Application in organic synthesis of Lawesson’s reagent, 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide, provides a possibility to replace an oxygen atom for a sulfur atom in the carbonyl group of ketones, esters, amides, in ether group, and also either to induce a rearrangement of the initial structure of organic compounds with or without inclusion of sulfur atoms or to lead to the formation of various types of organophosphorus compounds. The formed organosulfur compounds exhibit a wide range of biological action.

The analysis of stability of biologically active compounds requires an accurate determination of their structure. We have found that 5-aryl-3-(2-aminoethyl)-1,2,4-oxadiazoles are generally unstable in the presence of acids and bases and are rearranged into the salts of spiropyrazolinium compounds. Hence, there is a significant probability that it is the rearranged products that should be attributed to biological activity and not the primarily screened 5-aryl-3-(2-aminoethyl)-1,2,4-oxadiazoles. A series of the 2-amino-8-oxa-1,5-diazaspiro[4.5]dec-1-en-5-ium (spiropyrazoline) benzoates and chloride was synthesized by Boulton–Katritzky rearrangement of 5-substituted phenyl-3-[2-(morpholin-1-yl)ethyl]-1,2,4-oxadiazoles and characterized using FT-IR and NMR spectroscopy and X-ray diffraction. Spiropyrazolylammonium chloride demonstrates in vitro antitubercular activity on DS (drug-sensitive) and MDR (multidrug-resistant) of MTB (M. tuberculosis) strains (1 and 2 µg/mL, accordingly) equal to the activity of the basic antitubercular drug rifampicin; spiropyrazoline benzoates exhibit an average antitubercular activity of 10–100 μg/mL on MTB strains. Molecular docking studies revealed a series of M. tuberculosis receptors with the energies of ligand–receptor complexes (−35.8–−42.8 kcal/mol) close to the value of intermolecular pairwise interactions of the same cation in the crystal of spiropyrazolylammonium chloride (−35.3 kcal/mol). However, only in complex with transcriptional repressor EthR2, both stereoisomers of the cation realize similar intermolecular interactions.

Methodology was developed to obtain a series of unusual alkoxy- and phenoxyalkyl ethers of secondary and tertiary ethynylpiperidin-4-ols representative examples of which were evaluated for analgesic, anti-bacterial, anti-spasmotic, and anti-allergic activity. Twenty-two new compounds were prepared and identified by elemental and spectra analyses. Etherification of 4-hydroxypiperidin-4-ols was accomplished via Williamson ether-type syntheses in dry DMF. Side reactions of the bromides used appeared to involve complex processes with DMF under a variety of conditions employed which led to modest yields of products. Since all target molecules were oils at room temperature, conversions to β-cyclodextrins were accomplished and served as vehicles for pharmacological screening. Several ethynyl-substituted agents displayed deep analgesic activity in the “tail flick” model although some alkoxy- and phenoxy ethers from secondary alcohols were less effective as analgesics (Table 1). Interestingly, LD50 values for the agents exceeded that of a number of clinical agents including Dimedrole, Klemastine, Lidocaine, No-spa, Tramal, Streptomycin, and Euphilline. Three representative examples of the agents (Table 2) exhibited moderate anti-bacterial action against Escherichia coli, Salmonella chloerae suis, Salmonella typhimurium, and Staphylococcus aureus, but did not exceed that of Streptomycin. The absence of the ethynyl ether group resulted in no anti-bacterial activity in several ethers. A few agents possessed anti-spasmotic ability, especially the ethers of 1-(2-ethoxyethyl)-4-ethynyl-4-hydroxypiperidines in various preparations (Table 3), and included the systems of acetylcholine-induced spasms, the histamine-induced spasms, and the calcium chloride-induced spasms. Two examples void of the ethynyl group were not effective as anti-spasmotic compounds. A small survey of five agents for anti-allergic properties (Table 4) revealed that two with ethynyl groups were similar in activity with Dimedrole but less than that of Klemastine in screens using acetylcholine and histamine systems. Overall, these families of piperidines possess a wide variety of important biological properties which require further exploration