About half of the world's population is at risk of malaria, and in tropical countries it remains a major cause of morbidity and death in children. Drug resistance to current established antimalarial drugs such as chloroquine is driving the rise in malaria-attributed deaths. In the mid-1990s, two groupsin France and in Venezuelaprobed the potential contribution of organometallic analogues as a means of discovering new antimalarial drugs. In the present review, key topics of organometallic antimalarials are outlined using examples from the literature. The interdisciplinary research environment of bioorganometallics allows researchers to investigate the whole spectrum of the drugs' mechanisms of action. Targeting the digestive vacuole and inhibiting hemozoin formation is believed to be the main mechanism by which these drugs induce parasite death.

Despite recent encouraging advances against the disease, malaria remains a major public health problem affecting almost half a billion people and killing almost a million per annum. Due to a short arsenal of efficient antimalarial agents and the frequent appearance of resistance to the drugs in current use, which consequently reduce our means to treat patients, there is a very urgent and continuous need to develop new compounds. This perspective outlines a unique strategy for that purpose through the development of metal-based antimalarial agents. The examples presented here illustrate an attractive alternative to classical drugs.

Ciprofloxacin (CP) is a fluoroquinolone that is highly active against diverse microorganisms. At concentrations less than 1 µg/ml it is active against a diverse types of bacteria, including Staphylococcus aureus, Staphylococcus epidermidis, Bacillius subtilius, Escherichia coli and Mycobacterium tuberculosis. In addition, it has shown to be effective against other diseases such as malaria, cancer and AIDS. The extended antimicrobial activity, lack of plasmid-mediated resistance, large volume of distribution and minimal adverse effects of CP are therapeutically advantageous. In the pursuit of increasing their effectiveness against these diseases and prevent unwanted resistance, researchers have begun to synthesize a class of organic, inorganic and organometallic derivatives, which have displayed interesting activities. This review describes the development and recent advances on the evaluation of CP and its derivatives as a new class of drugs with potential for clinical development.

The mechanism of antimalarial action of [Au(CQ)(PPh 3 )] PF 6 (1), which is active in vitro against CQ-resistant P. falciparum and in vivo against P. berghei, has been investigated in relation to hemozoin formation and DNA as possible important targets. Complex 1 interacts with heme and inhibits β-hematin formation both in aqueous medium and near water/n-octanol interfaces at pH 5 to a greater extent than chloroquine diphosphate (CQDP) or other known metal-based antimalarial agents; the higher inhibition activity is probably related to the higher lipophilicity observed for 1 through partition coefficient measurements at low pH, with respect to CQDP. The interactions of complex 1 with DNA were explored using spectrophotometric and fluorimetric titrations, circular dichroism spectroscopy, viscosity and melting point studies, as well as electrophoresis and covalent binding assays. The experimental data indicate that complex 1 interacts with DNA predominantly by intercalation and electrostatic association of the CQ moiety, similarly to free CQDP, while no covalent metal-DNA binding seems to take place. The most likely antimalarial mechanism for complex 1 is thus heme aggregation inhibition; the high activities observed against resistant parasites are probably due to the structural modification of CQ introduced by the presence of the gold-triphenylphosphine fragment, together with the enhanced lipophilic character.

BackgroundMalaria still has significant impacts on the world; particularly in Africa, South America and Asia where spread over several millions of people and is one of the major causes of death. When chloroquine diphosphate (CQDP) lost its efficiency as a first-line anti-malarial drug, this was a major setback in the effective control of malaria. Currently, malaria is treated with a combination of two or more drugs with different modes of action to provide an adequate cure rate and delay the development of resistance. Clearly, a new effective and non-toxic anti-malarial drug is urgently needed.MethodsAll metal-chloroquine (CQ) and metal-CQDP complexes were synthesized under N2 using Schlenk techniques. Their interactions with haematin and the inhibition of β-haematin formation were examined, in both aqueous medium and near water/n-octanol interfaces at pH 5. The anti-malarial activities of these metal- CQ and metal-CQDP complexes were evaluated in vitro against two strains, the CQ-susceptible strain (CQS) 3D7 and the CQ-resistant strain (CQR) W2.ResultsThe previously synthesized Au(CQ)(Cl) (1), Au(CQ)(TaTg) (2), Pt(CQDP)2Cl2 (3), Pt(CQDP)2I2 (4), Pd(CQ)2Cl2 (5) and the new one Pd(CQDP)2I2 (6) showed better anti-malarial activity than CQ, against the CQS strain; moreover, complexes 2, 3 and 4 were very active against CQR strain. These complexes (1–6) interacted with haem and inhibited β-haematin formation both in aqueous medium and near water/n-octanol interfaces at pH 5 to a greater extent than chloroquine diphosphate (CQDP) and other known metal-based anti-malarial agents.ConclusionsThe high anti-malarial activity displayed for these metal-CQ and metal-CQDP complexes (1–6) could be attributable to their effective interaction with haem and the inhibition of β-haematin formation in both aqueous medium and near water/n-octanol interfaces at pH 5.Electronic supplementary materialThe online version of this article (doi:10.1186/1475-2875-13-471) contains supplementary material, which is available to authorized users.

Three platinum-chloroquine complexes, trans-Pt(CQDP)2(I)2 [1], trans-Pt(CQDP)2(Cl)2 [2] and trans-Pt(CQ)2(Cl)2 [3], were prepared and their most probable structure was established through a combination of spectroscopic analysis and density functional theory (DFT) calculations. Their interaction with DNA was studied and their activity against 6 tumor cell lines was evaluated. Compounds 1 and 2 interact with DNA primarily through electrostatic contacts and hydrogen bonding, with a minor contribution of a covalent interaction, while compound 3 binds to DNA predominantly in a covalent fashion, with weaker secondary electrostatic interactions and possibly hydrogen bonding, this complex also exerted greater cytotoxic activity against the tumor cell lines.

TREM like transcript-1 (TLT-1) is a membrane protein receptor found in α-granules of platelets and megakaryocytes. Upon platelet activation TLT-1 is rapidly brought to the surface of platelets. Recently, we demonstrated that activated platelets release a soluble form of TLT-1 (sTLT-1) that is found in serum but not in the plasma of healthy individuals and can enhance platelet aggregation in vitro. Furthermore, evaluation of patients diagnosed with inflammatory diseases, such as sepsis, show that these patients have significantly elevated levels of sTLT-1 in their blood. Accordingly, mice deficient in TLT-1 are predisposed to bleeding in response to an inflammatory challenge; however the mechanism of TLT-1 function remains unknown. In this investigation we demonstrate an increase in the amount of platelets that adhere to endothelial cell monolayers in the presence of recombinant sTLT-1 (rsTLT-1). Additionally we present evidence that rsTLT-1 increases platelet adherence to glass slides by stimulating actin polymerization in platelets as determined by increased staining of rodamine phalloidin. These results suggest that during inflammation, sTLT-1 may mediate hemostasis by enhancing actin polymerization, resulting in increased platelet aggregation and adherence to the endothelium.

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