Anti-Infective Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Infective Agents) - Volume 5, Issue 2, 2006

The situation of tuberculosis disease has recently been complicated by the human immunodeficiency virus epidemic and the increased prevalence of multi-drug resistant strains of Mycobacterium tuberculosis. The new drugs which are affordable and more effective compared to clinically used, are required to target resistant strains of M. tuberculosis and emerging pathogens, such as M. avium complex. Most of the reported natural products exhibited antimycobacterial activity against whole mycobacteria species viz. M. tuberculosis, M. avium complex and M. bovis. An analysis of the literature examples of target-based natural products reveals insights into mechanism of their antimycobacterial activity that might help medicinal chemists to design and develop novel antimycobacterial compounds. In the present review the attempt has been made to cover target-based natural products that exhibited antimycobacterial activity. The enzymes involved in the metabolism of mycolic acids represent attractive targets for the design of new anti-mycobacterial agents, as mycolic acids are vital in bacterial survival. The antimycobacterial targets such as β-ketoacyl-acyl-carrier protein synthases, KasA and KasB (belong to the fatty-acid synthase type II system involved in fatty acid and mycolic acid biosynthesis), inhA, an enoyl-acyl carrier protein (ACP) reductase, mycothiol-S-conjugate Amidase (MCA) and inhibitors (of natural product origin) acting on these are discussed in detail.

Ureides are compounds, which essentially incorporate urea as a substructural component either in open or cyclic form. Ureido derivatives are one of the oldest classes of bioactive compounds, widely used as anti-infective agents. Several of these compounds, including aminoquinuride, aminocarbalide, imidurea, cloflucarban, nitrofurazone, urosulfan, are viomycin are used in clinical situations. One of the ureides, the triclocarban is compulsorily used as antibacterial agent in cleansing and disinfecting solutions in hospitals, household, cosmetics, toys, textiles and plastics. It disables the activity of ENR, an enzyme vital for building the cell wall of the bacteria and fungus. Besides, the ureido-penicillins in clinical use, there have been several ureido-lactam derivatives which have been reported to exhibit significant antibacterial activity. A urea containing dipeptide TAN-1057A isolated from Flexibacter spp. has potent bioactivity against MRSA. The metal complexes of sulfonyl ureido derivatives are effective antifungal agents by inhibiting the activity of phosphomannose isomerase, a key enzyme in the biosynthesis of yeast cell walls. There have been a number of ureides including the cyclic ureas, which are potent HIV protease inhibitors and display significant anti-HIV activity. The urea derivative, merimepodib that has been derived using structure based design, is a potent inhibitor of IMPDH and is active against hepatitis-C infection. This review will primarily focus on the significant work reported for this class of compounds including design, synthesis and biological activity.

The purpose of this contribution is to introduce the bananins or trioxa-adamantane-triols (TATs), a newly discovered class of anti-RNA-coronaviral agents which are active against human severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV). The prototype compound bananin inhibited replication of SARS-CoV, probably through inhibition of SARS-CoV nsp13 ATPase/NTPase DNA/RNA helicase protein enzymatic function(s). Up-to-date eleven bananins [BN, IBNCA, ABNCA, ansaBN, euBN, VANBA, ethylVANBA, euVANBA, Ehrlich BN, [6]prismaneBN, nitrodiBN] were produced, four of which (BN, IBNCA, euBN, VANBA) inhibited both SARS-CoV replicase 1b protein nsp13 ATPase and DNA helicase enzymatic activity in vitro. The unique cage structure of the TATs was proofed by NMR spectroscopy, IR spectroscopy, and UV/VIS spectrophotometry. Some modern two-dimensional NMR techniques (HHCOSY, gs-HMBC, gs-HSQC) and high resolution electrospray mass spectrometry (HR-ESI MS) were used to investigate the more complex bananins like [6]prismaneBN. The latter compound was reacted with all-trans-retinoic acid (ATRA) to yield the 12th TAT [6]prismaneBN-ATRA which served as tool for proofing the general bananin structure(s) by HR-ESI MS. The group of TATs includes compounds with very unusual structures [ansaBN, [6]prismaneBN, nitrodiBN, [6]prismaneBN-ATRA], achieved only by skillful combination of organic synthetic achievements. The triazahexaprismane derivative [6]prismaneBN, and the dinitrohexaprismane derivative nitrodiBN, are the first successfully synthesized true hexaprismane [[6]prismane] derivatives. Because of theoretical considerations the bananins bear a great future intrinsic potential to inhibit RNA-viral replication of various RNA viruses, especially of hepatitis C virus (Flaviviridae), avian flu (influenza virus H5N1, Orthomyxoviridae), Ebola and Marburg virus (Filoviridae), Nipah and Hendra virus (Paramyxoviridae), Hantaan virus (Bunyaviridae), Lassa virus (Arenaviridae), yellow fever virus and dengue virus (Flaviviridae), tick-borne encephalitis virus (FSME virus, Flaviviridae), rabies virus (Rhabdoviridae), and, possibly, certain Picornaviridae (poliovirus, hepatitis A virus, coxsackievirus, echovirus, rhinovirus). Future work will be needed to define the true antiviral chemotherapeutic spectrum of the bananins which might in some way resemble the capacity of the first broad-spectrum virustatic drug ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), but, as to be expected, without exhibiting the pronounced host cell toxicity of ribavirin.

Chagas disease is endemic from Mexico to Argentina, where it is estimated that 16 to 18 million people are infected with its causative agent, Trypanosoma cruzi, and 100 million remain at risk of infection, emphasizing the necessity to sustain and extend control measures and strategies to combat this disease. Specific chemotherapy with benznidazole or nifurtimox has been recommended for treatment of recent and congenital infection. However, clinical trials with nifurtimox and benznidazole have shown that these compounds have very low activity in preventing the development of chronic Chagas disease. Moreover, the drugs induce a number of toxic side effects. The discovery of new active, non-toxic compounds would probably expand treatment, including those patients in which clinical manifestations are absent or can only be disclosed by more elaborate medical procedures. Recent developments in the study of basic biochemical aspects of T. cruzi have allowed for the identification of new targets for chemotherapy. Like many fungi, T. cruzi has a strict requirement for specific endogenous sterol synthesis for cell viability and growth and is extremely susceptible to sterol biosynthesis inhibitors (SBI). An intensive investigation of the potential trypanocidal effect of specific SBI has been performed, and it was demonstrated that some of these compounds exhibited suppressive and curative activity in murine and dog models of acute and chronic Chagas disease. Other potential targets for anti-T. cruzi chemotherapy that include the antiproliferative lysophospholipid analogs (evaluated in clinical trials as the first oral treatment for visceral leishmaniasis), cysteine protease inhibitors and compounds that interfere with purine salvage and inositol metabolism are also discussed.

In addition to sulfur-containing compounds that form essential and indispensable constituents of all living cells, there is a plethora of less wide-spread sulfur-containing compounds with much less common and often unexpected properties, chemical structures and biological activities. Some of these compounds have long been known as efficient antibiotics. This review surveys these less known compounds with two and more sulfur atoms in their molecule. In particular, it deals with natural heterocyclic compounds isolated, e.g., from bacteria, fungi, lichens, plants, and animals but also from unusual and exotic sources such as sea invertebrates (coelenterates, sponges, tunicates, sea worms), etc. Compounds such as calicheamicins, thiazole-related compounds and epipolythiodioxopiperazines may serve as examples. Because of their vast variety, individual compounds are grouped according to their chemical structure (only compounds whose chemical structure has been identified are included). These compounds affect a huge array of organisms from microorganisms to man, and the pharmacological activities they exert range from antiviral, antibacterial, antifungal, insecticidal or antiprotozoan effects to regulation of gene expression, cytoskeleton disruption, immunomodulation, plant growth stimulation or inhibition, pro- or antioxidant action, effects on selected enzymes, receptors and signal transduction pathways, etc. The activities are however often known only sketchily, and this paucity of data, and the fact that the activities were tested on a diverse spectrum of test organisms, cell lines, etc., is of necessity reflected in our survey. Two seemingly trivial but important points deserve attention: (a) compounds with widely different structures and from widely different sources have often very similar pharmacological effects; (b) a slight modification in the molecule may bring vast changes in the biological effects of the compound, in terms of quality, quantity and targeting. The purpose of the review was to show both the unique and common features of these compounds and to point out their potential usefulness for mankind.