäure zu einer beachtlichen Erhöhung der optischen Induktion. Bei α-Acetaminozimtsäure und 7 als Co-Katalysator beträgt die optische Induktion 80%! Hierbei übertrifft die (CH₃)₂N-Gruppe die CH₃O-Gruppe an Wirksamkeit.

4) Methyl-n-propyl-o-aminophenylphosphin 8 ist als Co-Katalysator unbrauchbar, da es offenbar durch Wechsel-wirkung der NH₂-Gruppe mit Rhodium die Koordinierung des prochiralen Olefins mit dem Komplex unterdrückt.

5) Eine experimentell begründete Deutung für das Zusammenwirken der am Aufbau der Homogenkatalysatoren beteiligten Komponenten konnte nicht gegeben werden.

Tabelle 5 zeigt die Abhängigkeit der Hydriergeschwindigkeit von Art und Stellung der Substituenten im Phenylrest. Die Hydriergeschwindigkeit ist bei den induktionsstarken Co-Katalysatoren 5 bis 7 deutlich vermindert.

The preparation of the optically active methyl-n-propyl(isopropy) aryl phosphines 1 ± 8 is described, whereby the aryl group is p-methoxyphenyl (1, 2), p-dimethylaminophenyl (3, 4), o-methoxyphenyl (5, 6), o-dimethylaminophenyl (7) and o-aminophenyl (8).

The phosphines 1–8 were used as chiral co-catalysts at the rhodium complex in the homogeneous hydrogenation of α- and ß-methyl cinnamic acids, α-acetaminoacrylic acid and α-acetaminocinnamic acid. The optical induction in the products was measured. The following results (see Tables 1–4) were obtained:

1) The methoxy and dimethylamino groups, independent of their site, have only negligible influence on the optical yield in the reduction of α- and ß-methylcinnamic acids compared with the parent methyl-propylphenylphosphine.

2) In the hydrogenation of acetaminoacrylic acid and α-acetaminocinnamic acid, para methoxy- or dimethylamino groups (compounds 1–4) show likewise no special influence on the optical yield.

3) Ortho methoxy or dimethylamino groups (compounds 5–7), however, result in a measurable increase in optical yield in the reduction of α-acetaminoacrylic- and α-acetaminocinnamic acids. In the case of compound 7 with α-acetaminocinnamic acid, an optical purity of 80% was obtained! The dimethylamino group is in this case more effective than the methoxy group.