Bicyclic Isoxazoline Derivatives: Synthesis and Evaluation of Biological Activity

Abstract

The application of non-planar scaffolds in drug design allows for the enlargement of the chemical space, and for the construction of molecules that have more effective target–ligand interactions or are less prone to the development of resistance. Among the works of the last decade, a literature search revealed spirothiazamenthane, which has served as a lead in the development of derivatives active against resistant viral strains. In this work, we studied the novel molecular scaffold, which resembles spirothiazamenthane, but combines isoxazoline as a heterocycle and cyclooctane ring as a hydrophobic part of the structure. The synthesis of new 3-nitro- and 3-aminoisoxazolines containing spiro-fused or 1,2-annelated cyclooctane fragments was achieved by employing 1,3-dipolar cycloaddition of 3-nitro-4,5-dihydroisoxazol-4-ol 2-oxide or tetranitromethane-derived alkyl nitronates with non-activated alkenes. A series of spiro-sulfonamides was obtained by the reaction of 3-aminoisoxazoline containing a spiro-fused cyclooctane residue with sulfonyl chlorides. Preliminary screening of the compounds for antiviral, antibacterial, antifungal and antiproliferative properties in vitro revealed 1-oxa-2-azaspiro[4.7]dodec-2-en-3-amine and 3a,4,5,6,7,8,9,9a-octahydrocycloocta[d]isoxazol-3-amine with activity against the influenza A/Puerto Rico/8/34 (H1N1) virus in the submicromolar range, and high values of selectivity index. Further study of the mechanism of the antiviral action of these compounds, and the synthesis of their analogues, is likely to identify new agents against resistant viral strains.

Nitrile Oxide, Alkenes, Dipolar Cycloaddition, Isomerization and Metathesis Involved in the Syntheses of 2-Isoxazolines

“…3,5,5-trisubstituted isoxazolines possessing a NO 2 group in position 3 cannot be obtained via 1,3-DP cycloaddition, but recently, an effective method dedicated to the preparation of such isoxazolines was presented by Sedenakova and coworkers in their article from 2022— Scheme 278 [ 309 ].…”

“… Syntheses of 3,5,5-trisubstituted isoxazolines possessing nitro group in position 3 (an example) [ 309 ]. a = DCE, 55 °C, 24 h, then NaHCO 3 , benzene/H 2 O, 25 °C, 0.5 h; 62% yield.…”

Green synthesis, characterization, and biochemical impacts of new bioactive isoxazoline‐sulfonamides as potential insecticidal agents against the Sphodroxia maroccana Ley

“…While optimizing the reaction conditions, the 1,3‐dipolar cycloaddition (1,3‐DC) and ring‐opening reactions of the saccharin system were developed to obtain novel isoxazoline‐sulfonamide compounds. Compared with previous strategies to obtain isoxazoline sulfonamides, this important method shows higher feasibility and milder reaction conditions 47–49 . In particular, the high structural adaptability of the reaction products allowed us to systematically diversify biologically active 3,5‐disubstituted isoxazoline sulfonamides, making them ideal tools for the development of highly insecticidal molecules.…”

“…Compared with previous strategies to obtain isoxazoline sulfonamides, this important method shows higher feasibility and milder reaction conditions. [47][48][49] In particular, the high structural adaptability of the reaction products allowed us to systematically diversify biologically active 3,5-disubstituted isoxazoline sulfonamides, making them ideal tools for the development of highly insecticidal molecules. Considering structural aspects of isoxazoline insecticides, our strategy in this work will be the preparation of the isoxazoline disubstituted at the C-3 carbon atom with an aromatic ring group; and at position C5 with secondary and tertiary sulfonamide.…”

Bis(oxiranes) Containing Cyclooctane Core: Synthesis and Reactivity towards NaN3

“…Cyclooctane, alongside other medium rings, is characterized by an optimal balance of conformational rigidity and flexibility and is of interest as a novel molecular platform for the design of target-oriented leads [ 15 , 16 , 17 , 18 ]. On the other hand, the synthetic application of ring-closure reactions to medium rings is often limited because of the entropy factor disfavoring ring closure.…”