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A new, one-step method for the synthesis of substituted 3,5-dicyanospiro-4(piperidine-4′)-1H,4H-dihydropyridine-3-thiolates and 2,6-diamino-3,5-dicyanospiro-4-[(piperidine-4′) or (2′ -oxoindole-3′)]-4H-thiopyrans using a multicomponent reaction of N-substituted piperidine-4-ones and isatins with derivatives of cyanoacetic acid is described. The regioselectivity of this reaction can be controlled by varying the substituents at the nitrogen atom of the piperidine-4-ones. The multicomponent reaction of N-alkylpiperidine-4-ones with malononitrile and cyanothioacetamide gives spiro-4-(1′ -alkylpiperidine-4′)-1H,4H-dihydropyridine-2-thiolates, whereas a similar reaction of N-(acyl)alkoxycarbonylpiperidine-4-ones leads exclusively to spiro-4-(1′ -(acyl)alkoxycarbonylpiperidine-4′)-4H-thiopyrans.

Diverse substituted 4-di(tri)fluoromethyl-3-cyanopyridine-2(1H)-thiones were synthesized via the Claisen condensation of alpha-methyl(methylene)ketones with di(tri)fluoroacetate, followed by the immediate Thorpe-Guareschi reaction of the preformed di(tri)fluoromethyl-1,3-diketones with cyanothioacetamide. The procedure allows facile synthesis of the di(tri)flouromethylated pyridine-2(1H)-thiones in 50-95% yields, without the need for isolation and purification of intermediates. Resultant 4-di(tri)fluoromethyl-3-cyanopyridine-2(1 H)-thiones were subsequently utilized in domino reactions to produce first various substituted thieno[2,3-b]pyridines and, then, thienopyridines polyannulated with pyridine, pyrimidine, benzodiazocine, diazepine, and pyran rings.

Treatment of α-benzotriazolyl-α,β-unsaturated aldehydes with monosubstituted hydrazines followed by alkylation at the 4-position of the pyrazoline ring and elimination of the benzotriazole group affords 1,4,5-trisubstituted pyrazoles in overall yields of 52–79%.

Thiosemicarbazides 5 (yields 50-97%) and N-hydroxythioureas 6 (yields 71-99%) of variable substitution patterns are prepared efficiently by reactions of 1-(thiocarbamoyl)benzotriazoles 4a-i with hydrazines or hydroxylamines, respectively.

Tetrazolium-5-dinitromethylide sodium salt has been prepared (91%) by cyclization of 1-amino-1-hydrazino-2,2-dinitroethene with nitrous acid in water. 5-Imino-1-(hydroxyiminonitromethyl) derivatives were obtained by nitration of 2-(5-amino-1,3-dimethyl-1H-1,2,4-triazol-4-ium-4-yl)- and 2-(5-amino-4-methyl-1H-tetrazolium-1-yl)acetate complex salts. Treatment of 4-methyl-1-(2-oxopropyl)-1-tetrazolium methylsulfate with nitric and sulfuric acid gave methyl (3-nitro-1,2,4-oxadiazol-5-yl)amine (27%) probably via dinitromethylide followed by cyclization and loss of nitrogen.

Substituted 3-hydroxypyrazoles, which were prepared based on ethyl esters of substituted 4-(pyridin-2-ylthio)- or 4-(1,4-dihydropyridin-2-ylthio)acetoacetic acids and hydrazine hydrate, were used in the synthesis of 6-amino-4-aryl-5-cyano-3-(pyridin-2-ylthiomethyl)-2,4-dihydropyrano[2,3-c]pyrazoles. The molecular and crystal structure of 6-amino-5-cyano-3-(3-cyano-4,6-dimethylpyridin-2-ylthiomethyl)-4-(2-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole was established by X-ray diffraction analysis.

Structure-based drug design relies on static protein structures despite significant evidence for the need to include protein dynamics as a serious consideration. In practice, dynamic motions are neglected because they are not understood well enough to model – a situation resulting from a lack of explicit experimental examples of dynamic receptor-ligand complexes. Here, we report high-resolution details of pronounced ~1 ms timescale motions of a receptor-small molecule complex using a combination of NMR and X-ray crystallography. Large conformational dynamics in Escherichia coli dihydrofolate reductase are driven by internal switching motions of the drug-like, nanomolar-affinity inhibitor. Carr-Purcell-Meiboom-Gill relaxation dispersion experiments and NOEs revealed the crystal structure to contain critical elements of the high energy protein-ligand conformation. The availability of accurate, structurally resolved dynamics in a protein-ligand complex should serve as a valuable benchmark for modeling dynamics in other receptor-ligand complexes and prediction of binding affinities.

The phenomenon of antibiotic resistance has created a need for the development of novel antibiotic classes with nonclassical cellular targets. Unfortunately, target-based drug discovery against proteins considered essential for in vitro bacterial viability has yielded few new therapeutic classes of antibiotics. Targeting the large proportion of genes considered nonessential that have yet to be explored by high-throughput screening, for example, RecA, can complement these efforts. Recent evidence suggests that RecA-controlled processes are responsible for tolerance to antibiotic chemotherapy and are involved in pathways that ultimately lead to full-fledged antibiotic resistance. Therefore inhibitors of RecA may serve as therapeutic adjuvants in combination chemotherapy of bacterial infectious diseases. Toward the goal of validating RecA as a novel target in the chemotherapy of bacterial infections, the authors have screened 35,780 small molecules against RecA. In total, 80 small molecules were identified as primary hits and could be clustered in 6 distinct chemotype clades. The most potent class of hits was further examined, and 1 member compound was found to inhibit RecA-mediated strand exchange and prevent ciprofloxacin-induced SOS expression in Escherichia coli. This compound represents the first small molecule demonstrating an ability to inhibit the bacterial SOS response in live bacterial cell cultures.

Polyfunctional 4-(3-cyanopyridin-2-ylthio)acetoacetates were used in the synthesis of 4-hydroxy-1H-thieno[2,3-b:4,5-b]dipyridin-2-ones. The latter were used in reactions with arylidene-malononitriles or in three-component reactions with aldehydes and malononitrile to give 2-amino-4-aryl-3-cyano-5-oxo-5,6-dihydro-4H-pyrano[2,3-d]pyrido[3',2':4,5]thieno[3,2-b]pyridines. Utilizing 4-(3-cyanopyridin-2-ylthio)acetoacetates and arylidenemalononitriles or aldehydes and malononitrile, we developed a method for the synthesis of substituted 3-alkoxycarbonyl-6-amino-4-aryl-2-(3-cyanopyridin-2-ylthiomethyl)-4H-pyrans. Reactions of substituted 4-(3-cyanopyridin-2-ylthio)acetoacetates with hydrazine hydrate yielded substituted 3-hydroxypyrazoles, which were further used for the preparation of 6-amino-4-aryl-5-cyano-3-(pyrid-2-ylthiomethylene)-2,4-dihydropyrano[2,3-c]pyrazoles. Analogously, ethyl 4-(3-cyano-1,4-dihydropyridin-2-ylthio)acetoacetates were used for the synthesis of substituted 2-amino-4H-pyrans.

[Reaction: see text]. Readily available N-acylbenzotriazoles 2a-l (derived from a variety of aliphatic, (hetero)aromatic, and N-protected alpha-amino carboxylic acids) smoothly convert primary 3a-c and alpha-functionalized primary nitroalkanes 3d into the corresponding alpha-nitro ketones 5a-p in yields of 39-86% (average 63%).

[Reaction: see text]. Readily available N-acylbenzotriazoles 2a-l (derived from a variety of aliphatic, (hetero)aromatic, and N-protected alpha-amino carboxylic acids) smoothly convert primary 3a-c and alpha-functionalized primary nitroalkanes 3d into the corresponding alpha-nitro ketones 5a-p in yields of 39-86% (average 63%).

The allyllithium generated from 1-[(2EZ)-3-chloroprop-2-enyl]-1H-1,2,3-benzotriazole (5) and LDA, in the presence of HMPA, reacts with enolizable and nonenolizable carbonyls solely at the CCl terminus to give 1-(2-oxiranylvinyl)benzotriazoles 6a−g in 61−82% yields. Allyllithiums generated from 6a,c reacted exclusively at the CBt terminus to give 10a−d in 68−88% yields. Acidic hydrolysis of (oxiranylvinyl)benzotriazoles 6a−g and 10a−d provided 4-hydroxyalk-2-en-1-one derivatives 12a,b,c,e,g, 13a−d, and furan 14 in 54−86% yields.

The allyllithium generated from 1-[(2EZ)-3-chloroprop-2-enyl]-1H-1,2,3-benzotriazole (5) and LDA, in the presence of HMPA, reacts with enolizable and nonenolizable carbonyls solely at the CCl terminus to give 1-(2-oxiranylvinyl)benzotriazoles 6a−g in 61−82% yields. Allyllithiums generated from 6a,c reacted exclusively at the CBt terminus to give 10a−d in 68−88% yields. Acidic hydrolysis of (oxiranylvinyl)benzotriazoles 6a−g and 10a−d provided 4-hydroxyalk-2-en-1-one derivatives 12a,b,c,e,g, 13a−d, and furan 14 in 54−86% yields.

4,6-Diaryl-3-cyanopyridine-2(1H)-thiones were synthesized in one step by the reaction of elemental sulfur, malononitrile, and 2-aryl-1-aroylethylenes in the presence of excess triethylamine. The products were used in one-pot syntheses of substituted thieno[2,3-b;4,5-b]dipyridines and pyrido[3",2":4,5]thieno[3,2-d]pyrimidines.

Substituted 2-amino-4-aryl-3-cyano-5-oxo-5,6-dihydro-4H-pyrano[2,3-d]pyrido[3",2":4,5]thieno[3,2-b]pyridines were synthesized by the reactions of 4-hydroxy-1H-thieno[2,3-b;4,5-b]dipyridin-2-ones with arylidenemalononitriles or by the three-component reactions of hydroxythienodipyridinones with aldehydes and malononitrile in DMF in the presence of triethylamine. Methods for syntheses of substituted 3-alkoxycarbonyl-6-amino-4-aryl-2-(3-cyanopyridin-2-ylthiomethyl)-4H-pyrans were developed on the basis of the reactions of 4-(3-cyanopyridin-2-ylthio)acetoacetates and arylidenemalononitriles or aldehydes and malononitrile. Ethyl 4-(3-cyanopyridin-2-ylthio)acetoacetate and 4-methoxybenzylidenecyanothioacetamide were used for the synthesis of 6-(pyridin-2-ylthiomethyl)-3-cyanopyridine-2(1H)-thione.

The ability to carry out simultaneous orthogonal exchange chemistries has opened new opportunities for increasing the numerical and structural diversity accessible to Dynamic Combinatorial Chemistry. We present proof-of-concept experiments demonstrating this concept is transferrable to resin-bound DCC, facilitating the generation and analysis of libraries with greater structural diversity.