Anti-Infective Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Infective Agents) - Volume 7, Issue 1, 2008

To review the treatments currently used to treat mycobacteria (latent tuberculosis, clinical tuberculosis, infections due to mycobacteria), focussing on : Doses administered and duration of treatment Levels reached in different body tissues in relation to the chemical characteristics of the drugs The relation between these data and the microbiological parameters of each microorganism To review the above parameters for the new groups of drugs being investigated for treatment of the three pathologies. a. fluorquinolones b. macrolides c. rifampicins d. oxazolidinones e. tetracyclines f.- other drugs undergoing investigation

Tuberculosis remains the leading cause of mortality worldwide even in the 21st century. This review summarises all facts concerning a front-line antituberculotic drug isoniazide - metabolism, mechanism of activity and resistance. The antimycobacterial pharmacophore moiety of isoniazide has been introduced in a number of various types of molecules (about 510 derivatives have been found) to improve their activity against Mycobacteria species, as well as their multidrug-resistant strains. Several Schiff bases, hydrazones, hydrazides and metal complexes of isoniazide have shown very good activity. Various types of the most active isoniazide derivatives classified according to their structure are reported, their lipophilicity has been calculated and structure-activity relationships are discussed. The original new highly active isoniazide prodrug forms prepared at the Faculty of Pharmacy, Charles University, Czech Republic are presented in a separate chapter of the paper.

Oxazolidinones are important synthetic antibacterial agents useful for the treatment of multi antibiotic resistant Gram-positive bacterial infections. Since the launch of Linezolid, the first member of the oxazolidinone antibacterial family, there have been many studies directed towards structural optimization and the development of second generation oxazolidinones. The N-aryl 5-acetamido methyl oxazolidinone is the core structure for this class of antibacterial agents and the oxazolidinone component is essential for antibacterial activities. The chiral cyclic carbamate 5-hydroxymethyloxazolidin- 2-one and 6-hydroxymethyl-[1,3]oxazinan-2-one are also important building blocks for synthesizing other biologically active compounds. Because of the importance of these compounds, many methods have been developed for their facile syntheses. In the first part of this paper, the synthesis of Linezolid and its analogs, as well as the preparation of the oxazolidinone core structures, will be reviewed. Secondly, recent developments in the area of oxazolidinone antibacterial agents including structure-activity relationships will be reviewed.

Tuberculosis (TB) remains the leading cause of mortality due to a single bacterial pathogen, Mycobacterium tuberculosis. The reemergence of tuberculosis as a potential public health threat, the high susceptibility of human immunodeficiency virus-infected persons to the disease, the proliferation of multi-drug-resistant strains (MDR-TB) and, more recently, of extensively drug resistant isolates (XDR-TB) have created a need for the development of new antimycobacterial agents. There is an ongoing need for innovation in proposing new structural scaffolds for chemotherapeutic agent development to control TB. Mycolic acids, the hallmark of mycobacteria, are high-molecular-weight α-alkyl, β-hidroxy fatty acids, which appear mostly as bound esters in the mycobacterial envelope. Isoniazid (INH) is the most prescribed chemotherapeutic agent for active TB and prophylaxis and requires activation by the catalase-peroxidase activity of KatG. The product of the M. tuberculosis inhA structural gene (InhA) has been shown to be the primary target for INH. InhA was identified as an NADH-dependent enoyl-ACP reductase specific for long chain enoyl thioesters. InhA is a member of the mycobacterial Type II fatty acid biosynthesis system, which elongates acyl fatty acid precursors of mycolic acids. The main focus of our contribution is on data describing the mode of action of an inorganic complex, pentacyano (isoniazid) ferrateII that requires no KatG-activation and is an in vitro slow-onset inhibitor of WT and INH-resistant M. tuberculosis enoyl reductases. This inorganic complex represents a new class of lead compounds to the development of anti-tubercular agents aiming the inhibition of a validated target. We also describe the recent developments in the search for inorganic complexes with anti-tubercular activity.

Pulmonary tuberculosis is an intracellular infection caused by Mycobacterium tuberculosis. Because its intracellular site is commonly the macrophage of the pulmonary system, and that cell has little killing action of its own, an antibiotic that is to be effective against this organism must be able to penetrate the macrophage and exert its action at the intracellular site where the organism resides. The anti-tubercular drugs which are most effective against this intracellular infection and which constitute the “first line of defence” are isoniazid and rifampin, both of which have activity against phagocytosed M. tuberculosis. Unfortunately, resistance to both of these agents (multi-drug resistant tuberculosis) continues to increase in frequency, and regardless of therapy, mortality is very high, nearing 100% within one year if the patient is co-infected with HIV or presents with AIDS. There is an obvious urgent need for effective anti-tubercular drugs. This review discusses the in vitro and ex vivo (phagocytosed bacteria) activity of phenothiazines and their derivatives and the mechanism by which these agents manifest their antibacterial activity in vitro and ex vivo. Because these and other agents promote the killing of intracellular bacteria by inhibiting the loss of K+ from the phagolysosome, it may be wiser to design drugs that enhance intracellular killing as opposed to those that have activity against the bacterium itself, since the latter approach will eventually be limited due to ensued resistance.