Molecules

Research

Jump to: Review

149 KiB

Open AccessArticle

Heterocyclic-2-carboxylic Acid (3-Cyano-1,4-di-N-oxidequinoxalin-2-yl)amide Derivatives as Hits for the Development of Neglected Disease Drugs

by 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 and Antonio Monge

Molecules 2009, 14(6), 2256-2272; https://doi.org/10.3390/molecules14062256 - 22 Jun 2009

Cited by 52 | Viewed by 15126

Abstract

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- [...] Read more.

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. Full article

(This article belongs to the Special Issue Neglected Diseases: Medicinal Chemistry and Natural Product Chemistry)

► Show Figures

Graphical abstract

419 KiB

Open AccessArticle

Quantitative Structure ‒ Antiprotozoal Activity Relationships of Sesquiterpene Lactones

by Thomas J. Schmidt, Amal M. M. Nour, Sami A. Khalid, Marcel Kaiser and Reto Brun

Molecules 2009, 14(6), 2062-2076; https://doi.org/10.3390/molecules14062062 - 8 Jun 2009

Cited by 109 | Viewed by 19369

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Neglected Diseases: Medicinal Chemistry and Natural Product Chemistry)

► Show Figures

Figure 1

1819 KiB

Open AccessArticle

Comparative Molecular Docking of Antitrypanosomal Natural Products into Multiple Trypanosoma brucei Drug Targets

by Ifedayo V. Ogungbe and William N. Setzer

Molecules 2009, 14(4), 1513-1536; https://doi.org/10.3390/molecules14041513 - 14 Apr 2009

Cited by 47 | Viewed by 13978

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Neglected Diseases: Medicinal Chemistry and Natural Product Chemistry)

► Show Figures

Figure 1

420 KiB

Open AccessArticle

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

by Jin Zhu, Tong Chen, Lili Chen, Weiqiang Lu, Peng Che, Jin Huang, Honglin Li, Jian Li and Hualiang Jiang

Molecules 2009, 14(1), 494-508; https://doi.org/10.3390/molecules14010494 - 21 Jan 2009

Cited by 13 | Viewed by 17909

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Neglected Diseases: Medicinal Chemistry and Natural Product Chemistry)

► Show Figures

Figure 1

126 KiB

Open AccessArticle

Screening of Agelasine D and Analogs for Inhibitory Activity against Pathogenic Protozoa; Identification of Hits for Visceral Leishmaniasis and Chagas Disease

by Anders Vik, Ágnes Proszenyák, Marieke Vermeersch, Paul Cos, Louis Maes and Lise-Lotte Gundersen

Molecules 2009, 14(1), 279-288; https://doi.org/10.3390/molecules14010279 - 8 Jan 2009

Cited by 46 | Viewed by 16721

Abstract

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, [...] Read more.

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. Full article

(This article belongs to the Special Issue Neglected Diseases: Medicinal Chemistry and Natural Product Chemistry)

► Show Figures

Graphical abstract

196 KiB

Open AccessArticle

Synthesis and Evaluation of Non-peptidic Cysteine Protease Inhibitors of P. falciparum Derived from Etacrynic Acid

by 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 and Christoph Gelhaus

Molecules 2009, 14(1), 19-35; https://doi.org/10.3390/molecules14010019 - 23 Dec 2008

Cited by 9 | Viewed by 14723

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Neglected Diseases: Medicinal Chemistry and Natural Product Chemistry)

► Show Figures

Graphical abstract

156 KiB

Open AccessArticle

Ferroquine, an Ingenious Antimalarial Drug –Thoughts on the Mechanism of Action

by Faustine Dubar, Jamal Khalife, Jacques Brocard, Daniel Dive and Christophe Biot

Molecules 2008, 13(11), 2900-2907; https://doi.org/10.3390/molecules13112900 - 20 Nov 2008

Cited by 144 | Viewed by 17326

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Neglected Diseases: Medicinal Chemistry and Natural Product Chemistry)

► Show Figures

Figure 1

Review

Jump to: Research

599 KiB

Open AccessReview

The Trypanocidal Activity of Naphthoquinones: A Review

by Antônio Ventura Pinto and Solange Lisboa de Castro

Molecules 2009, 14(11), 4570-4590; https://doi.org/10.3390/molecules14114570 - 10 Nov 2009

Cited by 195 | Viewed by 17893

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Neglected Diseases: Medicinal Chemistry and Natural Product Chemistry)

► Show Figures

Figure 1

392 KiB

Open AccessReview

Protein Turnover in Mycobacterial Proteomics

by Prahlad K. Rao and Qingbo Li

Molecules 2009, 14(9), 3237-3258; https://doi.org/10.3390/molecules14093237 - 28 Aug 2009

Cited by 11 | Viewed by 15245

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Neglected Diseases: Medicinal Chemistry and Natural Product Chemistry)

► Show Figures

Figure 1

520 KiB

Open AccessReview

Plant-Derived Antimalarial Agents: New Leads and Efficient Phytomedicines. Part II. Non-Alkaloidal Natural Products

by Ronan Batista, Ademir De Jesus Silva Júnior and Alaíde Braga De Oliveira

Molecules 2009, 14(8), 3037-3072; https://doi.org/10.3390/molecules14083037 - 13 Aug 2009

Cited by 233 | Viewed by 28048

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Neglected Diseases: Medicinal Chemistry and Natural Product Chemistry)

► Show Figures

Graphical abstract

824 KiB

Open AccessReview

Recent Advances in the Discovery of Haem-Targeting Drugs for Malaria and Schistosomiasis

by Katherine A. De Villiers and Timothy J. Egan

Molecules 2009, 14(8), 2868-2887; https://doi.org/10.3390/molecules14082868 - 4 Aug 2009

Cited by 48 | Viewed by 16003

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Neglected Diseases: Medicinal Chemistry and Natural Product Chemistry)

► Show Figures

Graphical abstract

537 KiB

Open AccessReview

Pentavalent Antimonials: New Perspectives for Old Drugs

by Frédéric Frézard, Cynthia Demicheli and Raul R. Ribeiro

Molecules 2009, 14(7), 2317-2336; https://doi.org/10.3390/molecules14072317 - 30 Jun 2009

Cited by 359 | Viewed by 31430

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Neglected Diseases: Medicinal Chemistry and Natural Product Chemistry)

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

Neglected Diseases: Medicinal Chemistry and Natural Product Chemistry

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (12 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI