1-Aryl-3-(4-methoxybenzyl)ureas as potentially irreversible glycogen synthase kinase 3 inhibitors: Synthesis and biological evaluation.

Glycogen synthase kinase 3 (GSK-3) has become known for its multifactorial involvement in the pathogenesis of Alzheimer's disease. In this study, a benzothiazole- and benzimidazole set of 1-aryl-3-(4-methoxybenzyl)ureas were synthesised as proposed Cys199-targeted covalent inhibitors of GSK-3ß, through the incorporation of an electrophilic warhead onto their ring scaffolds. The nitrile-substituted benzimidazolylurea 2b (IC50 = 0.086 ±â€¯0.023 µM) and halomethylketone-substituted benzimidazolylurea 9b (IC50 = 0.13 ±â€¯0.060 µM) displayed high GSK-3ß inhibitory activity, in comparison to reference inhibitor AR-A014418 (1, IC50 = 0.072 ±â€¯0.043) in our assay. The results suggest further investigation of 2b and 9b as potential covalent inhibitors of GSK-3ß, since a targeted interaction might provide improved kinase-selectivity.

Synthesis of five libraries of 6,5-fused heterocycles to establish the importance of the heterocyclic core for antiplasmodial activity.

Research has indicated that N-myristoyl transferase, an enzyme that catalyzes the addition of a myristate group to the N-terminal glycine residues of proteins, is involved in the myristoylation of more than 100 proteins. Genetic knockdown of the enzyme proved detrimental for the viability of the parasite P. knowlesi. A crystal structure of P. vivax N-myristoyl transferase (pvNMT), containing a 3-methyl benzofuran ligand has made it possible to assess key amino acid residue-ligand interactions. We synthesized five libraries of 6,5-fused heterocycles to establish the importance of the heterocycles as core scaffolds, as well as introduced various aromatic amides and esters to determine which carbonylic group affects the potency of each heterocyclic antiplasmodial agent.

Design, Synthesis, and Evaluation of Novel Ferroquine and Phenylequine Analogues as Potential Antiplasmodial Agents.

7-Chloroquinoline-based antimalarial drugs are effective in the inhibition of hemozoin formation in the food vacuole of the Plasmodium parasite, the causative agent of malaria. We synthesized five series of ferroquine (FQ) and phenylequine (PQ) derivatives, which display good in vitro efficacy toward both the chloroquine-sensitive (CQS) NF54 (IC50 : 4.2 nm) and chloroquine-resistant (CQR) Dd2 (IC50 : 33.7 nm) strains of P. falciparum. Several compounds were found to have good inhibitory activity against ß-hematin formation in an NP-40 detergent assay, with IC50 values ranging between 10.4 and 19.2 µm.

In vitro antiplasmodial activity of triazole-linked chloroquinoline derivatives synthesized from 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-amine.

The synthesis and in vitro evaluation of novel triazole-linked chloroquinoline derivatives as potential antiplasmodial agents against Plasmodium falciparum is reported. The 15 synthesized target compounds were obtained by means of a copper(I)-mediated click reaction between a variety of 1,2- and 1,3-azidoamines and 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-amine in moderate to good yields (53-85%). The compounds were screened for antiplasmodial activity against NF54 chloroquine-sensitive and Dd2 chloroquine-resistant strains, alongside chloroquine and artesunate as reference compounds. Six of the test compounds revealed a 3-5 fold increase in antiplasmodial activity against chloroquine-resistant strain Dd2 compared to chloroquine. Among the six compounds with good antiplasmodial activity, a reduced cross-resistance relative to artesunate (>3 fold in comparison to chloroquine) was observed, mainly in derivatives that incorporated chloroquine-resistance reversing pharmacophores. A general trend for reduced chloroquine cross-resistance was also detected among 12 out of the 15 compounds tested.

Synthesis of novel triazole-linked mefloquine derivatives: biological evaluation against Plasmodium falciparum.

Using 2,8-bis(trifluoromethyl)quinoline, the pharmacophore of mefloquine, as scaffold, eleven novel triazole-linked compounds have been synthesised by the application of CuAAC chemistry. The in vitro biological activity of the compounds on the Plasmodium falciparum chloroquine-sensitive strain NF54 was then determined. The compounds all showed IC50s in the lower µM range with (1R,3S,5R)-N-{[1-(2,8-bis(trifluoromethyl)quinoline-4-yl)-1H-1,2,3-triazol-4-yl]methyl}adamantan-2-amine (29) exhibiting the best activity of 1.00 µM.

Tetraoxanes as antimalarials: harnessing the endoperoxide.

With the emergence of resistance to artemesinin, the need for new antimalarial compounds is pressing. Several research groups have made significant contributions to the exploration of the use of 1,2,4,5-tetraoxanes and 1,2,4- trioxanes as synthetic analogues of artemesinin. This short review highlights the recent developments in this field detailing both biological results and useful synthetic methodology. In addition, the current understanding of the mode of action of this class of compounds has been described.

A structural comparative approach to identifying novel antimalarial inhibitors.

Malaria continues to affect millions of people annually. With the rise of drug resistant strains, the need for alternative treatments has become increasingly urgent. Recently, PfUCHL3 was identified as an essential deubiquitinating enzyme. The increasing number of drug target structures being solved has increased the feasibility of utilizing a structural comparative approach to identifying novel inhibitors. Using AutoDock Vina, we recently screened the NCI library of about 320,000 compounds against the crystal structure of PfUCHL3. The top hits were subsequently screened against its human ortholog UCHL3 as to identify compounds that could specifically target the PfUCHL3 over its human counterpart. This method was used to identify small molecule inhibitors that can preferentially inhibit the parasitic enzyme. Several compounds were identified that demonstrated significant binding affinity preference for the malaria target over the human enzyme. Two of these compounds demonstrated ng/mL activity.

Metal containing chloroquinolines: beyond hit and miss antimalarial efficacy to solid science.

Research into metal complexes of known antimalarial drugs have been known for 30 years. Initial exploration into this field was fairly slow and largely limited to the synthesis of the complexes and reporting of antiplasmodial efficacy. In the last five years this approach has shifted substantially. Increasingly papers dealing with the mechanism of action, the speciation of the complexes, and other aspects of the interaction of these complexes in the biological system are appearing. This shift in focus indicates that the application of bioinorganic and bioorganometallic chemistry are beginning to mature into well established fields of research. This paper tracks the development of this field from the humble beginnings to the development of a substantial body of research.

Synthesis and evaluation of phenylequine for antimalarial activity in vitro and in vivo.

Synthesis of the potent antiplasmodial 4-aminoquinoline, phenylequine (PQ), is reported for the first time. PQ and the two analogues show increased efficacy in moving from the chloroquine sensitive D10 to the chloroquine resistant K1 strain in vitro. The in vivo efficacy of PQ, and salts thereof, have been determined in Plasmodium berghei ANKA and Plasmodium yoelii. Phenylequine hydrochloride has shown an ED(50) of 0.81 in P. yoelii (cf chloroquine ED(50)=1.31).

Metallocene antimalarials: the continuing quest.

Over the last decade, a significant body of research has been developed around the inclusion of a metallocene moiety into known antimalarial compounds. Ferroquine is the most successful of these compounds. Herein, we describe our contribution to metallocene antimalarials. Our approach has sought to introduce diversity sites in the side chain of ferroquine in order to develop a series of ferroquine derivatives. The replacement of the ferrocenyl moiety with ruthenocene has given rise to ruthenoquine and a modest series of analogues. The reaction of ferroquine and selected analogues with Au(PPh3)NO3, Au(C6F5)(tht), and [Rh(COD)Cl2] has resulted in a series of heterobimetallic derivatives. In all cases, compounds have been evaluated for in vitro antiplasmodial activity in both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Preliminary structure-activity relationships have been delineated.

Metallocene-based antimalarials: an exploration into the influence of the ferrocenyl moiety on in vitro antimalarial activity in chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum.

To establish the role of the ferrocenyl moiety in the antiplasmodial activity of ferroquine, compounds in which this moiety is replaced by the corresponding ruthenium-based moieties were synthesized and evaluated. In both the sensitive (D10) and resistant (K1) strains of Plasmodium falciparum, ruthenoquine analogues showed comparable potency to ferroquine. This suggests that a probable role of the ferrocenyl fragment is to serve simply as a hydrophobic spacer group. In addition, ferroquine analogues with different aromatic substituents were synthesized and evaluated. Unexpectedly high activity for quinoline compounds lacking the 7-chloro substituent suggests the ferrocenyl moiety may have an additive and/or synergistic effect.