Drug Discovery Advances: Deep-Sea Natural Products, Alkylamine Functionalization, and Indoline Synthesis

Recent studies report advances in drug discovery chemistry. One global analysis of Marine Natural Products (MNPs) from deep-sea organisms reveals chronic undersampling of the deep ocean as a reservoir of new and diverse chemical structures and bioactivity. Another study describes a method for the γ-selective functionalization of tertiary alkylamines, which are present in a large share of pharmaceuticals. A third study develops a practical protocol for dearomative annulation of indoles with 2-aminoaryl disulfides.

Alkylamines are present in ~43% (primary 2%, secondary 15%, tertiary 26%) of small-molecule agrochemicals and pharmaceuticals, and remote C–H functionalization of alkylamines is a powerful strategy for accelerating drug development. Remote C–H functionalization enables selective modification of the periphery of the active nitrogen site and can improve bioactivity and pharmacokinetics. Remote functionalization of tertiary amines has remained challenging, despite their prevalence in 60% of alkylamine-containing pharmaceuticals. The new study exploits the reactivity of α-ammonio radicals, a class of distonic radical cations, to achieve γ-selective functionalization of tertiary amines, using halomethylammonium salts as α-ammonio radical precursors. The resulting γ-radicals enable diverse γ-selective C–H functionalizations, including thioetherification, amination, alkylation, (hetero)arylation and alkenylation. The method has a broad substrate scope and enables the late-stage functionalization of complex pharmaceutical molecules.

The deep-sea analysis compiled 2909 compounds and extracts from published records and found a sampling bias towards benthic and shallower deep-sea habitats, with relatively few records from areas beyond national jurisdictions and a concentration of records along seamounts and hydrothermal vents. The phylogenetic distribution of deep-sea MNPs is dominated by non-metazoan sources (76% of records) and Ascomycota fungi in particular (55%). Polyketides are the most prevalent metabolites in deep-sea MNPs, and cytotoxic and antibacterial properties are the most commonly reported bioactivities. The deep sea constitutes 90% of the global area of the ocean and likely hosts at least 50% of the estimated ~2.2 million marine species; ~43,000 Marine Natural Products have been reported in the last 50 years. The analysis highlights a need for systematic sampling and consistent data reporting to explore potential relationships between bioactivity, new chemical structures, phylogeny and deep-sea environmental conditions.

The dearomative annulation protocol accesses three-dimensional (3D) indoline frameworks under mild conditions and shows remarkable tolerance toward different functional groups. It was applied for the late-stage modification of drugs and natural products. Mechanistic studies reveal that the reaction proceeds via activation of aryl disulfide by NFSI, generating an electrophilic sulfur as a key intermediate.