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In the effort to define a set of rules useful in tuning the properties for a successful blood-brain barrier (BBB) permeation, we statistically analyzed a set of 328 compounds and correlated their experimental in vivo logBB with a series of computed descriptors. Contingency tables were constructed, observed and expected distributions were calculated, and chi-square (χ 2 ) distributions were evaluated. This allowed to point out a significant dependence of certain physicochemical properties in influencing the BBB permeation. Of over 15 computed descriptors, 9 resulted to be particularly important showing highly significant χ 2 distribution: polar surface area (χ 2 = 66.79; p = 1.08 × 10 -13 ), nitrogen and oxygen count (χ 2 = 51.17; p = 2.06 × 10 -10 ), logP (χ 2 = 47.38; p = 1.27 × 10 -9 ), nitrogen count (χ 2 = 38.29; p = 9.77 × 10 -8 ), logD (χ 2 = 36.80; p = 36.80), oxygen count (χ 2 = 35.83; p = 3.13 × 10 -7 ), ionization state (χ 2 = 33.02, p = 3.19 × 10 -7 ), hydrogen bond acceptors (χ 2 = 30.80; p = 3.36 × 10 -6 ), and hydrogen bond donors (χ 2 = 29.29; p = 6.81 × 10 -6 ). Other parameters describing the mass and size of the molecules (molecular weight: 11.18; p = 2.46 × 10 -2 ) resulted in being not significant since the population within the observed and expected distribution was similar. Depending on the combination of the significant descriptors, we set a three cases probabilistic scenario (BBB + , BBB - , BBB + /BBB - ) that would prospectively be used to tune properties for BBB permeation.

In the search of novel strategies for the treatment of cancer, photodynamic therapy (PDT) has emerged as an effective, safe for repeated use, and non-invasive method. This technique involves the use of two major non-toxic components, a photosensitizer (PS) and a visible or near-infrared (NIR) light source, combined to induce cellular damage in an oxygen-dependent or -independent manner. Macrocyclic compounds, involving porphyrin and their derivatives, represent the major class of PS agents used in PDT. However, due to the drawbacks associated with these PS, like photosensitivity, dark toxicity, and low wavelength absorbance, new classes of PS appear to be needed. This review summarizes over the recent advances in drug discovery of non-porphyrinic PS suitable as anticancer therapeutics in PDT. The different compounds are grouped by chemical classes and discussed in terms of phototoxicity, together with the critical aspects of design and structure-activity relationship., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Tropical protozoal infections are a significant cause of morbidity and mortality worldwide; four in particular (human African trypanosomiasis (HAT), Chagas disease, cutaneous leishmaniasis, and malaria) have an estimated combined burden of over 87 million disability-adjusted life years. New drugs are needed for each of these diseases. Building on the previous identification of NEU-617 (1) as a potent and nontoxic inhibitor of proliferation for the HAT pathogen (Trypanosoma brucei), we have now tested this class of analogs against other protozoal species: T. cruzi (Chagas disease), Leishmania major (cutaneous leishmaniasis), and Plasmodium falciparum (malaria). Based on hits identified in this screening campaign, we describe the preparation of several replacements for the quinazoline scaffold and report these inhibitors' biological activities against these parasites. In doing this, we have identified several potent proliferation inhibitors for each pathogen, such as 4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-6-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)quinoline-3-carbonitrile (NEU-924, 83) for T. cruzi and N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-7-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)cinnolin-4-amine (NEU-1017, 68) for L. major and P. falciparum.

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.

Chagas disease is caused by the intracellular protozoan parasite Trypanosomal cruzi , and current drugs are lacking in terms of desired safety and efficacy profiles. Following on a recently reported high-throughput screening campaign, we have explored initial structure-activity relationships around a class of imidazole-based compounds. This profiling has uncovered compounds 4c (NEU321) and 4j (NEU704), which are potent against in vitro cultures of T. cruzi and are greater than 160-fold selective over host cells. We report in vitro drug metabolism and properties profiling of 4c and show that this chemotype inhibits the T. cruzi CYP51 enzyme, an observation confirmed by X-ray crystallographic analysis. We compare the binding orientation of 4c to that of other, previously reported inhibitors. We show that 4c displays a significantly better ligand efficiency and a shorter synthetic route over previously disclosed CYP51 inhibitors, and should therefore be considered a promising lead compound for further optimization.