Single-Dose Drug Development Candidate for Schistosomiasis.

Aryl hydantoins were identified in the early 1980s as a promising antischistosomal chemotype. However, as exemplified by Ro 13-3978, this compound series produced antiandrogenic side effects on the host, a not unexpected outcome given their structural similarity to the antiandrogenic drug nilutamide. The two key advances in our optimization of Ro 13-3978 were swapping the aryl trifluoromethyl substituent with a difluoroethyl to abolish antiandrogenic effects and replacing the hydrogen atoms of the -dimethyl substructure with deuterium atoms to increase metabolic stability.

Medium-Ring Keto Bislactams with Antischistosomal Activity.

We discovered medium-ring keto bislactams as a new antischistosomal chemotype. The ketone functional group and isoindolinone substructure were required for high antischistosomal activity. Aryl substitution with EWG functional groups decreased the chemical stability.

Antimalarial Dibenzannulated Medium-Ring Keto Lactams.

We discovered dibenzannulated medium-ring keto lactams (11,12-dihydro-5-dibenzo[,]azonine-6,13-diones) as a new antimalarial chemotype. Most of these had chromatographic LogD values ranging from <0 to 3 and good kinetic solubilities (12.5 to >100 μg/mL at pH 6.

and Antischistosomal Activity Profiling and Pharmacokinetics of Ozonide Carboxylic Acids.

Praziquantel, the only drug in clinical use for the treatment and control of schistosomiasis, is inactive against developing infections. Ozonides are synthetic peroxide derivatives inspired by the naturally occurring artemisinin and show particularly promising activity against juvenile schistosomes. We conducted an in-depth characterization of the and antischistosomal activity and pharmacokinetics of lead ozonide carboxylic acid OZ418 and four of its active analogs.

Metabolic, Pharmacokinetic, and Activity Profile of the Liver Stage Antimalarial (RC-12).

The catechol derivative RC-12 (WR 27653) () is one of the few non-8-aminoquinolines with good activity against hypnozoites in the gold-standard -rhesus monkey () model, but in a small clinical trial, it had no efficacy against hypnozoites. In an attempt to better understand the pharmacokinetic and pharmacodynamic profile of and to identify potential active metabolites, we now describe the phase I metabolism, rat pharmacokinetics, and liver-stage activity of and its metabolites. Compound had a distinct metabolic profile in human vs monkey liver microsomes, and the data suggested that the -desmethyl, combined -desmethyl/-desethyl, and -didesethyl metabolites (or a combination thereof) could potentially account for the superior liver stage antimalarial efficacy of in rhesus monkeys vs that seen in humans.

Synthesis and antimalarial activity of amide and ester conjugates of siderophores and ozonides.

Despite advances in chemotherapeutic interventions for the treatment of malaria, there is a continuing need for the development of new antimalarial agents. Previous studies indicated that co-administration of chloroquine with antioxidants such as the iron chelator deferoxamine (DFO) prevented the development of persistent cognitive damage in surrogate models of cerebral malaria. The work described herein reports the syntheses and antimalarial activities of covalent conjugates of both natural (siderophores) and artificial iron chelators, namely DFO, ferricrocin and ICL-670, with antimalarial 1,2,4-trioxolanes (ozonides).

Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in .

A search for alternative treatments led to our interest in the two-component regulator DosRS, which, in , is required for the bacterium to establish a state of nonreplicating, drug-tolerant persistence in response to a variety of host stresses. We show here that the genetic disruption of impairs the adaptation of to hypoxia, resulting in decreased bacterial survival after oxygen depletion, reduced tolerance to a number of antibiotics in vitro and in vivo, and the inhibition of biofilm formation. We determined that three antimalarial drugs or drug candidates, artemisinin, OZ277, and OZ439, can target DosS-mediated hypoxic signaling in and recapitulate the phenotypic effects of genetically disrupting .

Antischistosomal tetrahydro-γ-carboline sulfonamides.

We discovered tetrahydro-γ-carboline sulfonamides as a new antischistosomal chemotype. The aryl sulfonamide and tetrahydro-γ-carboline substructures were required for high antischistosomal activity. Increasing polarity improved solubility and metabolic stability but decreased antischistosomal activity.

Peroxide Antimalarial Drugs Target Redox Homeostasis in Infected Red Blood Cells.

causes the most lethal form of malaria. Peroxide antimalarials based on artemisinin underpin the frontline treatments for malaria, but artemisinin resistance is rapidly spreading. Synthetic peroxide antimalarials, known as ozonides, are in clinical development and offer a potential alternative.

Virtual screening and biological evaluation of PPARγ antagonists as potential anti-prostate cancer agents.

The peroxisome proliferator-activated receptor gamma (PPARγ) was identified as an oncogene and it plays a key role in prostate cancer (PC) development and progression. PPARγ antagonists have been shown to inhibit PC cell growth. Herein, we describe a virtual screening-based approach that led to the discovery of novel PPARγ antagonist chemotypes that bind at the allosteric pocket.

Cytochrome P450-Mediated Metabolism and CYP Inhibition for the Synthetic Peroxide Antimalarial OZ439.

OZ439 is a potent synthetic ozonide evaluated for the treatment of uncomplicated malaria. The metabolite profile of OZ439 was characterized using human liver microsomes combined with LC/MS-MS, chemical derivatization, and metabolite synthesis. The primary biotransformations were monohydroxylation at the three distal carbon atoms of the spiroadamantane substructure, with minor contributions from -oxidation of the morpholine nitrogen and deethylation cleavage of the morpholine ring.

Diaryl Ureas as an Antiprotozoal Chemotype.

We now describe the physicochemical profiling, ADME, and antiparasitic activity of eight ,-diarylureas to assess their potential as a broad-spectrum antiprotozoal chemotype. Chromatographic LogD values ranged from 2.5 to 4.

Selection Implicates ROP1 as a Resistance Gene for an Experimental Therapeutic Benzoquinone Acyl Hydrazone in Toxoplasma gondii.

is a globally distributed apicomplexan parasite and the causative agent of toxoplasmosis in humans. While pharmaceuticals exist to combat acute infection, they can produce serious adverse reactions, demonstrating a need for enhanced therapies. KG8 is a benzoquinone acyl hydrazone chemotype identified from a previous chemical screen for which we previously showed and efficacy against However, the genetic target and mechanism of action of KG8 remain unknown.

Efficacy, metabolism and pharmacokinetics of Ro 15-5458, a forgotten schistosomicidal 9-acridanone hydrazone.

Background: Treatment of schistosomiasis, a neglected disease, relies on just one partially effective drug, praziquantel. We revisited the 9-acridanone hydrazone, Ro 15-5458, a largely forgotten antischistosomal lead compound.

Methods: Ro 15-5458 was evaluated in juvenile and adult Schistosoma mansoni-infected mice.

Targeted Amino Acid Substitution Overcomes Scale-Up Challenges with the Human C5a-Derived Decapeptide Immunostimulant EP67.

EP67 is a second-generation, human C5a-derived decapeptide agonist of C5a receptor 1 (C5aR1/CD88) that selectively activates mononuclear phagocytes over neutrophils to potentiate protective innate and adaptive immune responses while potentially minimizing neutrophil-mediated toxicity. Pro and -methyl-Leu (Me-Leu) amino acid residues within EP67 likely induce backbone structural changes that increase potency and selective activation of mononuclear phagocytes over neutrophils versus first-generation EP54. The low coupling efficiency between Pro and Me-Leu and challenging purification by HPLC, however, greatly increase scale-up costs of EP67 for clinical use.

Structure-Activity Relationship of Antischistosomal Ozonide Carboxylic Acids.

Semisynthetic artemisinins and other bioactive peroxides are best known for their powerful antimalarial activities, and they also show substantial activity against schistosomes-another hemoglobin-degrading pathogen. Building on this discovery, we now describe the initial structure-activity relationship (SAR) of antischistosomal ozonide carboxylic acids OZ418 () and OZ165 (). Irrespective of lipophilicity, these ozonide weak acids have relatively low aqueous solubilities and high protein binding values.

Ligand-based design of GLUT inhibitors as potential antitumor agents.

Glucose transporters (GLUTs) regulate glucose uptake and are often overexpressed in several human tumors. To identify new chemotypes targeting GLUT1, we built a pharmacophore model and searched against a NCI compound database. Sixteen hit molecules with good docking scores were screened for GLUT1 inhibition and antiproliferative activities.

Tricyclic Imidazolidin-4-ones by Witkop Oxidation of Tetrahydro-β-carbolines.

1-Substituted and 1,1-disubstituted tetrahydro-β-carbolines undergo sodium periodate oxidative ring expansion in the presence of formaldehyde and other aldehydes to form 5,6-dihydro-7-1,4-methanobenzo[][1,4]diazonine-2,7(3)-diones in 30-81% yield. In most cases, the reaction to form this new 6/8/5-tricyclic ring system proceeds with high diastereoselectivity. These benzannulated medium-ring keto imidazolidin-4-ones expand the menu of tetrahydro-β-carboline oxidation products.

A new chemotype with promise against Trypanosoma cruzi.

Pyridyl benzamide 2 is a potent inhibitor of Trypanosoma cruzi, but not other protozoan parasites, and had a selectivity-index of ≥10. The initial structure-activity relationship (SAR) indicates that benzamide and sulfonamide functional groups, and N-methylpiperazine and sterically unhindered 3-pyridyl substructures are required for high activity against T. cruzi.

Stochastic Protein Alkylation by Antimalarial Peroxides.

Antimalarial peroxides such as the phytochemical artemisinin or the synthetic ozonides arterolane and artefenomel undergo reductive cleavage of the pharmacophoric peroxide bond by ferrous heme, released by parasite hemoglobin digestion. The generated carbon-centered radicals alkylate heme in an intramolecular reaction and proteins in an intermolecular reaction. Here, we determine the proteinaceous alkylation signatures of artemisinin and synthetic ozonides in using alkyne click chemistry probes to identify target proteins by affinity purification and mass spectrometry-based proteomics.

Ozonide Antimalarials Alkylate Heme in the Malaria Parasite .

The mechanism of action of ozonide antimalarials involves activation by intraparasitic iron and the formation of highly reactive carbon-centered radicals that alkylate malaria parasite proteins. Given free intraparasitic heme is generally thought to be the iron source responsible for ozonide activation and its likely close proximity to the activated drug, we investigated heme as a possible molecular target of the ozonides. Using an extraction method optimized for solubilization of free heme, untargeted LC-MS analysis of ozonide-treated parasites identified several regioisomers of ozonide-alkylated heme, which resulted from covalent modification of the heme porphyrin ring by an ozonide-derived carbon-centered radical.

Conformational Studies of Glucose Transporter 1 (GLUT1) as an Anticancer Drug Target.

Glucose transporter 1 (GLUT1) is a facilitative glucose transporter overexpressed in various types of tumors; thus, it has been considered as an important target for cancer therapy. GLUT1 works through conformational switching from an outward-open (OOP) to an inward-open (IOP) conformation passing through an occluded conformation. It is critical to determine which conformation is preferred by bound ligands because the success of structure-based drug design depends on the appropriate starting conformation of the target protein.

SAR of a new antischistosomal urea carboxylic acid.

Urea carboxylic acids, products of aryl hydantoin hydrolysis, were recently identified as a new antischistosomal chemotype. We now describe a baseline structure-activity relationship (SAR) for this compound series. With one exception, analogs of lead urea carboxylic acid 2 were quite polar with Log D values ranging from -1.

Inhibition of Cytomegalovirus Replication with Extended-Half-Life Synthetic Ozonides.

Artesunate (AS), a semisynthetic artemisinin approved for malaria therapy, inhibits human cytomegalovirus (HCMV) replication , but therapeutic success in humans has been variable. We hypothesized that the short half-life of AS may contribute to the different treatment outcomes. We tested novel synthetic ozonides with longer half-lives against HCMV and mouse cytomegalovirus (MCMV) Screening of the activities of four ozonides against a pp28-luciferase-expressing HCMV Towne recombinant identified OZ418 to have the best selectivity; its effective concentration inhibiting viral growth by 50% (EC) was 9.

Synthesis of 2-Azaadamantan-6-one: A Missing Isomer.

2-Azaadamantan-6-one and its Boc and ethylene ketal derivatives were synthesized from 9-oxo -bicyclo[3.3.1]non-6-ene-3-carboxylic acid.