Drug Discovery Chemistry Advances: New Syntheses, Screening, and Analytical Methods
Researchers report advances in drug discovery chemistry, including a stereoselective THF synthesis, an SF6-based phosphonylation method, a large androgen receptor binding screen, and improved oligonucleotide chromatography.
New research in drug discovery chemistry spans synthetic methodology, safety screening, and analytical separations. Researchers have reported a stereoselective one-pot route to tetrasubstituted tetrahydrofuran rings, a photoinduced phosphonylation of amino acids that consumes the greenhouse gas sulfur hexafluoride, and a large-scale screening campaign that identified 4,183 androgen receptor binders among over 72,000 agrochemical compounds. Additional work examined visible-light dearomatization, a total breakthrough strategy for oligonucleotide chromatography, and an HFIP-promoted coupling of azabicyclo[1.1.0]butanes.
An unexpected cyclisation offers a generalised route to heavily substituted tetrahydrofuran (THF) units. The stereoselective reaction combines simple building blocks to construct the densely functionalised ring in a one-pot sequence and is well-suited to applications in drug discovery and high-throughput synthesis. The discovery was made accidentally when a trace silyl reagent remaining in a reaction mixture rapidly cyclised a reactive allylic alcohol intermediate to form a di-substituted THF as the major product. By tweaking the conditions, the team generated three different tri- and tetra-substituted structures, incorporating one or two distinct aldehyde units and an additional alkene, with complete stereocontrol. The sequence tolerated a wide variety of functional groups and a high level of structural complexity, including aldehydes derived from drugs or natural products. In a high-throughput screen, the team generated a library of 73 different polysubstituted THFs from a panel of 12 electrophiles. As a proof-of-concept, they completed a formal synthesis of the antifungal agent monocerin, generating the key intermediate in a single step with excellent stereocontrol.
α-Aminophosphonates are crucial molecular scaffolds in drug development due to their diverse biological activities. A new photoinduced strategy enables the site-selective phosphonylation of amino acids and peptide derivatives to synthesize α-aminophosphonates. The method utilizes sulfur hexafluoride (SF6) as an electron acceptor and achieves its degradation during the reaction, enabling the effective utilization of the greenhouse gas SF6.
A review of visible-light-enabled excited-state dearomatization reactions notes that modern drug discovery places growing emphasis on designing three-dimensional molecular frameworks with high sp3-carbon content. The review covers dearomatization reactions via direct excitation, energy transfer, and exciplex formation.
In a large-scale high-throughput screening campaign, researchers assessed androgen receptor (AR) binding for over 72,000 compounds from an agrochemical library using a fluorescence polarization displacement assay. Confirmatory dose–response testing identified 4,183 AR binders (5.7% hit rate) with substantial structural diversity and numerous novel scaffolds. The team curated an unrestricted data set of 24,953 compounds with associated activity data, which was published with the paper. Machine learning models trained on this data set, with gradient-boosted trees achieving a balanced accuracy of 0.77 and a negative predictive value of 0.98. External validation on existing publicly available AR data sets (CoMPARA and PubChem) demonstrated balanced accuracies of 0.66 and 0.72.
For oligonucleotide analysis, a total breakthrough strategy in hydrophilic interaction chromatography (HILIC) was investigated to eliminate solvent mismatch effects in two-dimensional liquid chromatography (2D-LC). Oligonucleotides exhibit total breakthrough behavior in HILIC under appropriate conditions, which allows large injection volumes into the second dimension without peak distortion. The IP-RPLC × HILIC configuration offers improved mass spectrometry compatibility compared to IP-RPLC or HILIC × IP-RPLC. The work provides guidance for implementing successful IP-RPLC × HILIC conditions for oligonucleotide analysis.
Another study reports the activation of oxetanyl, azetidinyl, and thietanyl trichloroacetimidates with 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), which rapidly couple with azabicyclo[1.1.0]butanes (ABB). The protocol is operationally simple and enables access to a library of medicinally relevant 3,3-functionalized oxetanes, azetidines, and thietanes with N1/C3-functionalized ABB. The strategy was demonstrated with more than 50 examples, including gram-scale synthesis.