Peptidomimetic inhibitors of bacterial peptide deformylase.

A series of N-formyl hydroxylamine peptide deformylase inhibitors containing a cyclic azaamino acid moiety between the P1' and P3' substituents are presented. Selected compounds display antibacterial activity against pathogens associated with respiratory tract infections with representative compounds showing excellent MICs against Haemophilus influenzae.

An orally bioavailable positive allosteric modulator of the mGlu4 receptor with efficacy in an animal model of motor dysfunction.

A high-throughput screening campaign identified 4-((E)-styryl)-pyrimidin-2-ylamine (11) as a positive allosteric modulator of the metabotropic glutamate (mGlu) receptor subtype 4. An evaluation of the structure-activity relationships (SAR) of 11 is described and the efficacy of this compound in a haloperidol-induced catalepsy rat model following oral administration is presented.

An in silico method for predicting Ames activities of primary aromatic amines by calculating the stabilities of nitrenium ions.

In this paper, we describe an in silico first principal approach to predict the mutagenic potential of primary aromatic amines. This approach is based on the so-called "nitrenium hypothesis", which was developed by Ford et al. in the early 1990s. This hypothesis asserts that the mutagenic effect for this class of molecules is mediated through the transient formation of a nitrenium ion and that the stability of this cation is correlated with the mutagenic potential. Here we use quantum mechanical calculations at different levels of theory (semiempirical AM1, ab initio HF/3-21G, HF/6-311G(d,p), and DFT/B3LYP/6-311G(d,p)) to compute the stability of nitrenium ions. When applied to a test set of 257 primary aromatic amines, we show that this method can correctly differentiate between Ames active and inactive compounds, and furthermore that it is able to rationalize and predict SAR trends within structurally related chemical series. For this test set, the AM1 nitrenium stability calculations are found to provide a good balance between speed and accuracy, resulting in an overall accuracy of 85%, and sensitivity and specificity of 91% and 72%, respectively. The nitrenium-based predictions are also compared to the commercial software packages DEREK, MULTICASE, and the MOE-Toxicophore descriptor. One advantage of the approach presented here is that the calculation of relative stabilities results in a continuous spectrum of activities and not a simple yes/no answer. This allows us to observe and rationalize subtle trends due to the different electrostatic properties of the organic molecules. Our results strongly indicate that nitrenium ion stability calculations should be used as a complementary approach to assist the medicinal chemist in prioritizing and selecting nonmutagenic primary aromatic amines during preclinical drug discovery programs.

Antibacterial alkoxybenzamide inhibitors of the essential bacterial cell division protein FtsZ.

3-Methoxybenzamide is a weak inhibitor of the essential bacterial cell division protein FtsZ. Exploration of the structure-activity relationships of 3-methoxybenzamide analogues led to the identification of potent anti-staphylococcal compounds.

DNA gyrase (GyrB)/topoisomerase IV (ParE) inhibitors: synthesis and antibacterial activity.

The synthesis and antibacterial activities of three chemotypes of DNA supercoiling inhibitors based on imidazolo[1,2-a]pyridine and [1,2,4]triazolo[1,5-a]pyridine scaffolds that target the ATPase subunits of DNA gyrase and topoisomerase IV (GyrB/ParE) is reported. The most potent scaffold was selected for optimization leading to a series with potent Gram-positive antibacterial activity and a low resistance frequency.

Arylsulfonamide CB2 receptor agonists: SAR and optimization of CB2 selectivity.

A high-throughput screening campaign resulted in the discovery of a highly potent dual cannabinoid receptor 1 (CB1) and 2 (CB2) agonist. Following a thorough SAR exploration, a series of selective CB2 full agonists were identified.

Multitarget ligands in antibacterial research: progress and opportunities.

INTRODUCTION: Resistance to current antibacterial therapies is an inevitability that represents a significant global health concern. Bacteria have the capacity to render all current drug treatments ineffective, which places a demand on the drug discovery community to constantly develop new antibacterial agents. Compounds that inhibit multiple biological targets, often referred to as multitarget ligands, are an inviting prospect in antibacterial research because, although they will not solve the issue of resistance, they might help to delay the onset. AREAS COVERED: This review covers some of the recent progress in identifying new ligands that deliberately interact with more than one essential biological target in bacteria. The two principal areas covered are inhibitors of DNA replication and cell wall biosynthesis. EXPERT OPINION: Antibacterial programs for the design of multitarget ligands present an important opportunity for production of antibacterial agents. Their longevity, due to slow development of resistance, is comparable to that seen with other successful agents - but is much improved over single-targeted agents for which resistance can appear in vitro overnight. The preclinical development of these agents will have to overcome the standard problems of antibacterial discovery. Such problems include optimization of characteristics favoring cell entry and particularly the demonstration of selectivity of inhibition of the desired multiple targets without inhibition of other bacterial or any mammalian functions.

mGluR4 positive allosteric modulators with potential for the treatment of Parkinson's disease: WO09010455.

Stimulation of the metabotropic glutamate receptor 4 (mGluR4) represents a promising new approach to the symptomatic treatment of the neurodegenerative disorder Parkinson's disease (PD). Preclinical models using both agonists and positive allosteric modulators of mGluR4 have demonstrated the potential for this receptor for the treatment of PD. The present article evaluates a recent patent filed by Addex Pharma S.A. claiming a novel series of mGluR4 positive allosteric modulators. Many of the examples disclosed are active at EC(50)'s < 500 nM.

The azulene-to-naphthalene rearrangement revisited: a DFT study of intramolecular and radical-promoted mechanisms.

Intramolecular and radical-promoted mechanisms for the rearrangement of azulene to naphthalene are assessed with the aid of density functional calculations. All intramolecular mechanisms have very high activation energies (>/=350 kJ mol(-1) from azulene) and so can only be competitive at temperatures above 1000 degrees C. Two radical-promoted mechanisms, the methylene walk and spiran pathways, dominate the reaction below this temperature. The activation energy for an orbital symmetry-allowed mechanism via a bicyclobutane intermediate is 382 kJ mol(-1). The norcaradiene-vinylidene mechanism that has been proposed in order to explain the formation of small amounts of 1-phenyl-1-buten-3-ynes from flash thermolysis of azulene has an activation energy of 360 kJ mol(-1); subtle features of the B3LYP/6-31G(d) energy surface for this mechanism are discussed. All intermediates and transition states on the spiran and methylene walk radical-promoted pathways have been located at the B3LYP/6-31G(d) level. Interconversion of all n-H-azulyl radicals via hydrogen shifts was also examined, and hydrogen shifts around the five-membered ring are competitive with the mechanisms leading to rearrangement to naphthalene, but those around the seven-membered ring are not. Conversion of a tricyclic radical to the 9-H-naphthyl radical is the rate-limiting transition state on the spiran pathway, and lies 164.0 kJ mol(-1) above that of the 1-H-azulyl radical. The transition state for the degenerate hydrogen shift between the 9-H-azulyl and 10-H-azulyl radicals is 7.4 kJ mol(-1) lower. Partial equilibration of the intermediates in the spiran pathway via this shift may therefore occur, and this can account for the surprising formation of 1-methylnaphthalene from 2-methylazulene. The rate-limiting transition state for the methylene walk pathway involves the concerted transfer of a methylene group from one ring to the other and lies 182.3 kJ mol(-1) above that of the 1-H-azulyl radical. It is shown that rearrangement via a combination of 31% methylene walk and 69% spiran pathways can account semiquantitatively for all the products from 1-(13)C-azulene, 9-(13)C-azulene, and 4,7-(13)C(2)-azulene, in addition to accounting for the products from methylazulenes, and the formation of naphthalene-d(0) and -d(2) from azulene-4-d. It is also pointed out that a small extension to the spiran pathway could provide an alternative explanation for the formation of 1-phenyl-1-buten-3-ynes.

Peptide deformylase inhibitors with activity against respiratory tract pathogens.

A series of analogues of the peptide deformylase (PDF) inhibitor BB-3497 where the P3' amide bond was replaced with a ketone functionality is described. The in vitro antibacterial profiling of these compounds revealed that they demonstrate activity against pathogens associated with respiratory tract infections.

Structure-activity relationships of the peptide deformylase inhibitor BB-3497: modification of the metal binding group.

A series of analogues of the potent peptide deformylase (PDF) inhibitor BB-3497 containing alternative metal binding groups was synthesised. Enzyme inhibition and antibacterial activity data for these compounds revealed that the bidentate hydroxamic acid and N-formyl hydroxylamine structural motifs represent the optimum chelating groups on the pseudopeptidic BB-3497 backbone.