Current Topics in Medicinal Chemistry - Volume 7, Issue 5, 2007

In 1993 the World Health Organization declared tuberculosis a global emergency. Currently, it is estimated that one-third of the World's population are infected with Mycobacterium tuberculosis, the organism that causes TB, and that over two million people die each year from this disease. While 5-10% of those infected will develop active TB infections, this percentage rises dramatically in patients with HIV/AIDS. Indeed, TB is a major opportunistic disease in individuals with HIV/AIDS, accounting for 11% of the AIDS-related deaths worldwide each year. Our ability to combat the spread of TB is hindered by poor patient compliance, the accompanying increase in multi-drug resistant TB strains (MDR-TB) and the strong link between TB and HIV/AIDS. In industrialized countries TB treatment costs around US $2,000 per patient, but rises more than 100-fold to up to US $250,000 per patient with MDR-TB. Chemotherapeutics that are active against MDR-TB would therefore be of tremendous benefit and desperately needed now. These compounds would be expected to have unique mechanisms of action, so that mechanisms of resistance as a result of current drug use would not be expected to impact the mode of action. Consequently, new TB chemotherapeutics are needed that (1) improve compliance by either shortening the total duration of treatment or increasing the time between treatment intervals or both, (2) improve efficacy against MDR strains, and (3) target metabolically altered bacterial populations such as latent TB infections. The Guest Editor organized a symposium on “Drug-Resistant Tuberculosis --- Challenge in Chemotherapy” at the American Chemical Society National Meeting, San Diego, in March 2005, on behalf of the ACS Medicinal Chemistry Division. This symposium summarized the current status and ongoing endeavors in the anti-TB chemotherapeutics research to promote the recognition of this serious problem and stimulate the interest of the medicinal chemist community. Due to the small profit making nature of the traditional anti-TB drugs, major pharmaceutical industries are not working on the anti-TB chemotherapy and chemotherapeutics at present. However, this unfortunate situation should be changed to prevent the outbreak of formidable drug-resistant TB in advanced countries. Following up this ACS Symposium, the Guest Editor assembled leading scientists relevant to drug discovery and medicinal chemistry of new generation anti-TB agents and organized this special issue of the Current Topics in Medicinal Chemistry. This special issue includes a very informative overview by Dr. Barbara Laughon, NIAID, NIH, followed by five articles, representing different approaches to this challenging problem. The Guest Editor would like to thank all authors for their excellent contributions to this special issue and sincerely hopes that this special issue attracts shear interests of medicinal chemists in academia and industry to join the worldwide endeavor to combat against drug-resistant TB.

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Over the past 50 years, no new drug classes have been introduced to treat tuberculosis. Tuberculosis (TB) kills nearly two million people a year mainly in the poorest communities in the developing world. It afflicts millions more. About one third of the world's population is silently infected with TB that may erupt into disease with increased age or suppression of the immune system. Nearly nine million new active cases develop every year. The World Health Organization (WHO) declared the disease a global emergency as long ago as 1993. Although huge efforts in public health control have reduced the disease burden within most established market economies, in Africa and Asia the epidemic continues to accelerate, particularly fueled by the HIV epidemic. Furthermore, resistance to the standard drugs isoniazid and rifampicin is increasing worldwide. Since the 1990s, mycobacteria have emerged with resistance patterns rendering all currently available antibiotics ineffectual. The pharmaceutical industry has mostly abandoned TB drug development due to perceived non-profitable consumer market and the diminishing number of companies engaged in anti-infective research. The public sector and infectious disease researchers have responded to advance fundamental science and to create new chemical entities as early drug candidates. With support from research funding agencies, philanthropic donors, and the STOP-TB Partnership, new chemical tools and new approaches to effectively implement TB control programs are evolving. Advanced preclinical development and strategies for Phase III clinical trials remain gap areas that will require additional engagement from all sectors.

Present-day understanding of the architecture of the entire cell-wall of Mycobacterium tuberculosis amounts to a “core” template comprised of peptidoglycan with phosphodiester linkage, via a linker disaccharide, to a linear Dgalactofuran, to which, in turn, are attached several strands of a highly branched D-arabinofuran. The cell-wall mycolic acids are linked via an ester to the majority of the non-reducing termini of the D-arabinan. The mycolic acids are oriented perpendicular to the plane of the membrane and provide a truly special lipid barrier responsible for many of the physiological and disease-inducing aspects of M. tuberculosis. Intercalated within this environment are the phthiocerol dimycocerosates, cord factor or dimycolyltrehalose, sulfolipids, phosphatidylinositol mannosides and the related lipomannan and lipoarabinomannan, etc., agents responsible for much of the pathogenesis of tuberculosis. Interest in the biosynthesis of the cell-wall core, regarded, unlike the ancillary lipids, as essential to bacterial viability and integrity, is now driven by the pressing need for alternative drugs to counteract drug-resistant tuberculosis. In a manner analogous to the roles of lipid I and II in peptidglycan formation, synthesis of the entire arabinogalactan is initiated by transferring activated sugars to decaprenyl-phosphate, giving rise to the linker disaccharide, followed by stepwise elongation of the galactan, and the arabinan, apparently one sugar at a time. The genetics and enzymology of these polymerization events have not been well defined, nor have the final steps, namely the attachment of mycolic acids and ligation to peptidoglycan. However, what is known of the earlier events in cell-wall core synthesis has attracted interest in terms of new anti-tuberculosis drug development.

Strategies for the development of novel tuberculosis chemotherapeutics against existing drug resistant strains involve the identification and inhibition of novel drug targets as well as the design and synthesis of compounds against historical targets. InhA, the enoyl reductase from the mycobacterial type II fatty acid biosynthesis pathway, is a target of the frontline chemotherapeutic, isoniazid (INH). Importantly, the majority of INH-resistant clinical isolates arise from mutations in KatG, the enzyme responsible for activating isoniazid, into its active form. Thus compounds that inhibit InhA without first requiring KatG activation will be active against the majority of INH resistant strains of Mycobacterium tuberculosis. This review describes the role of InhA in cell wall biosynthesis and recent progress in the development of novel diphenyl ether-based InhA inhibitors that have activity against both sensitive and drug resistant strains of M. tuberculosis.

The challenges in preventing and controlling tuberculosis are further complicated by the deadly rise of multidrug- resistant tuberculosis (MDR-TB). Recognizing the seriousness of the situation, we initiated a program to screen new agents that would satisfy these unmet needs and have a favorable safety profile. Mycobacteria are well known for their lipid-rich properties. In Mycobacterium tuberculosis, mycolic acid in particular has been established the wall component related to the pathogenesis in the host. There are approximately 250 identified genes related to biosynthesis of the lipid turnover that contain InhA, the main target of isoniazid. Thus, the logical approach for developing a chemotherapy agent against tubercle bacilli included screening compounds that could inhibit the biosyntheses of mycolic acid and that had a novel chemical structure to ensure improved efficacy against MDR-TB. Some of the screening systems established for those purposes and some of the candidates are outlined.

During a search for new anti-tuberculosis agents, a screen of a commercially available library provided a hit nitrofuranyl amide. This hit was selected for further development due to its potential as an anti-tuberculosis agent with a novel mechanism of action, and its potential for activity against both actively growing and latent bacteria. This review covers the optimization of this lead and the strategies applied for developing this series into anti-tuberculosis agents. To optimize the hit, a series of libraries were synthesized, producing several compounds that showed increased antituberculosis activity along with a strong structure activity relationship. The most active compounds from the first optimization series showed good in vitro anti-tuberculosis activity and limited in vivo efficacy, but their application was restricted due to solubility problems. Therefore, a second generation optimization library was designed and synthesized in order to increase bioavailability and solubility while maintaining good anti-tuberculosis activity. Hydrophilic cyclic secondary amines were substituted to the core scaffold and a benzyl piperazine substitution was found to be most effective in achieving improved solubility and potent anti-tuberculosis activity. However, bioactivity studies of these 2nd generation leads showed that the in vivo anti-tuberculosis activity of these compounds was limited due to rapid metabolism. Consequently, a 3rd generation of compounds was designed and synthesized in which potential sites of metabolism were blocked.

The emergence of multi-drug resistant Mycobacterium tuberculosis (Mtb) strains has made many of the currently available anti-TB drugs ineffective. Accordingly there is a pressing need to identify new drug targets. FtsZ, a bacterial tubulin homologue, is an essential cell division protein that polymerizes in a GTP-dependent manner, forming a highly dynamic cytokinetic ring, designated as the Z ring, at the septum site. Following recruitment of other cell division proteins, the Z ring contracts, resulting in closure of the septum and then formation of two daughter cells. Since inactivation of FtsZ or alteration of FtsZ assembly results in the inhibition of Z ring and septum formation, FtsZ is a very promising target for new antimicrobial drug development. This review describes the function and dynamic behaviors of FtsZ, its homology to tubulin, and recent development of FtsZ inhibitors as potential anti-TB agents.