Synthesis and Properties of N-Stituted Amides and Their Isosteric Analogs Containing Polycyclic Fragments: I. N-((1S,2S,3S,5R)-(+)-Isopinocampheyl)amides and thioamides

Abstract

A series of N-((1S,2S,3S,5R)-(+)-isopinocampheyl)aryl amides and the corresponding thioamides bearing H/F/Cl substituents in the aryl fragment was synthesized by the reaction of (1S,2S,3S,5R)-(+)-isopinocampheylamine with aromatic acid chlorides or thioacyl chlorides. The target compounds were isolated in 71-81% yields and characterized by melting points, ¹H/¹³C NMR spectroscopy and elemental analysis. In silico property profiling (SwissADME, SILICOS-IT) indicated low micromolar aqueous solubility (4.3-27.0 µM) that decreases upon aryl halogenation, while Molinspiration LogP values fall in the range 4.03-5.69; replacement of C=O by C=S additionally lowers the predicted solubility for matched analog pairs. PASSOnline screening revealed Prostaglandin E1 antagonist as the most probable activity for all compounds (Pa = 0.763-0.838, Pi = 0.001-0.002), together with high-probability profiles for autoimmune disorders treatment (Pa = 0.630-0.759) and rheumatoid arthritis treatment (Pa = 0.559-0.739), whereas antiobesity potential is predicted for the thioamide subset (Pa = 0.724-0.783). SwissTargetPrediction suggests recurrent interactions with P2X purinoceptor 7, epoxide hydratase, acetylcholinesterase, muscarinic acetylcholine receptor M2 and histamine H2 receptor.