Antituberculosis drugs: ten years of research.

Tuberculosis (TB) caused by Mycobacterium tuberculosis remains a leading cause of mortality worldwide into 21st century. The mortality and spread of this disease has further been aggravated because of synergy of this disease with HIV. A number of anti-TB drugs are ineffective against this disease because of development of resistance strains. Internationally efforts are being made to develop new anti-tubercular agents. A number of drug targets from cell wall biosynthesis, nucleic acid biosynthesis, and many other biosynthetic pathways are being unraveled throughout the world and are being utilized for drug development. In this review, socioeconomic problems in developing countries, efforts to control this disease in different individuals, the targets (known already and newly discovered), existing anti-tubercular agents including natural products and lead molecules, and the future prospects to develop new anti-TB agents are described.

Fighting tuberculosis: an old disease with new challenges.

In a biologically active molecule the replacement of an atom or a group of atoms by another one presenting the same physiochemical properties is based on the concept of isosterism. The extensive application of isosterism to modify a part of a biologically active molecule to get another one of similar activity has given rise to the term of bioisosterism or nonclassical isosterism. The development of the concept of isosterism takes its roots in the attempts to extend to the whole molecules the knowledge acquired for elements, namely that two elements possessing an identical peripheral electronic distribution do also possess similar chemical properties. The importance of chemical rings in drug discovery is never overstated. Rings are responsible for the basic shape of the molecule, rendering it rigid or flexible, and are also responsible for a suitable spatial orientation of the pharmacophoric groups. This chapter presents an example to illustrate the possibility to mimick the pyramidal structure of phosphates or phosphonates by means of two planar carboxylic groups, the three-dimensionality originating from the malonic methylenic carbon atom. Most of the studies based on virtual screening use a hierarchical approach combining several conceptually different techniques. Finally, two applications of the bioisosterism concept that imply unusual behaviors of commonly encountered atoms or groups are discussed.

Molecular Variations Based on Isosteric Replacements

The synthesis, the chemical and photochemical reactivity, and the use of 1,2,4-oxadiazoles in materials and as bioactive compounds have been reviewed. The material in this survey includes some historical background, general features, state-of-the-art applications together with a critical discussion about current limitations and suggestions for future developments.

The new era of 1,2,4-oxadiazoles

A series of spiro[[2]benzopyran-1,4‘-piperidines] and spiro[[2]benzofuran-1,4‘-piperidines] of general structure 10 is prepared, and the affinity for σ1- and σ2-receptors is investigated by means of radioligand binding assays. The synthesis of the spiropiperidines 14a and 23 proceeds from bromine/lithium exchange of the bromoacetals 11 and 21, addition to piperidin-4-one 12a, and subsequent cyclization. Systematic variations of the substituent R at the nitrogen atom, the group X in position 3, and the ring size of the oxygen heterocycle are performed. The σ1- and σ2-receptor affinities are determined with guinea pig brain and rat liver membrane preparations using [3H]-labeled (+)-pentazocine and ditolylguanidine, respectively. Test results show that a benzyl residue at the piperidine nitrogen atom and a methoxy group in position 3 are advantageous for high σ1-receptor affinity. In this series the 1‘-benzyl-3-methoxy-3,4-dihydrospiro[[2]benzopyran-1,4‘-piperidine] (14a) and the 1‘-benzyl-3-methoxy-3H-spiro...

Novel spiropiperidines as highly potent and subtype selective σ-receptor ligands. Part 1

Pyridines and pyrazines substituted with 1,2,4-oxadiazole-5-ones, 1,2,4-oxadiazole-5-thiones, and 1,3,4-oxathiazoline-2-ones were synthesized and tested against Mycobacterium tuberculosis. The two former ring systems were documented in the literature to act as carboxylic acid isosteres. The latter series was synthesized as possible synthetic intermediates to 1,2,4-thiadiazole-3-ones and was included in this study due to their interesting activity. Pivaloyloxymethyl derivatives of the isosteres were also prepared in order to increase their lipophilicity and therefore improve their cellular permeability. The derivatized isosteres were expected to be biotransformed by esterases to the active species after penetration of the mycobacterial cell wall. Biological properties of the compounds were compared with the unmodified polar isosteres of pyrazinoic and nicotinic acids. The majority of the compounds exhibited activities ranging from 0.5 to 16 times the potency of pyrazinamide.

and Arnold R. Martin

Papers

Antimycobacterial Activity of Substituted Isosteres of Pyridine- and Pyrazinecarboxylic Acids