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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.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.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.

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.

Fused carbocyclic systems containing seven- and eight-membered rings can be constructed from allylic ethers in a stereoselective manner by tandem carbenoid generation, ylide formation and [2,3] rearrangement. Exceptionally high yields are obtained in cases where the substrate possesses favourable relative stereochemistry. The dienes resulting from [2,3] rearrangement of gem-divinyl ylides undergo Diels–Alder cycloaddition with reactive dienophiles at room temperature. Ylide formation, rearrangement and cycloaddition can be performed in a one-pot process to generate complex tetracyclic systems in a highly stereoselective manner. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

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.

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.

The naturally occurring cyclopeptide alkaloid sanjoinine G1 and its C-11 epimer were synthesized in 18 steps from D -serine. The key steps in the synthesis were the formation of the alkylaryl ether linkage via an SNAr reaction with 4-fluorobenzonitrile and the macrocyclization to form the 14-membered ring using a modification of the Schmidt protocol involving an activated pentafluorophenyl ester.

A strained 14-membered cyclopeptide was prepared from the Garner aldehyde derived from D-serine. The key steps in the synthesis were the construction of the alkyl-aryl ether linkage via an SNAr reaction involving 4-fluorobenzonitrile and the macrolactamization using a modification of the Schmidt protocol involving an activated pentafluorophenyl ester.

The naturally occurring hydroxamic acid actinonin was isolated from species of actinomycetes and characterised as an antibiotic in the 1960s. More than 30 years later the antibacterial activity of actinonin was attributed to inhibition of the metallohydrolase peptide deformylase (PDF), an enzyme that performs an essential step in bacterial protein synthesis. To date, three PDF inhibitors have progressed into clinical trials and one compound, GSK1322322, is currently in Phase II for the treatment of respiratory tract infections and skin and soft tissue infections. This chapter provides an introduction to PDF as an antibacterial target and discusses PDF inhibitors described in the literature that are structurally related to actinonin. Structure–activity relationships, in vivo data, potential resistance mechanisms and recent developments in the area of PDF inhibition are presented.

The discovery of new antibacterials to combat the emergence of resistant organisms is of global importance. One strategy to reduce the development of resistance in new drugs is to identify a single pharmacophore that has the ability to target more than one essential bacterial enzyme. This opportunity has already been realised with certain drugs from the quinolone/fluoroquinolone class of antibiotics, and these drugs act via the GyrA and ParC subunits on the bacterial type II topoisomerases DNA gyrase and topoisomerase IV. This class of enzymes also presents a second opportunity for single pharmacophore multi-target inhibitors as they contain similarly conserved binding sites on the GyrB and ParE subunits which are responsible for the hydrolysis of ATP, a critical step in these enzymes’ function. Competitive inhibitors of ATP have been shown to inhibit both GyrB and ParE and to reduce spontaneous resistance in vitro which is indicative of dual-target action. This chapter will focus on one chemical class of dual-targeting DNA gyrase and topoisomerase IV inhibitors, the ethyl ureas, and will present some of the preclinical data supporting their mechanism of action as a novel series of antibacterials.

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.

A strained 14-membered cyclopeptide was prepared from the Garner aldehyde derived from D-serine. The key steps in the synthesis were the construction of the alkyl-aryl ether linkage via an SNAr reaction involving 4-fluorobenzonitrile and the macrolactamization using a modification of the Schmidt protocol involving an activated pentafluorophenyl ester.

The naturally occurring cyclopeptide alkaloid sanjoinine G1 and its C-11 epimer were synthesized in 18 steps from D -serine. The key steps in the synthesis were the formation of the alkylaryl ether linkage via an SNAr reaction with 4-fluorobenzonitrile and the macrocyclization to form the 14-membered ring using a modification of the Schmidt protocol involving an activated pentafluorophenyl ester.

Sanjoinine A ( 1 ) was synthesized from a 14-membered cyclopeptide prepared from a Garner aldehyde derived from d -serine. The key steps in the synthesis were the catalytic asymmetric reduction of ketone 2(b) and the final removal of the Boc group.

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.

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.

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.

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.

Structure-guided de novo drug design led to the identification of a novel series of substituted pyridine derivatives as HIF-1alpha prolyl hydroxylase inhibitors. Pyridine carboxyamide derivatives bearing a substituted aryl group at the 5-position of the pyridine ring show appreciable activity, while constraining the side chain by placing a pyrazole carboxylic acid generated a potent lead series with consistent activity against EGLN-1.

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.

Sanjoinine A ( 1 ) was synthesized from a 14-membered cyclopeptide prepared from a Garner aldehyde derived from d -serine. The key steps in the synthesis were the catalytic asymmetric reduction of ketone 2(b) and the final removal of the Boc group.