ABSTRACT
The identification of an alternative chemical space in order to address the global challenge posed by emerging antimicrobial resistance is very much needed for the discovery of novel antimicrobial lead compounds. Boron clusters are currently being explored in drug discovery due to their unique steric and electronic properties. However, the challenges associated with the synthesis and derivatization techniques of these compounds have limited their utility in the rapid construction of a library of molecules for screening against various biological targets as an alternative molecular platform. Herein, we report a transition-metal-catalyzed regioselective direct B-H alkylation-annulation of the closo-dodecaborate anion with natural products such as menthol and camphor as the directing groups. This method allowed the rapid construction of a library of 1,2,3-trisubstituted clusters, which were evaluated in terms of their antibacterial activity against WHO priority pathogens. Several of the synthesized dodecaborate derivatives displayed medium- to high-level bactericidal activity against Gram-positive and Gram-negative bacteria.
ABSTRACT
Muscarinic acetylcholine receptors (mAChRs) are important therapeutic targets for several diseases of the central nervous system and periphery. However, the lack of subtype-selective ligands for these receptors is a major challenge. A novel approach involving the integration of a natural product framework with a bioactive molecule (iNPBM) by using gephyrotoxin and the isoindoline framework is demonstrated for the discovery of new and selective mAChR modulators. We established a scalable and versatile synthetic scheme to enable the synthesis of various analogues that provided the first structure-activity relationship study of this class of compounds. Pharmacological profiling of these compounds demonstrated several ligands with high affinity and selectivity for mAChRs. Specifically, RG-06 and RG-09 were found to be antagonists of M3-mAChR, whereas RG-02 was found to be an agonist at M2-mAChR. Furthermore, RG-02 exhibited salutary effects in an established pharmacological model of a cognitive deficit in mice.
Subject(s)
Biological Products/metabolism , Receptors, Muscarinic/metabolism , Alkaloids/chemistry , Alkaloids/metabolism , Alkaloids/pharmacology , Animals , Biological Products/chemistry , Biological Products/pharmacology , Catalysis , Drug Evaluation, Preclinical , HEK293 Cells , Humans , Isoindoles/chemistry , Isoindoles/metabolism , Isoindoles/pharmacology , Locomotion/drug effects , Male , Maze Learning/drug effects , Metals/chemistry , Mice , Mice, Inbred C57BL , Molecular Conformation , Protein Isoforms/chemistry , Protein Isoforms/metabolism , Receptors, Muscarinic/chemistry , Structure-Activity RelationshipABSTRACT
An efficient and scalable synthesis of various enantiopure 1,3- disubstituted isoindolines is reported. The base catalyzed nucleophilic fragmentation of a rigid overbred template is established with various substrates to afford the corresponding 1,3-disubstituted isoindoline ester, amide, thioate, 1,3-amino alcohol and isoindolylcarboxylic acid. The crucial rigid overbred template is synthesized in an optically pure form in multigram scale by asymmetric desymmetrization of the corresponding meso compound.
