New prospects for the treatment of malaria

This update focuses on drugs for both uncomplicated and severe falciparum malaria. Chloroquine, long the mainstay of therapy, is no longer reliable because of widespread resistance, but is still attractive because of its very low cost. The following strategies for the future use of 4-aminoquinolines in uncomplicated malaria are discussed: the use of other existing 4-aminoquinolines such as amodiaquine, drug-induced reversal of chloroquine resistance, and the development of new 4-aminoquinolines with activity against resistant isolates. Pyrim- ethamine-sulfadoxine is now the drug of first-choice in much of Africa, but resistance to this antifolate combination is expected to become clinically apparent within the next five years. Research into the utility of novel antifolate combinations is described. Mefloquine and halofantrine are drugs which are extensively used in Southeast Asia, but are too expensive for general use in most African countries. The possible roles for artemisinine derivatives (alone and in combination with either mefloquine or benflumitol), pyronaridine and atovaquone-proguanil are described. The absolute importance of drug cost as a determinant of its utility in poorer countries is emphasised.     

New prospects for the treatment of malaria

This update focuses on drugs for both uncomplicated and severe falciparum malaria. Chloroquine, long the mainstay of therapy, is no longer reliable because of widespread resistance, but is still attractive because of its very low cost. The following strategies for the future use of 4-aminoquinolines in uncomplicated malaria are discussed: the use of other existing 4-aminoquinolines such as amodiaquine, drug-induced reversal of chloroquine resistance, and the development of new 4-aminoquinolines with activity against resistant isolates. Pyrim- ethamine-sulfadoxine is now the drug of first-choice in much of Africa, but resistance to this antifolate combination is expected to become clinically apparent within the next five years. Research into the utility of novel antifolate combinations is described. Mefloquine and halofantrine are drugs which are extensively used in Southeast Asia, but are too expensive for general use in most African countries. The possible roles for artemisinine derivatives (alone and in combination with either mefloquine or benflumitol), pyronaridine and atovaquone-proguanil are described. The absolute importance of drug cost as a determinant of its utility in poorer countries is emphasised.     

Artesunate-amodiaquine for the treatment of uncomplicated malaria

Without an effective vaccine for the prevention of malaria, a fundamental component of the strategy for the control of this disease is based on prompt and effective treatment. Due to the high resistance level of Plasmodium falciparum to the most affordable drugs such as chloroquine and sulfadoxine-pyrimethamine, artemisinin-based combination therapies are presently used in many countries or are being developed for registration. One artemisinin combination therapy that is drawing a certain degree of interest is the combination of artesunate (a short half-life drug) plus amodiaquine (a long half-life drug that is presently used in loose combination in many countries). The short half-life drug achieves substantial and rapid parasite killing, while a high concentration of the long half-life drug kills off the remaining malaria parasites. In addition to the effectiveness of 3 days of treatment (rapid clearance of fever and malaria parasites) in western and central Africa, where resistance to amodiaquine is low, the combination of artesunate plus amodiaquine may delay or prevent the emergence of resistance to both drugs. An important step is the recent registration in Morocco (the country where the drug is manufactured) of a fixed combination of artesunate plus amodiaquine by the Drugs for Neglected Diseases initiative with sanofi-aventis as the industrial partner. A prequalification dossier of this fixed combination has been submitted to the WHO. This new co-formulation will almost certainly increase its effectiveness by improving drug compliance.     

Future target molecules for influenza treatment

Induction of apoptosis and pro-inflammatory cytokine gene expression in influenza virus-infected cells activates production of toxic superoxide by macrophages. Pyrrolidine dithiocarbamate and nordihydroguaiaretic acid inhibit influenza virus proliferation and scavenge superoxide. These results suggest that they can be potential candidates for a drug of choice for influenza chemotherapy.     

Chalcone-benzoxaborole hybrid molecules as potent antitrypanosomal agents

We report the novel chalcone-benzoxaborole hybrids and their structure-activity relationship against Trypanosoma brucei parasites. The 4-NH(2) derivative 29 and 3-OMe derivative 43 were found to have excellent potency. The synergistic 4-NH(2)-3-OMe compound 49 showed an IC(50) of 0.010 μg/mL and resulted in 100% survival and zero parasitemia in a murine infection model, which represents one of the most potent compounds discovered to date from the benzoxaborole class that inhibit T. brucei growth.     

Pharmacological small molecules for the treatment of lysosomal storage disorders

Importance of the field: Inherited lysosomal storage diseases often cause severe disability and have a devastating effect on quality of life. Enzyme replacement therapy (ERT) forms a cornerstone in the treatment of lysosomal enzyme deficiencies. Although for some lysosomal disorders ERT is lifesaving, important intrinsic restrictions of the approach are limited access of infused enzyme to less accessible body compartments such as theCNS, the burden of frequent intravenous administration, the emergence of antibodies and the high associated costs. Pharmacological small molecules may overcome these limitations.

Areas covered in this review: Several novel therapeutic approaches using small molecules are emerging: substrate reduction therapy, pharmacological chaperone therapy, premature nonsense mutation suppressors and proteostasis regulators.

What the reader will gain: Based on an extensive literature search up until June 2010, we here review the various therapeutic approaches with small compounds, including those currently in clinical use and those that have entered clinical trials. Compounds that are still in the preclinical phase are also briefly discussed.

Take home message: pharmacological small molecules are a new class of agents that show great promise for the treatment of lysosomal storage disorders.     

Advances in preclinical small molecules for the treatment of NSCLC

Background: NSCLC accounts for 85% of all lung cancer cases and is the leading cause of cancer mortality. Advances in the knowledge of molecular events governing oncogenesis have led to a number of novel therapeutic agents targeting specific pathways critical for tumor growth. Objective: To summarize the recent preclinical developments of small molecules for NSCLC therapy. Methods: This review primarily consists of patents and publications between 1997 and 2008. Results/conclusion: Small molecules with known targets, such as inhibitors for EGFR, VEGF, RAS-RAF-MAP kinase pathway, phosphoinositide 3-kinase pathway, histone deacetylase, protein phosphatase, topoisomerase, cyclin dependent kinases, heat-shock protein, tubulin, DNA and MET are reviewed. Other novel small molecules with potent efficacy without target information are also discussed.     

Ethnomedicine in malaria treatment

The most pressing problem in malaria is parasite resistance to classical antimalarial drugs such as chloroquine, particularly as no alternative antimalarial agents are currently available that combine the low cost, safety and efficacy that once characterized chloroquine. Indeed, people in these endemic countries must survive on less than US dollars 15 per month, and consequently a maximum cost of US dollars 1 per person is all that can be afforded for antimalarial treatment. Only chloroquine and sulfadoxine-pyrimethamine are widely available at this price but resistance to these drugs is widespread, hence the development of cheap alternative therapies are essential. For these endemic populations, traditional medicine appear indispensable in the fight against this disease. Moreover, with regard to the scientific community, natural products demonstrate the highest chemical structural diversity.     

Adhesion molecules as targets for the treatment of neoplastic diseases

The quest for therapeutic specificity is implicit in all branches of medicine. In cancer treatment, cytotoxic agents, such as chemotherapy and radiotherapy, comprise the current therapeutic modality. Unfortunately, when used against most solid malignancies, their therapeutic indices are relatively low due to the significant damage they inflict on normal tissues. Furthermore, cure rates have remained essentially static over the last two decades. Specificity in killing neoplastic cells, while sparing healthy ones is therefore the only alternative approach, with several molecules qualifying as candidates for targeting therapy. Reduction of cell-cell and cell-matrix adhesion are, early tumorigenesis events also implicated in the invasive and metastatic process. The fact that abnormal adhesive marker expression is a feature commonly shared by most malignancies, along with its tendency to occur as both an early and late event in neoplastic development, makes these molecules potential candidates for antineoplastic targeted therapies. This review presents the perspectives of specific anti-adhesion molecule targeting as a possible therapeutic approach in neoplastic diseases.     

Artemisinins in malaria treatment in the UK

Malaria is a potentially life-threatening disease caused by protozoal parasites of the genus Plasmodium. It is mainly a problem in developing countries, and cases in the UK involve travellers coming from endemic areas. Resistance is increasing to several antimalarial drugs (e.g. chloroquine, mefloquine, antifolates). Another group of drugs, known as artemisinins, have come into widespread use more recently. An oral artemisinin-combination therapy (ACT) is now one of the standard licensed treatments for uncomplicated malaria in the UK. However, the parenteral artemisinin for severe malaria, artesunate, is not licensed in developed countries. Here we consider the role of artemisinins as treatment for malaria in the UK.     

Novel approach for synthesis of potent antimicrobial hybrid molecules containing pyrimidine-based imidazole scaffolds

This report describes the novel approach for the synthesis and exploration of hybrid molecules containing pyrimidine-based imidazole scaffolds as potent antimicrobial agents. The targeted compounds N-(4-arylidene-2-mercapto-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamides (5a–l) were achieved by the Knoevenagel condensation of a key precursor (4) with different aldehydes in good yields having moderate to excellent antimicrobial activity. The structural identification of final products was carried out by known classical spectral techniques like IR, ¹H NMR, ¹³C NMR, and mass spectra. The obtained data indicated that the majority of the tested compounds exhibited good antibacterial activity over antifungal activity, particularly compounds 5j and 5b (having MIC values 12.5 μg/mL) showed a comparable effect to a standard antibacterial and antifungal agents.