Direct Access to Quinone-Fused 5-Substituted-1,4-Benzodiazepine Scaffolds from Azidoquinones with/without [1,2]-Azide-Nitrogen Migration: Mechanistic Insights.

Seven-membered nitrogen heterocycles have a strong influence in drug discovery due to their inherent 3D character, which allows the ability to explore a vast conformational space with a biological target. Notably, the privileged 1,4-benzodiazepine scaffold is dominant in treating the central nervous system due to its binding affinity with the GABAA receptor. Herein, we report a protocol for the transformation of azidoquinones to p-quinone fused 5-substituted-1,4-benzodiazepines (p-QBZDs) from InCl3-catalyzed intermolecular tandem cycloannulation of azidoquinones with amines and aldehydes. Detailed mechanistic studies reveal that the EDA complex between azidoquinones and InCl3 is crucial in determining the reaction pathway. In the absence of EDA complex formation, the reaction proceeds via the intermediacy of 2,3-bridged-2H-azirine followed by regiospecific addition of an amine to C═N/ring opening/cyclization to deliver p-QBZD with 1,2-azide-nitrogen migration. In the case of EDA complex formation, the reaction proceeds through regioselective aza-Michael addition/nitrene insertion with aldehyde and subsequent cyclization to deliver p-QBZD and p-quinone fused imidazole as a secondary product without 1,2-azide-nitrogen migration. This protocol provides straightforward access to redox-active quinone embedded 5-substituted-1,4-benzodiazepines from azidoquinones with diverse substrate scopes that would find potential applications in medicinal chemistry and drug discovery.

Exploring imidazo[4,5-g]quinoline-4,9-dione derivatives as Acinetobacter baumannii efflux pump inhibitor: an in silico approach.

Antimicrobial resistance (AMR) is fast becoming a medical crisis affecting the entire global population. World Health Organization (WHO) statistics show that globally 0.7 million people are dying yearly due to the emergence of AMR. By 2050, the expected number of lives lost will be 10 million per year. Acinetobacter baumannii is a dreadful nosocomial pathogen that has developed multidrug resistance (MDR) to several currently prescribed antibiotics worldwide. Overexpression of drug efflux transporters (DETs) is one of the mechanisms of multidrug resistance (MDR) in Acinetobacter baumannii. Therefore, blocking the DET can raise the efficacy of the existing antibiotics by increasing their residence time inside the bacteria. In silico screening of five synthetic compounds against three drug efflux pump from A. baumannii has identified KSA5, a novel imidazo[4,5-g]quinoline-4,9-dione derivative, to block the efflux of antibiotics. Molecular docking and simulation results showed that KSA5 could bind to adeB, adeG, and adeJ by consistently interacting with ligand-binding site residues. KSA5 has a higher binding free energy and a lower HOMO-LUMO energy gap than PAßN, suggesting a better ability to interact and inhibit DETs. Further analysis showed that KSA5 is a drug-like molecule with optimal physicochemical and ADME properties. Hence, KSA5 could be combined with antibiotics to overcome antimicrobial resistance.Communicated by Ramaswamy H. Sarma.

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 (2) and OZ165 (3). Irrespective of lipophilicity, these ozonide weak acids have relatively low aqueous solubilities and high protein binding values. Ozonides with para-substituted carboxymethoxy and N-benzylglycine substituents had high antischistosomal efficacies. It was possible to increase solubility, decrease protein binding, and maintain the high antischistosomal activity in mice infected with juvenile and adult Schistosoma mansoni by incorporating a weak base functional group in these compounds. In some cases, adding polar functional groups and heteroatoms to the spiroadamantane substructure increased the solubility and metabolic stability, but in all cases decreased the antischistosomal activity.

Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439).

Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often associated with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity.