Pilar Manzano

Identification and characterization of hundreds of potent and selective inhibitors of Trypanosoma brucei growth from a kinase-targeted library screening campaign.

In the interest of identification of new kinase-targeting chemotypes for target and pathway analysis and drug discovery in Trypanosomal brucei, a high-throughput screen of 42,444 focused inhibitors from the GlaxoSmithKline screening collection was performed against parasite cell cultures and counter-screened against human hepatocarcinoma (HepG2) cells. In this way, we have identified 797 sub-micromolar inhibitors of T. brucei growth that are at least 100-fold selective over HepG2 cells. Importantly, 242 of these hit compounds acted rapidly in inhibiting cellular growth, 137 showed rapid cidality. A variety of in silico and in vitro physicochemical and drug metabolism properties were assessed, and human kinase selectivity data were obtained, and, based on these data, we prioritized three compounds for pharmacokinetic assessment and demonstrated parasitological cure of a murine bloodstream infection of T. brucei rhodesiense with one of these compounds (NEU-1053). This work represents a successful implementation of a unique industrial-academic collaboration model aimed at identification of high quality inhibitors that will provide the parasitology community with chemical matter that can be utilized to develop kinase-targeting tool compounds. Furthermore these results are expected to provide rich starting points for discovery of kinase-targeting tool compounds for T. brucei, and new HAT therapeutics discovery programs.

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.

Establishment of a structure-activity relationship of 1H-imidazo[4,5-c]quinoline-based kinase inhibitor NVP-BEZ235 as a lead for African sleeping sickness.

Compound NVP-BEZ235 (1) is a potent inhibitor of human phospoinositide-3-kinases and mammalian target of rapamycin (mTOR) that also showed high inhibitory potency against Trypanosoma brucei cultures. With an eye toward using 1 as a starting point for anti-trypanosomal drug discovery, we report efforts to reduce host cell toxicity, to improve the physicochemical properties, and to improve the selectivity profile over human kinases. In this work, we have developed structure–activity relationships for analogues of 1 and have prepared analogues of 1 with improved solubility properties and good predicted central nervous system exposure. In this way, we have identified 4e, 9, 16e, and 16g as the most promising leads to date. We also report cell phenotype and phospholipidomic studies that suggest that these compounds exert their anti-trypanosomal effects, at least in part, by inhibition of lipid kinases.

New and unexpected developments of the carbanion-mediated sulfonate (sulfonamide) intramolecular cyclization reaction (CSIC reaction)

Abstract The Carbanion-mediated Sulfonate (Sulfonamide) Intramolecular Cyclization reaction (CSIC reaction) on conveniently functionalized cyanoalkylsulfonates and cyanoalkylsulfonamides derived from aldehydes is possible and gives the new heterocyclic ring systems 5-alkyl-5 H -4-amino-1,2-oxathiole-2,2-dioxide and 5-alkyl-5 H -4-amino-3-cyano-2,3-dihydroisothiazole-1,1-dioxide in good yield.

STEREOSELECTIVE NUCLEOPHILIC EPOXIDATION OF HYDROXY VINYL SULFOXIDE DERIVATIVES

Abstract The diastereoselectivity of the nucleophilic epoxidation of vinyl sulfoxides bearing oxygenated substituents at allylic positions, 1–4, with MOO-t-Bu (M = Na, K) is primarily controlled by the chiral sulfur atom.

Biased selection for building small-world networks

Small-world networks are currently present in many distributed applications and can be built augmenting a base network with long-range links using a probability distribution. Currently available distributed algorithms to select these long-range neighbors are designed ad hoc for specific probability distributions. In this paper we propose a new algorithm called Biased Selection (BS) that, using a uniform sampling service (that could be implemented with, for instance, a gossip-based protocol), allows to select long-range neighbors with any arbitrary distribution in a distributed way. This algorithm is of iterative nature and has a parameter r that gives its number of iterations. We prove that the obtained sampling distribution converges to the desired distribution as r grows. Additionally, we obtain analytical bounds on the maximum relative error for a given value of this parameter r. Although the BS algorithm is proposed in this paper as a tool to sample nodes in a network, it can be used in any context in which sampling with an arbitrary distribution is required, and only uniform sampling is available. The BS algorithm has been used to choose long-range neighbors in complete and incomplete tori, in order to build Kleinbergs small-world networks. We observe that using a very small number of iterations (1) BS has similar error as a simulation of the Kleinbergs harmonic distribution and (2) the average number of hops with greedy routing is no larger with BS than in a Kleinberg network. Furthermore, we have observed that before converging to the performance of a Kleinberg network, the average number of hops with BS is significantly smaller (up to 14% smaller in a 1000 × 1000 network).