Synthesis and SAR of novel GPR39 agonists and positive allosteric modulators.

We report a significant decrease in transcription of the G protein-coupled receptor GPR39 in striatal neurons of Parkinson's disease patients compared to healthy controls, suggesting that a positive modulator of GPR39 may beneficially impact neuroprotection. To test this notion, we developed various structurally diverse tool molecules. While we elaborated on previously reported starting points, we also performed an in silico screen which led to completely novel pharmacophores.

Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion.

Organic synthesis underpins the evolution of weak fragment hits into potent lead compounds. Deficiencies within current screening collections often result in the requirement of significant synthetic investment to enable multidirectional fragment growth, limiting the efficiency of the hit evolution process. Diversity-oriented synthesis (DOS)-derived fragment libraries are constructed in an efficient and modular fashion and thus are well-suited to address this challenge.

C(sp)-H arylation to construct all-syn cyclobutane-based heterobicyclic systems: a novel fragment collection.

All-syn fused cyclobutanes remain an elusive chemotype and thus present an interesting synthetic challenge. Herein, we report the successful application of Pd-catalysed C(sp3)-H arylation of cyclobutane compounds to generate all-syn heterobicyclic fragments using an innovative 'inside-out' approach. Through this strategy we generate a virtual collection of 90 fragments, which we demonstrate to have enhanced three-dimensionality and superior fragment-like properties compared to existing collections.

Hydroxylated Rotenoids Selectively Inhibit the Proliferation of Prostate Cancer Cells.

Prostate cancer is one of the leading causes of cancer-related death in men. The identification of new therapeutics to selectively target prostate cancer cells is therefore vital. Recently, the rotenoids rotenone () and deguelin () were reported to selectively kill prostate cancer cells, and the inhibition of mitochondrial complex I was established as essential to their mechanism of action.

Divergent Synthesis of Novel Cylindrocyclophanes that Inhibit Methicillin-Resistant Staphylococcus aureus (MRSA).

The cylindrocyclophanes are a family of macrocyclic natural products reported to exhibit antibacterial activity. Little is known about the structural basis of this activity due to the challenges associated with their synthesis or isolation. We hypothesised that structural modification of the cylindrocyclophane scaffold could streamline their synthesis without significant loss of activity.

Fsp-rich and diverse fragments inspired by natural products as a collection to enhance fragment-based drug discovery.

Herein, we describe the natural product inspired synthesis of 38 complex small molecules based upon 20 unique frameworks suitable for fragment-based screening. Utilising an efficient strategy, two key building block diastereomers were harnessed to generate novel, three-dimensional fragments which each possess numerous synthetically accessible fragment growth positions.

Spirocycles as Rigidified sp-Rich Scaffolds for a Fragment Collection.

Novel divergent methodology to access sp-rich spirocyclic fragments is reported. First, a robust modular synthesis of bis-alkene amino ester building blocks was developed. Three different carbocycles and six heterocycles were then constructed to assemble eight spirocycles.

Recent Applications of Diversity-Oriented Synthesis Toward Novel, 3-Dimensional Fragment Collections.

Fragment-based drug discovery (FBDD) is a well-established approach for the discovery of novel medicines, illustrated by the approval of two FBBD-derived drugs. This methodology is based on the utilization of small "fragment" molecules (<300 Da) as starting points for drug discovery and optimization. Organic synthesis has been identified as a significant obstacle in FBDD, however, in particular owing to the lack of novel 3-dimensional (3D) fragment collections that feature useful synthetic vectors for modification of hit compounds.

Synthesis of Structurally Diverse N-Substituted Quaternary-Carbon-Containing Small Molecules from α,α-Disubstituted Propargyl Amino Esters.

N-containing quaternary stereocenters represent important motifs in medicinal chemistry. However, due to their inherently sterically hindered nature, they remain underrepresented in small molecule screening collections. As such, the development of synthetic routes to generate small molecules that incorporate this particular feature are highly desirable.

Diversity-oriented synthesis of heterocycles and macrocycles by controlled reactions of oxetanes with α-iminocarbenes.

Using -sulfonyl triazoles as substrates, compounds as diverse as 2-imino tetrahydrofurans, 13- and 15-membered ring aza-macrocycles can be prepared selectively formal [1 + 4], [5 + 4 + 4] and [3 + 4 + 4 + 4] condensations of α-imino carbenes and oxetanes under Rh(ii)-catalysis or thermal activation. Spirocyclic N-heterocycles are also accessible by means of Buchwald-Hartwig and Pictet-Spengler cyclizations. By reaction control, substrate selection or further derivatization, a large variety of chemical structures is thus achievable.

Randomized, double-blind, multicenter comparison of oral cefditoren 200 or 400 mg BID with either cefuroxime 250 mg BID or cefadroxil 500 mg BID for the treatment of uncomplicated skin and skin-structure infections.

Background: Uncomplicated skin and skin-structure infections are commonly observed in medical practice. Because these infections typically are confined to the superficial layers and seldom lead to the destruction of skin structures and resultant systemic dissemination, in general they can be treated with an oral antibiotic with potent microbiologic activity against gram-positive pathogens.

Objective: This paper compares the efficacy and tolerability of 3 beta-lactam antibiotics in patients with uncomplicated skin and skin-structure infections.