1,5-Benzodiazepin-2(3H)-ones: In Vitro Evaluation as Antiparkinsonian Agents.

A new series of twenty-three 1,5-benzodiazepin-2(3H)-ones were synthesized and evaluated in the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), ferric reducing antioxidant power (FRAP), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays as a new chemotype with antioxidant and good drug-like properties. All of the derivatives showed low cytotoxicity in comparison to curcumin against the human neuroblastoma SH-SY5Y and the human hepatoma HepG2 cell lines. Experimental solubility in bio-relevant media showed a good relationship with melting points in this series.

Evaluation of the Antioxidant and Neuroprotectant Activities of New Asymmetrical 1,3-Diketones.

A series of fourteen new asymmetrical 1,3-diketone derivatives have been synthesized and evaluated in the ABTS, FRAP and DPPH assays as a new chemotype with antioxidant and drug-like properties. All the compounds displayed low cytotoxicity in comparison to curcumin against the human neuroblastoma SH-SY5Y cell line. Among them, (3,5)-6-(2,5-difluoro-4-hydroxy-phenyl)-1,1,1-trifluoro-4-hydroxyhexa-3,5-dien-2-one () and (3,5)-6-(2,3-difluoro-4-hydroxy-phenyl)-1,1,1-trifluoro-4-hydroxyhexa-3,5-dien-2-one () with excellent solubility and chemical stability in biorelevant media, have also shown a similar Fe chelation behavior to that of curcumin.

Functional screening of selective mitochondrial inhibitors of Plasmodium.

Phenotypic screening has produced most of the new chemical entities currently in clinical development for malaria, plus many lead compounds active against Plasmodium falciparum asexual stages. However, lack of knowledge about the mode of action of these compounds delays and may even hamper their future development. Identifying the mode of action of the inhibitors greatly helps to prioritise compounds for further development as novel antimalarials.

Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor.

Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb), but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment.

Mycobacterium tuberculosis gyrase inhibitors as a new class of antitubercular drugs.

One way to speed up the TB drug discovery process is to search for antitubercular activity among compound series that already possess some of the key properties needed in anti-infective drug discovery, such as whole-cell activity and oral absorption. Here, we present MGIs, a new series of Mycobacterium tuberculosis gyrase inhibitors, which stem from the long-term efforts GSK has dedicated to the discovery and development of novel bacterial topoisomerase inhibitors (NBTIs). The compounds identified were found to be devoid of fluoroquinolone (FQ) cross-resistance and seem to operate through a mechanism similar to that of the previously described NBTI GSK antibacterial drug candidate.

IGF-I increases markers of osteoblastic activity and reduces bone resorption via osteoprotegerin and RANK-ligand.

Background: Bone is one of the major target tissues for Insulin-like Growth Factor I (IGF-I). Low doses of IGF-I were able to improve liver-associated osteopenia. In the present work, a model of partial IGF-I deficiency was used in order to provide insight into the mechanisms of the beneficial actions of IGF-I replacement therapy in bone.

Fueling open-source drug discovery: 177 small-molecule leads against tuberculosis.

With the aim of fuelling open-source, translational, early-stage drug discovery activities, the results of the recently completed antimycobacterial phenotypic screening campaign against Mycobacterium bovis BCG with hit confirmation in M. tuberculosis H37Rv were made publicly accessible. A set of 177 potent non-cytotoxic H37Rv hits was identified and will be made available to maximize the potential impact of the compounds toward a chemical genetics/proteomics exercise, while at the same time providing a plethora of potential starting points for new synthetic lead-generation activities.

An Invitation to Open Innovation in Malaria Drug Discovery: 47 Quality Starting Points from the TCAMS.

In 2010, GlaxoSmithKline published the structures of 13533 chemical starting points for antimalarial lead identification. By using an agglomerative structural clustering technique followed by computational filters such as antimalarial activity, physicochemical properties, and dissimilarity to known antimalarial structures, we have identified 47 starting points for lead optimization. Their structures are provided.

Potent antimalarial 4-pyridones with improved physico-chemical properties.

Antimalarial 4-pyridones are a novel class of inhibitors of the plasmodial mitochondrial electron transport chain targeting Cytochrome bc1 (complex III). In general, the most potent 4-pyridones are lipophilic molecules with poor solubility in aqueous media and low oral bioavailability in pre-clinical species from the solid dosage form. The strategy of introducing polar hydroxymethyl groups has enabled us to maintain the high levels of antimalarial potency observed for other more lipophilic analogues whilst improving the solubility and the oral bioavailability in pre-clinical species.

Cyclodextrin/poly(anhydride) nanoparticles as drug carriers for the oral delivery of atovaquone.

The aim was to study the ability of bioadhesive cyclodextrin-poly(anhydride) nanoparticles as carriers for the oral delivery of atovaquone (ATO). In order to increase the loading capacity of ATO by poly(anhydride) nanoparticles, the following oligosaccharides were assayed: 2-hydroxypropyl-β-cyclodextrin (HPCD), 2,6-di-O-methyl-β-cyclodextrin (DCMD), randomly methylated-β-cyclodextrin (RMCD) and sulfobuthyl ether-β-cyclodextrin (SBECD). Nanoparticles were obtained by desolvation after the incubation between the poly(anhydride) with the ATO-cyclodextrin complexes.

Identification and activity of a series of azole-based compounds with lactate dehydrogenase-directed anti-malarial activity.

Plasmodium falciparum, the causative agent of malaria, relies extensively on glycolysis coupled with homolactic fermentation during its blood-borne stages for energy production. Selective inhibitors of the parasite lactate dehydrogenase (LDH), central to NAD(+) regeneration, therefore potentially provide a route to new antimalarial drugs directed against a novel molecular target. A series of heterocyclic, azole-based compounds are described that preferentially inhibit P.

Optimization of the pharmacophore model for 5-HT7R antagonism. Design and synthesis of new naphtholactam and naphthosultam derivatives.

We present in this study an optimization of a preliminary pharmacophore model for 5-HT(7)R antagonism, with the incorporation of recently reported ligands and using an efficient procedure with the CATALYST program. The model consists of five features: a positive ionizable atom (PI), a H-bonding acceptor group (HBA), and three hydrophobic regions (HYD). This model has been supported by the design, synthesis, and biological evaluation of new naphtholactam and naphthosultam derivatives of general structure I (39-72).