Sequential Allylic C–H Amination/Vinylic C–H Arylation: A Strategy for Unnatural Amino Acid Synthesis from α-Olefins

Tandem reaction sequences that selectively convert multiple C–H bonds of abundant hydrocarbon feedstocks to functionalized materials enable rapid buildup of molecular complexity in an economical way. A tandem C–H amination/vinylic C–H arylation reaction sequence is described under Pd(II)/sulfoxide-catalysis that furnishes a wide range of α- and β-homophenylalanine precursors from commodity α-olefins and readily available aryl boronic acids. General routes to enantiopure amino acid esters and densely functionalized homophenylalanine derivatives are demonstrated

Integrating Intramolecular Hydrogen Bonding (IMHB) Considerations in Drug Discovery Using ΔlogP As a Tool

This study demonstrates that ΔlogP_oct‑tol (difference between logP_octanol and logP_toluene) describes compounds propensity to form intramolecular hydrogen bonds (IMHB) and may be considered a privileged molecular descriptor for use in drug discovery and for prediction of IMHB in drug candidates. We identified experimental protocols for acquiring reliable ΔlogP_oct‑tol values on a set of compounds representing IMHB motifs most prevalent in medicinal chemistry, mainly molecules capable of forming 6-, 7-member IMHB rings. Furthermore, computational ΔlogP_oct‑tol values obtained with COSMO-RS software provided a good estimate of experimental results and can be used prospectively to assess IMHB. The proposed interpretation method based on ΔlogP_oct‑tol data allowed categorization of the compounds into 2 groups: with high propensity to form IMHB and poor propensity or poor relevance of IMHB. The relative ¹H NMR chemical shift of an exchangeable proton was used to verify presence of IMHB and to validate the IMHB interpretation scheme

Structure Guided Development of Novel Thymidine Mimetics Targeting <i>Pseudomonas aeruginosa</i> Thymidylate Kinase: From Hit to Lead Generation

Thymidylate kinase (TMK) is a potential chemotherapeutic target because it is directly involved in the synthesis of an essential component, thymidine triphosphate, in DNA replication. All reported TMK inhibitors are thymidine analogues, which might retard their development as potent therapeutics due to cell permeability and off-target activity against human TMK. A small molecule hit (<b>1</b>, IC₅₀ = 58 μM), which has reasonable inhibition potency against <i>Pseudomonas aeruginosa</i> TMK (PaTMK), was identified by the analysis of the binding mode of thymidine or TP₅A in a PaTMK homology model. This hit (<b>1</b>) was cocrystallized with PaTMK, and several potent PaTMK inhibitors (leads, <b>46</b>, <b>47</b>, <b>48</b>, and <b>56</b>, IC₅₀ = 100–200 nM) were synthesized using computer-aided design approaches including virtual synthesis/screening, which was used to guide the design of inhibitors. The binding mode of the optimized leads in PaTMK overlaps with that of other bacterial TMKs but not with human TMK, which shares few common features with the bacterial enzymes. Therefore, the optimized TMK inhibitors described here should be useful for the development of antibacterial agents targeting TMK without undesired off-target effects. In addition, an inhibition mechanism associated with the LID loop, which mimics the process of phosphate transfer from ATP to dTMP, was proposed based on X-ray cocrystal structures, homology models, and structure–activity relationship results

Potent Inhibitors of LpxC for the Treatment of Gram-Negative Infections

In this paper, we present the synthesis and SAR as well as selectivity, pharmacokinetic, and infection model data for representative analogues of a novel series of potent antibacterial LpxC inhibitors represented by hydroxamic acid <b>1a</b>