http://www.mdpi.com/journal/molecules/special_issues/neglected-diseases/ Aims: This special issue will focus on the top-ten neglected diseases as defined by the World Health Organization: Human African Trypanosomiasis (HAT or sleeping sickness) Chagas disease Dengue Leishmaniasis Leprosy Lymphatic filariasis (Elephantiasis) Malaria Onchocerciasis (River Blindness) Schistosomiasis ( Bilharzia) Tuberculosis Submission All papers should be submitted to molecules@mdpi.org with copy to the guest editor. To be published continuously until the deadline and papers will be listed together at the special websites. Submitted papers should not have been previously published nor be currently under consideration for publication elsewhere. All papers are refereed through a peer review process. A guide for authors, sample copies and other relevant information for submitting papers are available on the Instructions for Authors page. Molecules is an international peer-reviewed monthly journal published by Molecular Diversity Preservation International. Please visit the Instructions for Authors page before submitting a paper. Open Access publication fees are 800 CHF per paper. English correction fees (250 CHF) will be added in certain cases (1050 CHF per paper for those papers that require extensive additional formatting and/or English corrections.). http://www.mdpi.com/1420-3049/14/11/4570/ Naphthoquinones are compounds present in several families of higher plants. Their molecular structures confer redox properties, and they are involved in multiple biological oxidative processes. In folk medicine, especially among Indian populations, plants containing naphthoquinones have been employed for the treatment of various diseases. The biological redox cycle of quinones can be initiated by one electron reduction leading to the formation of semiquinones, unstable intermediates that react rapidly with molecular oxygen, generating free radicals. Alternatively, the reduction by two electrons, mediated by DT-diphorase, leads to the formation of hydroquinone. Lapachol, α-lapachone and β-lapachone, which are isolated from the heartwood of trees of the Bignoniaceae family, are examples of bioactive naphthoquinones. In this review, we will discuss studies investigating the activity of these natural products and their derivatives in the context of the search for alternative drugs for Chagas disease, caused by Trypanosoma cruzi, a neglected illness that is endemic in Latin America. http://www.mdpi.com/1420-3049/14/11/4570/ Tue, 10 Nov 2009 00:00:00 CET Molecules 2009-11-10 14 11 Review 4570 4590 1420-3049 The Trypanocidal Activity of Naphthoquinones: A Review 2009-11-10 doi: 10.3390/molecules14114570 Antônio Ventura Pinto Solange Lisboa de Castro http://www.mdpi.com/1420-3049/14/9/3237/ Understanding the biology of Mycobacterium tuberculosis is one of the primary challenges in current tuberculosis research. Investigation of mycobacterial biology using the systems biology approach has deciphered much information with regard to the bacilli and tuberculosis pathogenesis. The modulation of its environment and the ability to enter a dormant phase are the hallmarks of M. tuberculosis. Until now, proteome studies have been able to understand much about the role of various proteins, mostly in growing M. tuberculosis cells. It has been difficult to study dormant M. tuberculosis by conventional proteomic techniques with very few proteins being found to be differentially expressed. Discrepancy between proteome and transcriptome studies lead to the conclusion that a certain aspect of the mycobacterial proteome is not being explored. Analysis of protein turnover may be the answer to this dilemma. This review, while giving a gist of the proteome response of mycobacteria to various stresses, analyzes the data obtained from abundance studies versus data from protein turnover studies in M. tuberculosis. This review brings forth the point that protein turnover analysis is capable of discerning more subtle changes in protein synthesis, degradation, and secretion activities. Thus, turnover studies could be incorporated to provide a more in-depth view into the proteome, especially in dormant or persistent cells. Turnover analysis might prove helpful in drug discovery and a better understanding of the dynamic nature of the proteome of mycobacteria. http://www.mdpi.com/1420-3049/14/9/3237/ Fri, 28 Aug 2009 00:00:00 CEST Molecules 2009-08-28 14 9 Review 3237 3258 1420-3049 Protein Turnover in Mycobacterial Proteomics 2009-08-28 doi: 10.3390/molecules14093237 Prahlad K. Rao Qingbo Li http://www.mdpi.com/1420-3049/14/8/3037/ Malaria is still the most destructive and dangerous parasitic infection in many tropical and subtropical countries. The burden of this disease is getting worse, mainly due to the increasing resistance of Plasmodium falciparum against the widely available antimalarial drugs. There is an urgent need for new, more affordable and accessible antimalarial agents possessing original modes of action. Natural products have played a dominant role in the discovery of leads for the development of drugs to treat human diseases, and this fact anticipates that new antimalarial leads may certainly emerge from tropical plant sources. This present review covers most of the recently-published non-alkaloidal natural compounds from plants with antiplasmodial and antimalarial properties, belonging to the classes of terpenes, limonoids, flavonoids, chromones, xanthones, anthraquinones, miscellaneous and related compounds, besides the majority of papers describing antiplasmodial crude extracts published in the last five years not reviewed before. In addition, some perspectives and remarks on the development of new drugs and phytomedicines for malaria are succinctly discussed. http://www.mdpi.com/1420-3049/14/8/3037/ Thu, 13 Aug 2009 00:00:00 CEST Molecules 2009-08-13 14 8 Review 3037 3072 1420-3049 Plant-Derived Antimalarial Agents: New Leads and Efficient Phytomedicines. Part II. Non-Alkaloidal Natural Products 2009-08-13 doi: 10.3390/molecules14083037 Ronan Batista Ademir de Jesus Silva Júnior Alaíde Braga de Oliveira http://www.mdpi.com/1420-3049/14/8/2868/ Haem is believed to be the target of some of the historically most important antimalarial drugs, most notably chloroquine. This target is almost ideal as haem is host-derived and the process targeted, haemozoin formation, is a physico-chemical process with no equivalent in the host. The result is that the target remains viable despite resistance to current drugs, which arises from mutations in parasite membrane transport proteins. Recent advances in high-throughput screening methods, together with a better understanding of the interaction of existing drugs with this target, have created new prospects for discovering novel haem-targeting chemotypes and for target-based structural design of new drugs. Finally, the discovery that Schistosoma mansoni also produces haemozoin suggests that new drugs of this type may be chemotherapeutic not only for malaria, but also for schistosomiasis. These recent developments in the literature are reviewed. http://www.mdpi.com/1420-3049/14/8/2868/ Tue, 04 Aug 2009 00:00:00 CEST Molecules 2009-08-04 14 8 Review 2868 2887 1420-3049 Recent Advances in the Discovery of Haem-Targeting Drugs for Malaria and Schistosomiasis 2009-08-04 doi: 10.3390/molecules14082868 Katherine A. de Villiers Timothy J. Egan http://www.mdpi.com/1420-3049/14/7/2317/ Pentavalent antimonials, including meglumine antimoniate and sodium stibogluconate, have been used for more than half a century in the therapy of the parasitic disease leishmaniasis. Even though antimonials are still the first-line drugs, they exhibit several limitations, including severe side effects, the need for daily parenteral administration and drug resistance. The molecular structure of antimonials, their metabolism and mechanism of action are still being investigated. Some recent studies suggest that pentavalent antimony acts as a prodrug that is converted to active and more toxic trivalent antimony. Other works support the direct involvement of pentavalent antimony. Recent data suggest that the biomolecules, thiols and ribonucleosides, may mediate the actions of these drugs. This review will summarize the progress to date on the chemistry and biochemistry of pentavalent antimony. It will also present the most recent works being done to improve antimonial chemotherapy. These works include the development of simple synthetic methods for pentavalent antimonials, liposome-based formulations for targeting the Leishmania parasites responsible for visceral leishmaniasis and cyclodextrin-based formulations to promote the oral delivery of antimony. http://www.mdpi.com/1420-3049/14/7/2317/ Tue, 30 Jun 2009 00:00:00 CEST Molecules 2009-06-30 14 7 Review 2317 2336 1420-3049 Pentavalent Antimonials: New Perspectives for Old Drugs 2009-06-30 doi: 10.3390/molecules14072317 Frédéric Frézard Cynthia Demicheli Raul R. Ribeiro http://www.mdpi.com/1420-3049/14/6/2256/ Neglected diseases represent a major health problem. It is estimated that one third of the world population is infected with tuberculosis (TB). Besides TB, Chagas disease, affects approximately 20 million people. Quinoxalines display great activities against TB and Chagas. Forty new quinoxaline 1,4-di-N-oxide derivatives have been prepared and tested against M. tuberculosis and T. cruzi. Carboxylic acid quinoxaline 1,4-di-N-oxides (CAQDOs) 5 and 17 showed MIC values on the same order as the reference antituberculosis drug, rifampicin. Meanwhile, CAQDOs 12 and 22 presented IC50 values in the same order as the anti-chagasic drug, nifurtimox. http://www.mdpi.com/1420-3049/14/6/2256/ Mon, 22 Jun 2009 00:00:00 CEST Molecules 2009-06-22 14 6 Article 2256 2272 1420-3049 Heterocyclic-2-carboxylic Acid (3-Cyano-1,4-di-N-oxidequinoxalin-2-yl)amide Derivatives as Hits for the Development of Neglected Disease Drugs 2009-06-22 doi: 10.3390/molecules14062256 Saioa Ancizu Elsa Moreno Enrique Torres Asunción Burguete Silvia Pérez-Silanes Diego Benítez Raquel Villar Beatriz Solano Adoración Marín Ignacio Aldana Hugo Cerecetto Mercedes González Antonio Monge http://www.mdpi.com/1420-3049/14/6/2062/ Prompted by results of our previous studies where we found high activity of some sesquiterpene lactones (STLs) against Trypanosoma brucei rhodesiense (which causes East African sleeping sickness), we have now conducted a structure-(in-vitro)-activity study on a set of 40 STLs against T. brucei rhodesiense, T. cruzi, Leishmania donovani and Plasmodium falciparum. Furthermore, cytotoxic activity against L6 rat skeletal myoblast cells was assessed. Some of the compounds possess high activity, especially against T. brucei (e.g. helenalin and some of its esters with IC50-values of 0.05-0.1 µM, which is about 10 times lower than their cytotoxic activity). It was found that all investigated antiprotozoal activities are significantly correlated with cytotoxicity and the major determinants for activity are a,b-unsaturated structural elements, also known to be essential for other biological activities of STLs. It was observed, however, that certain compounds are considerably more toxic against protozoa than against mammalian cells while others are more cytotoxic than active against the protozoa. A comparative QSAR analysis was therefore undertaken, in order to discern the antiparasitic activity of STLs against T. brucei and cytotoxicity. Both activities were found to depend to a large extent on the same structural elements and molecular properties. The observed variance in the biological data can be explained in terms of subtle variations in the relative influences of various molecular descriptors. http://www.mdpi.com/1420-3049/14/6/2062/ Mon, 08 Jun 2009 00:00:00 CEST Molecules 2009-06-08 14 6 Article 2062 2076 1420-3049 Quantitative Structure ‒ Antiprotozoal Activity Relationships of Sesquiterpene Lactones 2009-06-08 doi: 10.3390/molecules14062062 Thomas J. Schmidt Amal M. M. Nour Sami A. Khalid Marcel Kaiser Reto Brun http://www.mdpi.com/1420-3049/14/4/1513/ Antitrypanosomal natural products with different structural motifs previously shown to have growth inhibitory activity against Trypanosoma brucei were docked into validated drug targets of the parasite, which include trypanothione reductase, rhodesain, farnesyl diphosphate synthase, and triosephosphate isomerase. The in-silico calculations predicted that lowest energy docked poses of a number of the compounds can interact with catalysis-dependent residues, thus making them possible catalytic inhibitors and of course physiologically active. Compounds that possess a number of hydrogen-bond-accepting and/or -donating groups like phenolics and quinones show extensive interactions with the targets. Compounds like cissampeloflavone, 3-geranylemodin and ningpogenin thus offer profound promise. http://www.mdpi.com/1420-3049/14/4/1513/ Tue, 14 Apr 2009 00:00:00 CEST Molecules 2009-04-14 14 4 Article 1513 1536 1420-3049 Comparative Molecular Docking of Antitrypanosomal Natural Products into Multiple Trypanosoma brucei Drug Targets 2009-04-14 doi: 10.3390/molecules14041513 Ifedayo V. Ogungbe William N. Setzer http://www.mdpi.com/1420-3049/14/1/494/ The Plasmodium falciparum cysteine protease falcipain-2 (FP-2) is an important cysteine protease and an essential hemoglobinase of erythrocytic P. falciparum trophozoites. The discovery of new FP-2 inhibitors is now a hot topic in the search for potential malaria treatments. In this study, a series of novel small molecule FP-2 inhibitors have been designed and synthesized based on three regional optimizations of the lead (R)-2-phenoxycarboxamido-3-(1H-indol-3-yl)-N-benzylpropanamide(1), which was identified using structure-based virtual screening in conjunction with surface plasmon resonance (SPR)-based binding assays. Four compounds – 1, 2b, 2k and 2l –showed moderate FP-2 inhibition activity, with IC50 values of 10.0-39.4 μM, and the inhibitory activityof compound 2k was ~3-fold better than that of the prototype compound 1 and may prove useful for the development of micromolar level FP-2 inhibitors. Preliminary SAR data was obtained, while molecular modeling revealed that introduction of H-bond donor or/and acceptor atoms to the phenyl ring moiety in the C region would be likely to produce some additional H-bond interactions, which should consequently enhance molecular bioactivity. http://www.mdpi.com/1420-3049/14/1/494/ Wed, 21 Jan 2009 00:00:00 CET Molecules 2009-01-21 14 1 Article 494 508 1420-3049 2-Amido-3-(1H-Indol-3-yl)-N-Substitued-Propanamides as a New Class of Falcipain-2 Inhibitors. 1. Design, Synthesis, Biological Evaluation and Binding Model Studies 2009-01-21 doi: 10.3390/molecules14010494 Jin Zhu Tong Chen Lili Chen Weiqiang Lu Peng Che Jin Huang Honglin Li Jian Li Hualiang Jiang http://www.mdpi.com/1420-3049/14/1/279/ There is an urgent need for novel and improved drugs against several tropical diseases caused by protozoa. The marine sponge (Agelas sp.) metabolite agelasine D, as well as other agelasine analogs and related structures were screened for inhibitory activity against Plasmodium falciparum, Leishmania infantum, Trypanosoma brucei and T. cruzi, as well as for toxicity against MRC-5 fibroblast cells. Many compounds displayed high general toxicity towards both the protozoa and MRC-5 cells. However, two compounds exhibited more selective inhibitory activity against L. infantum (IC50 <0.5 mg/mL) while two others displayed IC50 <1 mg/mL against T. cruzi in combination with relatively low toxicity against MRC-5 cells. According to criteria set up by the WHO Special Programme for Research & Training in Tropical Diseases (TDR), these compounds could be classified as hits for leishmaniasisand for Chagas disease, respectively. Identification of the hits as well as other SAR data from this initial screening will be valuable for design of more potent and selective potential drugs against these neglected tropical diseases. http://www.mdpi.com/1420-3049/14/1/279/ Thu, 08 Jan 2009 00:00:00 CET Molecules 2009-01-08 14 1 Article 279 288 1420-3049 Screening of Agelasine D and Analogs for Inhibitory Activity against Pathogenic Protozoa; Identification of Hits for Visceral Leishmaniasis and Chagas Disease 2009-01-08 doi: 10.3390/molecules14010279 Anders Vik Ágnes Proszenyák Marieke Vermeersch Paul Cos Louis Maes Lise-Lotte Gundersen http://www.mdpi.com/1420-3049/14/1/19/ A series of etacrynic acid derivatives was synthesized and screened for their in vitro activity against Plasmodium falciparum, as well as their activity against recombinantly expressed falcipain-2 and -3. The two most active compounds of the series displayed IC50 values of 9.0 and 18.8 μM against Plasmodia. http://www.mdpi.com/1420-3049/14/1/19/ Tue, 23 Dec 2008 00:00:00 CET Molecules 2008-12-23 14 1 Article 19 35 1420-3049 Synthesis and Evaluation of Non-peptidic Cysteine Protease Inhibitors of P. falciparum Derived from Etacrynic Acid 2008-12-23 doi: 10.3390/molecules14010019 Marie-Adrienne Dude Ulrich Kaeppler Monika Herb Markus Schiller Franziska Schulz Birgit Vedder Saskia Heppner Gabriele Pradel Jiri Gut Philip J. Rosenthal Tanja Schirmeister Matthias Leippe Christoph Gelhaus http://www.mdpi.com/1420-3049/13/11/2900/ Ferroquine (FQ or SR97193) is a novel antimalarial drug candidate, currently in development at Sanofi-Aventis. In contrast to conventional drugs, FQ is the first organometallic drug: a ferrocenyl group covalently flanked by a 4-aminoquinoline and a basic alkylamine. FQ is able to overcome the CQ resistance problem, an important limit to the control of Plasmodium falciparum, the principal causative agent of malaria. After fifteen years of effort, it is now possible to propose a multifactorial mechanism of action of FQ by its capacity to target lipids, to inhibit the formation of hemozoin and to generate reactive oxygen species. http://www.mdpi.com/1420-3049/13/11/2900/ Thu, 20 Nov 2008 00:00:00 CET Molecules 2008-11-20 13 11 Article 2900 2907 1420-3049 Ferroquine, an Ingenious Antimalarial Drug –Thoughts on the Mechanism of Action 2008-11-20 doi: 10.3390/molecules13112900 Faustine Dubar Jamal Khalife Jacques Brocard Daniel Dive Christophe Biot