Refinement of imidazo[2,1-a]pyrimidines in pursuit of potential drug candidates against group 2 influenza A viruses.

We discovered a series of imidazo[1,2-a]pyrimidines as potent, group 2 selective inhibitors of influenza A viruses (IAVs) that target the hemagglutinin-mediated viral entry process. Preliminary hit-to-lead optimization efforts afforded promising IAV inhibitors with improved activity against infectious H7N7 and H3N2 viruses. We now report a more comprehensive cycle of structure-activity relationship studies and optimization of metabolic stability, and overall druglike properties of this series of imidazo[1,2-a]pyrimidines, which allowed in the identification of two lead compounds that show promise as preclinical candidates.

Recombinant Pichinde reporter virus as a safe and suitable surrogate for high-throughput antiviral screening against highly pathogenic arenaviruses.

Several arenaviruses, such as the Old World (OW) Lassa virus (LASV) and the New World (NW) Junin virus (JUNV), can cause severe and lethal viral hemorrhagic fevers in humans. Currently, no vaccines or specific antiviral therapies are FDA-approved for treating arenavirus infections. One major challenge for the development of new therapeutic candidates against these highly pathogenic viruses is that they are BSL-3/4 pathogens that need to be handled in high biocontainment laboratories.

Guardians at the Gate: Optimization of Small Molecule Entry Inhibitors of Ebola and Marburg Viruses.

Ebola and Marburg (EBOV and MARV) filoviral infections lead to fatal hemorrhagic fevers and have caused over 30 outbreaks in the last 50 years. Currently, there are no FDA-approved small molecule therapeutics for effectively treating filoviral diseases. To address this unmet medical need, we have conducted a systematic structural optimization of an early lead compound, -(4-(4-methylpiperidin-1-yl)-3-(trifluoromethyl)phenyl)-4-(morpholinomethyl)benzamide (), borne from our previously reported hit-to-lead effort.

Synthesis of α3β4 Nicotinic Acetylcholine Receptor Modulators Derived from Aristoquinoline That Reduce Reinstatement of Cocaine-Seeking Behavior.

Growing evidence suggests that inhibition of the α3β4 nicotinic acetylcholine receptor (nAChR) represents a promising therapeutic strategy to treat cocaine use disorder. Recently, aristoquinoline (), an alkaloid from , was identified as an α3β4-selective nAChR inhibitor. Here, we prepared 22 derivatives of and evaluated their ability to inhibit the α3β4 nAChR.

Isolation and Pharmacological Characterization of Six Opioidergic Alkaloids.

The seeds of the akuamma tree () have been used as a traditional treatment for pain and fever. Previous studies have attributed these effects to a series of indole alkaloids found within the seed extracts; however, these pharmacological studies were significantly limited in scope. Herein, an isolation protocol employing pH-zone-refining countercurrent chromatography was developed to provide six of the akuamma alkaloids in high purity and quantities sufficient for more extensive biological evaluation.

Multi-modal antidepressant-like action of 6- and 7-chloro-2-aminodihydroquinazolines in the mouse tail suspension test.

Rationale: 2-Amino-6-chloro-3,4-dihydroquinazoline (e.g., A6CDQ) represents a novel putative antidepressant originally thought to act through a 5-HT serotonin receptor antagonist mechanism.

Allosteric inhibition of human factor XIa: discovery of monosulfated benzofurans as a class of promising inhibitors.

Factor XIa (fXIa) is being recognized as a prime target for developing safer anticoagulants. To discover synthetic, small, allosteric inhibitors of fXIa, we screened an in-house, unique library of 65 molecules displaying many distinct scaffolds and varying levels of sulfation. Of these, monosulfated benzofurans were the only group of molecules found to inhibit fXIa (∼100% efficacy) and led to the identification of monosulfated trimer 24 (IC50 0.