Design of COX-1 Inhibitors Utilizing Class I Isosteres, Class II Isosteres, and Nonclassical Bioisosteres for Substituent Substitution on Proved Parent Structures

Aims: To identify isosteres and bioisosteres suitable for substitution on the molecular scaffold of meclofenamic acid and tolfenamic acid. The compounds will be studied to determine drug-likeness and other properties.

Study Design: Isosteres and bioisosteres were selected and emplaced on the scaffold of meclofenamic acid and tolfenamic acid to ascertain drug-likeness outcome. Drug candidates were selected based on favorable drug-likeness.

Place and Duration of Study: Chemistry Department, University of Nebraska at Omaha, Omaha Nebraska from March 2015 to May 2015.

Methodology: Two non-steroidal anti-inflammatory drugs, meclofenamic acid and tolfenamic acid, are selected based on versatile isosteres and bioisosteres substitution. Placement of class I isosteres, class II isosteres, and nonclassical bioisosteres was accomplished using molecular modeling software. Physicochemical properties were determined and compared by numerical analysis and by pattern recognition. This approach is evaluated for success in generating drug-like compounds.

Results: Utilizing meclofenamic acid as parent compound, a total of 13 class I isosteres, five class II isosteres, and four non-classical bioisosteres were identified. For this group the Log P and polar surface area values ranged from 2.534 to 6.268 and 49.326 Angstroms2 to 101.372 Angstroms2, respectively. Utilizing tolfenamic acid as parent compound, a total of ten class I isosteres, five class II isosteres, and four non-classical bioisosteres were identified. For this group the range of Log P and polar surface area values were 1.904 to 5.408, and 37.299 Angstroms2 to 75.349 Angstroms2, respectively. Multiple regression analysis of properties produced equations useful for prediction of similar drugs for both groups.

Conclusion: Variations of physicochemical properties by isosteres (class I and class II) and bioisosteres, successfully produced 22 of meclofenamic acid based drug designs and 19 of tolfenamic acid based drug designs. All compounds were evaluated for drug-likeness and similarities by cluster analysis. New drug designs are needed for COX-1 inhibition.