Synthesis, Inhibitory Activity, and In Silico Modeling of Selective COX-1 Inhibitors with a Quinazoline Core

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Computational Chemistry

Background:

• Cyclooxygenase-1 (COX-1) is increasingly recognized for its role in cancer progression and cardiovascular health.
• Selective COX-1 inhibitors are under-explored despite their therapeutic potential.
• Understanding COX-1's role in thrombocyte aggregation and cancer necessitates novel inhibitory agents.

Purpose of the Study:

• To synthesize and evaluate novel quinazoline derivatives for selective inhibition of COX-1 and COX-2.
• To identify compounds with high COX-1 selectivity and potent inhibitory activity.
• To elucidate the structural basis of COX-1 selectivity using computational methods.

Main Methods:

• Synthesis of three series of quinazoline derivatives.
• In vitro enzyme inhibition assays against COX-1 and COX-2.
• In silico molecular modeling to understand structure-activity relationships.

Main Results:

• Eleven quinazoline derivatives demonstrated significant COX-1 selectivity.
• Eight compounds exhibited complete selectivity for COX-1 over COX-2.
• The most potent compound achieved an IC50 value of 64 nM against COX-1.
• In silico modeling provided insights into structural features driving COX-1 selectivity.

Conclusions:

• Novel quinazoline derivatives possess promising COX-1 selective inhibitory activity.
• These compounds represent potential leads for developing therapeutics targeting COX-1 related conditions.
• Further research is warranted to explore their therapeutic applications and safety profiles.