Synthesis, X-ray diffraction and theoretical studies to understand the molecular basis of druglikeness of isoxazole analogs

Here, we report the synthesis, X-ray crystallography, DFT calculation, and ADME prediction of some new isoxazole-based flexible analogs. The key acetimidamide intermediates (1) were synthesized exclusively in Zconfiguration due to strong N-H...O intramolecular H-bonding. The isoxazole-based flexible analogs (2) were obtained by cyclization of the acetimidamide by trifluoroacetic anhydride. Single crystal X-ray diffraction analysis of 1d-e and 2d-e shows a network of weak forces for crystal packing. More pi-interactions were observed in 2d-e, while significantly high number of intra and inter-H-bonds were observed in 1d-e. Hirshfeld surface analysis and 2D fingerprint plots revealed the involvement of N-H and O-H for strong intermolecular interaction in 1, whereas C-F contributed in 2. The HOMO-LUMO calculation demonstrated the high stability and less reactivity of 2. These studies indicate that the flexible analogs (2) have promising drug-likeness with notably low metabolite possibilities compared to acetimidamide (1) and open a scope to test for biological evaluation and drug development.

Automated summary

This article reports the synthesis, X-ray crystallography, DFT calculation, and ADME prediction of new isoxazole-based flexible analogs. The key acetimidamide intermediates (1) were exclusively synthesized in Z-configuration due to strong N-H...O intramolecular H-bonding. The isoxazole-based flexible analogs (2) were obtained by cyclization of the acetimidamide using trifluoroacetic anhydride. Single crystal X-ray diffraction analysis showed weak forces for crystal packing in 1d-e and 2d-e. More π-interactions were observed in 2d-e, while 1d-e had a higher number of intra and intermolecular H-bonds. HOMO-LUMO calculation demonstrated the high stability and less reactivity of 2. These studies indicate that the flexible analogs (2) show promising drug-likeness and have lower metabolite possibilities compared to acetimidamide (1), providing potential for biological evaluation and drug development.