Discovery of 1,3,4-oxadiazoles with slow-action activity against Plasmodium falciparum malaria parasites.

To achieve malaria eradication, new preventative agents that act differently to front-line treatment drugs are needed. To identify potential chemoprevention starting points we screened a sub-set of the CSIRO Australia Compound Collection for compounds with slow-action in vitro activity against Plasmodium falciparum. This work identified N,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines as a new antiplasmodial chemotype (e.g., 1 96 h IC50 550 nM; 3 96 h IC50 160 nM) with a different action to delayed-death slow-action drugs. A series of analogues were synthesized from thiotetrazoles and carbomoyl derivatives using Huisgen 1,3,4-oxadiazole synthesis followed by oxidation of the resultant thioethers to target sulfones. Structure activity relationship analysis of analogues identified compounds with potent and selective in vitro activity against drug-sensitive and multi-drug resistant Plasmodium parasites (e.g., 31 and 32 96 h IC50 <40 nM; SI > 2500). Subsequent studies in mice with compound 1, which had the best microsomal stability of the compounds assessed (T1/2 >255 min), demonstrated rapid clearance and poor oral in vivo efficacy in a P. berghei murine malaria model. These data indicate that while N,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines are a novel class of slow-acting antiplasmodial agents, the further development of this chemotype for malaria chemoprophylaxis will require pharmacokinetic profile improvements.

Binding inhibitors of the bacterial sliding clamp by design.

The bacterial replisome is a target for the development of new antibiotics to combat drug resistant strains. The ß(2) sliding clamp is an essential component of the replicative machinery, providing a platform for recruitment and function of other replisomal components and ensuring polymerase processivity during DNA replication and repair. A single binding region of the clamp is utilized by its binding partners, which all contain conserved binding motifs. The C-terminal Leu and Phe residues of these motifs are integral to the binding interaction. We acquired three-dimensional structural information on the binding site in ß(2) by a study of the binding of modified peptides. Development of a three-dimensional pharmacophore based on the C-terminal dipeptide of the motif enabled identification of compounds that on further development inhibited α-ß(2) interaction at low micromolar concentrations. We report the crystal structure of the complex containing one of these inhibitors, a biphenyl oxime, bound to ß(2), as a starting point for further inhibitor design.

Synthesis, binding and bioactivity of gamma-methylene gamma-lactam ecdysone receptor ligands: advantages of QSAR models for flexible receptors.

Nuclear hormone receptors, such as the ecdysone receptor, often display a large amount of induced fit to ligands. The size and shape of the binding pocket in the EcR subunit changes markedly on ligand binding, making modelling methods such as docking extremely challenging. It is, however, possible to generate excellent 3D QSAR models for a given type of ligand, suggesting that the receptor adopts a relatively restricted number of binding site configurations or 'attractors'. We describe the synthesis, in vitro binding and selected in vivo toxicity data for gamma-methylene gamma-lactams, a new class of high-affinity ligands for ecdysone receptors from Bovicola ovis (Phthiraptera) and Lucilia cuprina (Diptera). The results of a 3D QSAR study of the binding of methylene lactams to recombinant ecdysone receptor protein suggest that this class of ligands is indeed recognised by a single conformation of the EcR binding pocket.

Parasiticidal 2-alkoxy- and 2-aryloxyiminoalkyl trifluoromethanesulfonanilides.

A series of novel 2-alkoxy- and 2-aryloxyiminoalkyl trifluoromethanesulfonanilide derivatives have shown significant in vitro parasiticidal activity against the ectoparasites Ctenocephalides felis and Rhipicephalus sanguineus. A number of these compounds also displayed significant in vitro endoparasite activity against the nematode Haemonchus contortus.

Ring expansion reactions of 4-amino-1,1-dioxo-[1,2,3,5]-thiatriazoles.

An unusual ring-expansion reaction of 4-amino-1,1-dioxo-[1,2,3,5]-thiatriazoles has been identified that produces the relatively rare 5-amino-1,1-dioxo-[1,2,4,6]-thiatriazines and. Initial alkylation of the thiatriazole with alpha-halo-esters at N-3 produces alpha-substituted esters which, under basic reaction conditions, undergo opening of the thiatriazole ring and re-closure to a thiatriazine ring. Similar alkylations of with diethyl chloromalonate and ethyl dichloroacetate lead to the loss of SO2 and the production of triazine and triazole, apparently by an initial alkylation at N-5. The reaction of with phenacyl bromides or a phenacyl dibromide forms fully unsaturated 5-amino-1,1-dioxo-[1,2,4,6]-thiatriazines.