Synthesis, crystal structure and molecular docking study of novel isoxazole derivatives as CYP450 inhibitors in search of anticancer agents

Abstract

Synthesis of some novel isoxazole derivatives and their molecular docking with enzymes from CYP450 family carried out using erlotinib, gemcitabine and ketoconazole as reference drugs are reported in this work. Eight isoxazole derivatives of 3,4-substituted phenyl 3-chloroacrylaldehyde and one isoxazole derivative of cinnamaldehyde were synthesized. A molecular docking study of all nine compounds shows good docking score compared to standard drugs erlotinib, gemcitabine and ketoconazole. 4-OH and 4-F derivatives were found to have strong affinity for all six CYP450 proteins under study in the present work. 4-F and 3-NO₂ derivatives could be a suitable lead compound inhibitor to CYP1A2 followed by 4-OH derivatives. 4-OH derivative with significant binding affinity showed encouraging inhibition of CYP1A2, CYP2C9, CYP2C8, CYP2C19 and CYP2D6. The current predictions over these nine isoxazole derivatives of 3,4-substituted phenyl 3-chloroacrylaldehyde will be needed to be further investigated in vivo and in vitro conditions to identify the optimum therapeutic efficacy. Synthesis of the isoxazole derivatives is the first known report of the Knoevenagal condensation of acrylaldehyde derivatives to form isoxazole derivatives as per the literature survey. A detailed crystal structure study of five analogues gives insight into the solid-state structural features of this new framework with isoxazole moieties.

Communicated by Ramaswamy H. Sarma

Keywords:

• Isoxazole
• crystal structure
• molecular docking
• EGFR inhibitor
• anticancer agents

Acknowledgements

We thank the EN-FIST Centre of Excellence, Ljubljana, Slovenia, for using SuperNova diffractometer.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The authors are thankful for the financial support received from Gondwana University, Gadchiroli, under the minor research project scheme ‘SANSHODHAN’. Financial support for the spectral study of the compounds from the Slovenian Research Agency (ARRS) through project P1-0175 is gratefully acknowledged.