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.     

Human liver glycogen phosphorylase inhibitors bind at a new allosteric site

Background: Glycogen phosphorylases catalyze the breakdown of glycogen to glucose-1-phosphate for glycolysis. Maintaining control of blood glucose levels is critical in minimizing the debilitating effects of diabetes, making liver glycogen phosphorylase a potential therapeutic target.Results: The binding site in human liver glycogen phosphorylase (HLGP) for a class of promising antidiabetic agents was identified crystallographically. The site is novel and functions allosterically by stabilizing the inactive conformation of HLGP. The initial view of the complex revealed key structural information and inspired the design of a new class of inhibitors which bind with nanomolar affinity and whose crystal structure is also described. Conclusions: We have identified the binding site of a new class of allosteric HLGP inhibitors. The crystal structure revealed the details of inhibitor binding, led to the design of a new class of compounds, and should accelerate efforts to develop therapeutically relevant molecules for the treatment of diabetes.     

Piperidines: a new class of urease inhibitors

A variety of piperidines (2-12, 14-26) with variable substituents at N-atoms have been synthesized and evaluated as urease inhibitors. The synthesized compounds showed varying degree of urease inhibitory activity ranging from 31.97 to 254 microM. The size and electron-donating or -withdrawing effects of substituents influence the activity, which lead to the formation of urease inhibitors.     

Synthesis of galactose-linked uridine derivatives with simple linkers as potential galactosyltransferase inhibitors

Galactose-linked uridine derivatives without charge or dipole contributions in the linker were designed and synthesized via cross metathesis (CM). This strategy would provide a ready access to a range of hybrid compounds linking uridine and galactose derivatives.     

Synthesis of N-aryl spiro-sulfamides as potential glycogen phosphorylase inhibitors

A new C-glucosylated spiro-sulfamide has been prepared and evaluated toward glycogen phosphorylase inhibition. The synthesis was carried out successfully by nucleophilic displacement of 1-O-tosyl or 1-deoxy-1-iodo-α-d-gluco-hept-2-ulopyranose tetra-O-benzylated derivative using aryl amines, followed by the formation of the corresponding cyclic sulfamide.     

Identification of a new class of nonpeptidic inhibitors of cruzain

Cruzain is the major cysteine protease of Trypanosoma cruzi, which is the causative agent of Chagas disease and is a promising target for the development of new chemotherapy. With the goal of developing potent nonpeptidic inhibitors of cruzain, the substrate activity screening (SAS) method was used to screen a library of protease substrates initially designed to target the homologous human protease cathepsin S. Structure-based design was next used to further improve substrate cleavage efficiency by introducing additional binding interactions in the S3 pocket of cruzain. The optimized substrates were then converted to inhibitors by the introduction of cysteine protease mechanism-based pharmacophores. Inhibitor 38 was determined to be reversible even though it incorporated the vinyl sulfone pharmacophore that is well documented to give irreversible cruzain inhibition for peptidic inhibitors. The previously unexplored beta-chloro vinyl sulfone pharmacophore provided mechanistic insight that led to the development of potent irreversible acyl- and aryl-oxymethyl ketone cruzain inhibitors. For these inhibitors, potency did not solely depend on leaving group p K a, with 2,3,5,6-tetrafluorophenoxymethyl ketone 54 identified as one of the most potent inhibitors with a second-order inactivation constant of 147,000 s (-1) M (-1). This inhibitor completely eradicated the T. cruzi parasite from mammalian cell cultures and consequently has the potential to lead to new chemotherapeutics for Chagas disease.     

Synthesis of a new class of spiro heterocycles

A new class of spiro heterocycles viz., spiropyrazolidinediones, isoxazolidinediones, pyrimidinetriones or thioxopyrimidinediones are developed from methyl 3‐aryl‐2‐(Z‐arylethenenylsulfonyl)acrylate by double Michael addition reaction with dimethyl malonate followed by cyclocondensation with appropriate nucleophiles.     

Synthesis of a new class of keto-linked bis heterocycles

A new class of keto-linked bis heterocycles have been prepared by 1,3-dipolar cycloaddition of tosyl methyl isocyanide, nitrile imines and nitrile oxides to unsymmetrical bischalcones.     

Synthesis of a new class of sulfone linked bisheterocycles

Some bisheterocycles having pyrrole and oxazoline/thiazoline units were synthesized from Z‐styrylsulfonylacetic acid methyl esters using samarium chloride.     

Beta-N-cyanoethyl acyl hydrazide derivatives: a new class of beta-glucuronidase inhibitors

Eight new beta-N-substituted acyl hydrazides along with their corresponding acyl derivatives were synthesized and screened for in vitro beta-glucuronidase inhibition and found to be active against the enzyme. All of these compounds were found to be noncompetitive inhibitors except for N'-(2-cyanoethyl)-4-hydroxy benzohydrazide (10), which was found to be an uncompetitive inhibitor. Structure-activity relationship studies indicated that the benzyloxy group present in compounds 12 and 13 is responsible for the beta-glucuronidase inhibition activity.     

Bismethylene triphosphate nucleotides of uridine 4-phosphate analogues: a new class of anionic pyrimidine nucleotide analogues

Cytidine-5'-triphosphate synthase (CTPS) catalyzes the formation of cytidine triphosphate (CTP) from glutamine, uridine 5'-triphosphate (UTP), and adenosine 5'-triphosphate (ATP). This reaction proceeds via formation of the high-energy intermediate UTP-4-phosphate (UTP-4-P). Stable analogues of UTP-4-P may be potent inhibitors of CTPS and useful as lead structures for the development of anticancer and antiviral agents. Several bismethylene triphosphate (BMT) nucleotides of uridine 4-phosphate (U-4-P) analogues have been prepared. A key step was the selective methanolysis, with the aid of a tin catalyst, of the 5' ester moiety of 2',3',5'-tri-O-acetyl or tri-O-benzoyl U-4-P analogues. We believe this represents the first general approach to the selective cleavage of 5' benzoyl esters in benzoylated nucleosides. Mitsunobu coupling of these 5'-deprotected U-4-P analogues to an unsymmetrical, protected BMT bearing a free phosphonic acid moiety at one of the terminal positions gave fully protected BMT-U-4-P analogues. Global deprotection of these species was achieved using TMSBr followed by treatment with NH4OH-MeOH or NH4OH-pyridine. The resulting BMT nucleotides represent a new class of anionic pyrimidine nucleotide analogues.     

Trihydroxy-2-thiaquinolizidine derivatives as a new class of bicyclic glycosidase inhibitors

Trihydroxy-2-thiaquinolizidines, a new class of bicyclic dideoxy-iminohexitol glycosidase inhibitor derivatives with nominally the d-gluco, l-ido, d-manno and l-gulo configurations were synthesized. X-ray analyses indicated that the preferred conformation for d-gluco and d-manno derivatives was a flat trans-fused system. Unlike deoxynojirimycin, the compound with d-gluco configuration was selective for α-glucosidases (yeast and rice) and showed no inhibitory activity towards β-glucosidase (almond), α-galactosidase (green coffee beans), α-galactosidase (E. coli) and α-mannosidase (jack bean), while the l-ido derivative was specific for β-glucosidase (almond).     

Synthesis of functionalized acenaphthenes and a new class of homooxacalixarenes

The 5,6-dialkoxyethers of acenaphthene have been synthesized for the first time via modified Ullmann reaction conditions. Further modifications of the 5,6-dimethoxyacenaphthene allowed the synthesis of the first acenaphthene analogue of the octahomotetraoxacalixarenes. The X-ray structure of this new macrocycle and its complexation study with C(60) are reported.     

Glucose derived inhibitors of glycogen phosphorylase

Design, synthesis, and structure–activity relationships of glucose analogue inhibitors of glycogen phosphorylase are surveyed.     

Synthesis of enantiomers of 2′-aminomethyl-5-benzylacyclouridine (AM-BAU) and 2′-aminomethyl-5-benzyloxybenzylacyclouridine (AM-BBAU). Potent inhibitors of uridine phosphorylase

Racemic 2′-aminomethyl-5-benzyl-acyclouridine (AM-BAU, 5 ) and 2′-aminomethyl-5-benzyloxybenzyla-cyclouridine (AM-BBAU, 6 ) have been found to be very active inhibitors of uridine phosphorylase [1]. Their enantiomers were synthesized from chiral 2,2-dimethyl-1,3-dioxolane-4-methanol ( 7a,b ). S-(—)-AM-BAU ( 5a ) and S-(—)-AM-BBAU ( 6a ) were prepared from the R-(—) isomer 7a , and R(+)-AM-BAU ( 5b ) and R-(+)-AM-BBAU (6b) from the S-(+) isomer 7b . A different route from the S-(+) isomer 7b to S-(—)-AM-BBAU ( 6a ) was also determined to be feasible.     

Synthesis of nicotinonitrile derivatives as a new class of NLO materials

4,6-Diaryl-2-(pyrrolidin-1-yl)-nicotinonitriles 2a-k and 3-amino-2,4-dicyano-5-aryl-biphenyls 3a-c were synthesized from 1,3-diaryl-prop-2-en-1-ones 1a-k and malononitrile by a convenient one-pot method. Likewise, the reaction of aromatic aldehydes with malononitrile afforded 6-amino-4-aryl-2-(pyrrolidin-1-yl)-pyridine-3,5-dicarbonitriles 6a-f. The reaction of mesityl oxide with malononitrile gave 5-amino-7-(pyrrolidin-1-yl)-2,4,4-trimethyl-1,4-dihydro-1,6-naphthyridine-8-carbonitrile 8. The NLO studies of the pyridinedinitrile derivatives 6a, b, f showed a high value while that of nicotinonitrile 2b was weak.     

Synthesis and catalytic activity of a new class of cyclophosphazenic polypodands

A new class of solid-liquid phase-transfer catalysts (SL-PTC) has been prepared by the reaction of octachlo-rocyclotetraphosphazatetraene and polyethylene glycol monoalkyl ether. These polypodands are found to be powerful metal cation complexing agents and very efficient catalysts in anion promoted reactions (e.g. nucleophilic substitution and reduction reactions).     

Synthesis of a new class of acylplatinum complexes derived from salicylaldehyde

The synthesis of a new class of acylplatinum complexes of composition [Pt(OC₆H₄CO)L_aL_b] L_a = L_b = PR₃, P(OR)₃, Ph₂PCH₂CH₂PPh₂, AsR₃; L_a = 2-picoline, 3-picoline, 4-picoline, ¹⁵NH₂{CH₂}₅CH₃, L_b = DMSO, is described. The complexes are synthesized from o-hydroxybenzaldehyde (salicylaldehyde) and K₂PtCl₄ and contain an organic chelating ligand bound to platinum via the phenolic oxygen and the aldehyde carbon. ¹H, ¹³C, ³¹P and ¹⁹⁵Pt NMR data for the new complexes are reported.