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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.

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.

[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.

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.