Substituent effects on the geometries and conrotatory electrocyclic ring openings of cyclobutenes were studied. This work extends the original investigations to many more substituents and provides a comprehensive theory of substituent effects on geometries and reaction rates. The effects of substitution at the 1 position are minimal; donor substituents raise the activation energy slightly, and powerful acceptor substituents slightly lower the activation energy. Substituents on C(3) cause small distortions of the cyclobutene geometry, in the same direction as the favored stereochemistry of reaction. Donors prefer outward rotation, while strong acceptors prefer inward rotation. The activation energy changes and cyclobutene geometrical perturbations were found to correlate with Taft sigma(R)(0) parameters. Amino, hydroxy, fluoro, chloro, methyl, cyano, formyl, and vinyl substituents were studied in the 1 position. Boryl, dimethylboryl, nitroso, formyl, nitro, carboxyl (neutral, protonated, and deprotonated), cyano, trifluoromethyl, sulfoxyl, sulfonyl, sulfinic acid, imino, N-protonated imino, ammonio, ethynyl, methyl, mercapto, chloro, fluoro, hydroxyl, amino, lithium oxy, vinyl, and acetyl were calculated as substituents in the 3 position. Comparisons with experimental results are given when available, and predictions are made in other cases.

BackgroundChagas disease is a neglected tropical disease (NTD) caused by the eukaryotic parasite Trypanosoma cruzi. The current clinical and preclinical pipeline for T. cruzi is extremely sparse and lacks drug target diversity.Methodology/Principal FindingsIn the present study we developed a computational approach that utilized data from several public whole-cell, phenotypic high throughput screens that have been completed for T. cruzi by the Broad Institute, including a single screen of over 300,000 molecules in the search for chemical probes as part of the NIH Molecular Libraries program. We have also compiled and curated relevant biological and chemical compound screening data including (i) compounds and biological activity data from the literature, (ii) high throughput screening datasets, and (iii) predicted metabolites of T. cruzi metabolic pathways. This information was used to help us identify compounds and their potential targets. We have constructed a Pathway Genome Data Base for T. cruzi. In addition, we have developed Bayesian machine learning models that were used to virtually screen libraries of compounds. Ninety-seven compounds were selected for in vitro testing, and 11 of these were found to have EC50 < 10μM. We progressed five compounds to an in vivo mouse efficacy model of Chagas disease and validated that the machine learning model could identify in vitro active compounds not in the training set, as well as known positive controls. The antimalarial pyronaridine possessed 85.2% efficacy in the acute Chagas mouse model. We have also proposed potential targets (for future verification) for this compound based on structural similarity to known compounds with targets in T. cruzi.Conclusions/ SignificanceWe have demonstrated how combining chemoinformatics and bioinformatics for T. cruzi drug discovery can bring interesting in vivo active molecules to light that may have been overlooked. The approach we have taken is broadly applicable to other NTDs.

The development of a novel class of nonsteroidal human progesterone receptor (hPR) agonists, 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines 2, is described. The introduction of a 5-aryl group into the 1,2-dihydrocoumarino[3,4-f]quinoline core 1 is the key for progestational activities. The structure-activity relationship (SAR) studies of the 5-aryl substituents generated a series of potent hPR agonists, which exhibited similar biological activity (EC50 = 8-30 nM) to the natural hormone progesterone (EC50 = 2.9 nM) in cell-based assays with efficacies ranging from 28% to 96%. Most of the analogues displayed similar or greater binding affinity (Ki = 0.41-3.6 nM) than progesterone (Ki = 3.5 nM). Three representative analogues (13, 15, and 24) demonstrated in vivo activities in mammary gland morphology/uterine wet weight assay in ovariectomized rats.

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Torquoselectivity in the electrocyclic interconversions of 1-azapolyenes and their heterocyclic isomers was investigated theoretically. The ring openings of 1,2-dihydroazete, 1,2-dihydropyridine, and 1,2-dihydroazocine were examined using HF, MP2, and B3LYP calculations. A large preference for inward rotation of the nitrogen lone pair and outward rotation of the N-H group was found for the four- and six-electron systems. No strong preference was observed for the eight-electron system.