Endoperoxide antimalarials based on the ancient Chinese drug Qinghaosu (artemisinin) are currently our major hope in the fight against drug-resistant malaria. Rational drug design based on artemisinin and its analogues is slow as the mechanism of action of these antimalarials is not clear. Here we report that these drugs, at least in part, exert their effect by interfering with the plasmodial hemoglobin catabolic pathway and inhibition of heme polymerization. In an in vitro experiment we observed inhibition of digestive vacuole proteolytic activity of malarial parasite by artemisinin. These observations were further confirmed by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin, suggesting inhibition of hemoglobin degradation. We found artemisinin to be a potent inhibitor of heme polymerization activity mediated by Plasmodium yoelii lysates as well as Plasmodium falciparum histidine-rich protein II. Interaction of artemisinin with the purified malarial hemozoin in vitro resulted in the concentration-dependent breakdown of the malaria pigment. Our results presented here may explain the selective and rapid toxicity of these drugs on mature, hemozoin-containing, stages of malarial parasite. Since artemisinin and its analogues appear to have similar molecular targets as chloroquine despite having different structures, they can potentially bypass the quinoline resistance machinery of the malarial parasite, which causes sublethal accumulation of these drugs in resistant strains.

Eleven manzamine type alkaloids, two β-carbolines, and five nucleosides have been isolated from an Indonesian sponge. Among these are the previously characterized 12,34-oxamanzamine A, 12,34-oxamanzamine E, manzamine A (1), 8-hydroxymanzamine A, 6-deoxymanzamine X, manzamine E (2), manzamine X, manzamine F (4), norharman, thymine, 2′,3′-didehydro-2′,3′-dideoxyuridine, uracil, thymidine, and 2′-deoxyuridine. The structures for the five new compounds have been assigned as 32,33-dihydro-31-hydroxymanzamine A (3), 32,33-dihydro-6-hydroxymanzamine A-35-one (5), des-N-methylxestomanzamine A (6), 32,33-dihydro-6,31-dihydroxymanzamine A (7), and 1,2,3,4-tetrahydronorharman-1-one (8), on the basis of NMR and X-ray data. The bioactivity and SAR of the manzamines against malaria, TB, and leishmania are also presented. The structural revision of two previously reported pyrazoles as uracil and thymine is also discussed.Manzamines are unique β-carboline alkaloids isolated from Indo-Pacific sponges and characterized by having an intricate nitrogen-containing polycyclic system. In 1986, Higa and co-workers first reported manzamine A from the Okinawan sponge of the genus Haliclona. 1 These compounds exhibit a diverse range of bioactivities including cytotoxicity, 1 insecticidal, 2 and antibacterial 3 as well as the exciting curative activity against malaria in animal models. 4,5 Since the first report of manzamine A, an additional 40 manzamine-type alkaloids have been reported from nine different sponge genera. 6,7 In our continuing search for manzamine-related alkaloids with significant activity against infectious diseases, we have identified several novel manzamine alkaloids from an Indonesian sponge, and herein we describe their structure determination and biological activity. *To whom correspondence should be addressed. Tel: (662) 915-5730. Fax: (662) 915-6975. mthamann@olemiss.edu. Supporting Information Available: Copies of 1 H and 13 C NMR spectra for all new compounds, HMQC spectra for 3, 5-7, HMBC spectra for 5-8, and X-ray data for 3. This material is available free of charge via the Internet at http://pubs.acs.org. (Table 1) includes aromatic proton resonances similar to those of manzamine E. 12 Spectral data of how 3 differs from manzamine E (2) includes the presence of 13 CH carbons (manzamine E has 12 CH carbons) and the absence of the low-field C-31 carbonyl carbon signal of manzamine E. In place of the carbonyl carbon compound 3 has a signal at 70.9 ppm, which correlates with a multiplet at 4.05 ppm in the HMQC spectrum. The presence of this new OH-functionality is confirmed by a number of long-range 1 H-13 C correlations H 2 -29 and H 2 -33 to C-31, Figure 1 HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript C-12, C-24, C-25, C-26, and C-34 of 3 were elucidated to be the same as those of manzamine E by NOESY data as well as comparable 13 C chemical shifts. In addition both compounds were isolated from the same sponge and possessed dextrorotation. The relative config...

S-Adenosylmethionine decarboxylase (AdoMetDC) is a pyruvoyl enzyme, and the pyruvate is formed in an intramolecular reaction that cleaves a proenzyme precursor and converts a serine residue into pyruvate. The wild type potato AdoMetDC proenzyme processed much faster than the human proenzyme and did not require putrescine for an optimal rate of processing despite the presence of three acidic residues (equivalent to ) is not present in the potato sequence. The site of potato AdoMetDC proenzyme processing was found to be Ser 73 in the conserved sequence, YVLSESS, which is the equivalent of Ser 68 in the human sequence. Replacement of the serine precursor with threonine or cysteine by site-directed mutagenesis in either the potato or the human AdoMetDC proenzyme did not prevent processing but caused a significant reduction in the rate. Although the COOH-terminal regions of the known eukaryotic AdoMetDCs are not conserved, only relatively small truncations of 8 residues from the human protein and 25 residues from the potato proenzyme were compatible with processing. The maximally truncated proteins show no similarity in COOHterminal amino acid sequence but each contained 46 amino acid residues after the last conserved sequence, suggesting that the length of this section of the protein is essential for maintaining the proenzyme conformation needed for autocatalytic processing. AdoMetDC1 is an essential enzyme for the biosynthesis of polyamines and is one of a small class of decarboxylases that uses a covalently bound pyruvate as a prosthetic group (1, 2). These pyruvoyl-dependent decarboxylases form amines such as histamine, decarboxylated S-adenosylmethionine, phosphatidylethanolamine (a component of membrane phospholipids), and ␤-alanine (a precursor of coenzyme A), which are all of critical importance in cellular physiology and provide an important target for drug design. The mechanism of formation of the prosthetic group has been studied extensively using histidine decarboxylase from Lactobacillus (1, 3-6), and more preliminary studies with other decarboxylases including AdoMetDC (7-9) suggest that the mechanism is similar (Fig. 1). In all cases, the enzyme is synthesized as a proenzyme that then undergoes an intramolecular cleavage reaction forming the two subunits and generating the pyruvate at the amino terminus of the ␣ subunit from a serine precursor residue. Cleavage takes place via the formation of an intermediate ester resulting from a nucleophilic attack of this serine residue at the amide carbonyl group of the preceding amino acid. This is followed by ␤-elimination to form the ␤ subunit and the ␣ subunit containing a dehydroalanine at its amino terminus. The dehydroalanine then loses ammonia and is converted to pyruvate via the formation of imine and carbinolamine intermediates (1-3). The initial rearrangement step of this reaction to form a peptide ester linked to the hydroxyl side chain of serine is identical to that involved in protein splicing reactions (10, 11). Further information on such cleavage...

Trypanosomiasis, leishmaniasis, and malaria are major parasitic diseases in developing countries. The existing chemotherapy of these diseases suffers from lack of safe and effective drugs and/or the presence of widespread drug resistance. Cysteine proteases are exciting novel targets for antiparasitic drug design. Virtual screening was performed in an attempt to identify novel druglike nonpeptide inhibitors of parasitic cysteine proteases. The ChemBridge database consisting of approximately 241 000 compounds was screened against homology models of falcipain-2 and falcipain-3 in three consecutive stages of docking. A total of 24 diverse inhibitors were identified from an initial group of 84, of which 12 compounds appeared to be dual inhibitors of falcipain-2 and falcipain-3. Four compounds showed inhibition of both the malarial cysteine proteases as well as Leishmania donovani cysteine protease.

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Histone deacetylases (HADC) are the enzymes that remove acetyl group from lysine residue of histones and non-histone proteins and regulate the process of transcription by binding to transcription factors and regulating fundamental cellular process such as cellular proliferation, differentiation and development. In neurodegenerative diseases, the histone acetylation homeostasis is greatly impaired, shifting towards a state of hypoacetylation. The histone hyperacetylation produced by direct inhibition of HDACs leads to neuroprotective actions. This review attempts to elaborate on role of small molecule inhibitors of HDACs on neuronal differentiation and throws light on the potential of HDAC inhibitors as therapeutic agents for treatment of neurodegenerative diseases. The role of HDACs in neuronal cellular and disease models and their modulation with HDAC inhibitors are also discussed. Significance of these HDAC inhibitors has been reviewed on the process of neuronal differentiation, neurite outgrowth and neuroprotection regarding their potential therapeutic application for treatment of neurodegenerative diseases.

Three new manzamine-type alkaloids, 12,34-oxamanzamine E (3), 8-hydroxymanzamine J (4), and 6-hydroxymanzamine E (8), as well as 12 previously characterized manzamine alkaloids have been isolated from a common Indonesian sponge of the genus Acanthostrongylophora. The structures of the new compounds have been established on the basis of 1D and 2D NMR spectroscopic analysis and comparison of the data to literature values of related compounds. The biological activities and structure-activity relationship of the manzamines against malaria, Mycobacterium tuberculosis, Leishmania, HIV-1, and AIDS opportunistic infections are discussed. A plausible pathway for the formation of the 12,34-oxaether bridge in compound 3 is also provided.

Hypocrellins A and B were evaluated for in vitro antimicrobial and antileishmanial activities. Hypocrellin A exhibited promising activity against Candida albicans and moderate activity against Staphylococcus aureus, methicillin-resistant S. aureus, Pseudomonas aeruginosa, and Mycobacterium intracellulare. Hypocrellin B showed weak antimicrobial activities. Hypocrellin A exhibited potent antileishmanial activity, while hypocrellin B was only moderately active. These results of promising antifungal and antileishmanial activity of hypocrellin A may be useful for further structure-activity relationship and in vivo studies.Antifungal drugs, such as amphotericin B, ketoconazole (and other azoles), and griseofulvin, have been widely used in the treatment of patients with various fungal infections. However, their clinical use is limited, due either to lack of efficacy or their toxicity and resistance (8,17). Therefore, there is a need for new antifungal agents that are more effective and less toxic. For leishmanial infections, only a few drugs, which are highly toxic, are available (4), and their use has further been compromised due to development of drug resistance. Thus, there is a continuous interest in developing new antileishmanial compounds with different modes of action and low toxicities to satisfy clinical use.Hypocrellins A and B ( Fig. 1) are two main pigments isolated from the parasitic fungus Hypocrella bambusae (Berk. et Broome) Sacc., which grows abundantly in the northwest region of Yunnan Province, People's Republic of China, and the southeastern region of Xizang (Tibet), an autonomous region of the People's Republic of China. These pigments have a long history of use as traditional medicinal agents and were commonly used to treat rheumatoid arthritis, gastric diseases (20), and skin diseases related to fungal infections (18,19). Previous studies showed that hypocrellins exhibited photodynamic anticancer (2, 5, 12, 21) and antiviral (9, 10) activities. These activities were related to their ability to generate active oxygen•Ϫ , and • OH) (1, 16) and inhibit protein kinase C activity (6). However, no antifungal or antileishmanial activity has been reported. In this study, hypocrellins A and B were evaluated for activities against a panel of fungi and bacteria and for activity against Leishmania donovani, the causative agent of visceral leishmaniasis.Hypocrellins A and B were isolated from H. bambusae as described previously (3) at the Experimental Center of Yunnan University, Yunnan, People's Republic of China. Purity was determined to be 99.2%. Samples were dissolved in dimethyl sulfoxide (DMSO). The final concentration of DMSO in all assays was less than 0.2%, which has no effect on the tested organisms.Activity against a panel of microorganisms, including Candida albicans, Cryptococcus neoformans, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Pseudomonas aeruginosa, and Mycobacterium intracellulare, was evaluated in vitro. All organisms were obtained from the American Type Culture Col...