Electron Donor-Acceptor Complex-Assisted Photochemical Conversion of O-2-Nitrobenzyl Protected Hydroxamates to Amides.

The hydroxamic acid functionality is present in various medicinal agents and has attracted special interest for synthetic transformations in both organic and medicinal chemistry. The N-O bond cleavage of hydroxamic acid derivatives provides an interesting transformation for the generation of various products. We demonstrate, herein, that O-benzyl-type protected hydroxamic acids may undergo photochemical N-O bond cleavage, in the presence or absence of a catalyst, leading to amides. Although some O-benzyl protected aromatic hydroxamates may be photochemically converted to amides in the presence of a base and anthracene as the catalyst, employing O-2-nitrobenzyl group allowed the smooth conversion of both aliphatic and aromatic hydroxamates to primary or secondary amides in good to excellent yields in the presence of an amine, bypassing the need of a catalyst. DFT and UV-Vis studies supported the effective generation of an electron donor-acceptor (EDA) complex between O-2-nitrobenzyl hydroxamates and amines, which enabled the successful product formation under these photochemical conditions. An extensive substrate scope was demonstrated, showcasing that both aliphatic or aromatic hydroxamates are compatible with this protocol, affording a wide variety of primary and secondary amides.

N-Acylated and N-Alkylated 2-Aminobenzothiazoles Are Novel Agents That Suppress the Generation of Prostaglandin E2.

The quest for novel agents to regulate the generation of prostaglandin E2 (PGE2) is of high importance because this eicosanoid is a key player in inflammatory diseases. We synthesized a series of N-acylated and N-alkylated 2-aminobenzothiazoles and related heterocycles (benzoxazoles and benzimidazoles) and evaluated their ability to suppress the cytokine-stimulated generation of PGE2 in rat mesangial cells. 2-Aminobenzothiazoles, either acylated by the 3-(naphthalen-2-yl)propanoyl moiety (GK510) or N-alkylated by a chain carrying a naphthalene (GK543) or a phenyl moiety (GK562) at a distance of three carbon atoms, stand out in inhibiting PGE2 generation, with EC50 values ranging from 118 nM to 177 nM. Both GK510 and GK543 exhibit in vivo anti-inflammatory activity greater than that of indomethacin. Thus, N-acylated or N-alkylated 2-aminobenzothiazoles are novel leads for the regulation of PGE2 formation.

The design and discovery of phospholipase A2 inhibitors for the treatment of inflammatory diseases.

AREAS COVERED: This review article summarizes the most important synthetic PLA2 inhibitors developed to target each one of the four major types of human PLA2 (cytosolic cPLA2, calcium-independent iPLA2, secreted sPLA2, and lipoprotein-associated Lp-PLA2), discussing their in vitro and in vivo activities as well as their recent applications and therapeutic properties. Recent findings on the role of PLA2 in the pathobiology of COVID-19 are also discussed. EXPERT OPINION: Although a number of PLA2 inhibitors have entered clinical trials, none has reached the market yet. Lipoprotein-associated PLA2 is now considered a biomarker of vascular inflammation rather than a therapeutic target for inhibitors like darapladib. Inhibitors of cytosolic PLA2 may find topical applications for diseases like atopic dermatitis and psoriasis. Inhibitors of secreted PLA2, varespladib and varespladib methyl, are under investigation for repositioning in snakebite envenoming. A deeper understanding of PLA2 enzymes is needed for the development of novel selective inhibitors. Lipidomic technologies combined with medicinal chemistry approaches may be useful tools toward this goal.