Buprofen, and celecoxib as reference drugs (Table 1). The efficacies of our compounds was evaluated by estimating the half-maximal inhibitory concentration (IC50) along with the selectivity index (SI) values calculated as IC50 (COX-1)/IC50 (COX-2). The incorporation of a bioactive anti-inflammatory moiety (either indomethacin-like (compounds 4a,c) or ibuprofen (compounds 7a-e) to position three with the Trk Receptor site quinazolinone scaffold, as wellTable 1. In vitro COX-1/COX-2 inhibition assay Compound Code Celecoxib Indomethacin Ibuprofen 4a 4b 4c 7a 7b 7c 7d 7e 13a 13b 14a 14b 14c 14da bCOX-1 mM IC50 14.75 0.15 0.09 0.13 four.13 0.08 12.68 0.11 six.93 0.15 11.21 0.13 12.76 0.ten 13.35 0.10 14.73 0.13 14.37 0.16 11.85 0.15 10.19 0.14 16.92 0.16 ten.86 0.20 12.98 0.12 15.44 0.17 12.56 0.aCOX-2 mM IC50 0.04 0.20 0.71 0.15 1.67 0.25 0.04 0.08 0.07 0.22 0.03 0.33 0.05 0.13 0.04 0.13 0.037 0.20 0.04 0.25 0.04 0.23 0.04 0.18 0.045 0.18 0.03 0.17 0.04 0.29 0.04 0.33 0.04 0.abSelectivity Index (SI) 368.78 0.13 2.47 317.00 99.00 373.67 255.02 333.75 398.11 359.25 296.25 254.75 373.77 362.00 324.5 359.74 314.IC50 in (mM) concentration as expressed as imply SEM, for three replications. Selectivity indexCOX-1 IC50/COX-2 IC50).because the incorporation of a thioacetohydrazide linker at position 2 on the quinazolinone moiety (compounds 13a,b and 14a-d), not simply succeeded in producing our new compounds exhibit superior potency and selectivity towards COX-2 (SI 25498) more than previously reported quinazolinones (I)13 (SI38.639.67), but additionally showed practically precisely the same COX-1 and COX-2 inhibitory activities (COX-1 IC50, 10.19 16.92 and COX-2 IC500.03.05 mM) as that of celecoxib. Excitingly, the SI values of your new compounds are comparable to that of celecoxib (SI 368.75) with the exception of compound 4 b which has relatively reduce COX-2 selectivity (SI99, COX-1 IC50 six.93 mM, COX-2 IC50 .07 mM). For Scheme 1: compounds (4a,c) of indole bioactive molecule showed SI values (SI 37317) which might be several-fold higher than that of indomethacin (SI 0.13) and nearly exactly the same as that of celecoxib. The distinction within the para substituent of the phenyl ring PI3Kδ site attached to position 2 of your quinazolinone in this series brought on a dramatic modify in COX-1 inhibitory activity, as the para nitro derivative (four b) showed a drastically higher potency (2-JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRYfold) towards COX-1 than compounds (4a,c) carrying para Cl or OCH3, respectively. The latter modification resulted within a lower in four b selectivity index (SI 99.00) that is superior to that of indomethacin. For Scheme two: series (7a-e) of ibuprofen bioactive molecule showed SI (SI 25598) of roughly 150-fold higher than that of ibuprofen (SI two.47) and practically the exact same as that of celecoxib. Conversely for the indole series (4a-c), no important alter in COXs inhibitory activity was observed upon alternating the para substituent with the phenyl ring attached to position 2 of the quinazolinone. Importantly, the para nitro derivative (7c) showed slight improvement in SI value (SI 398.11) when compared with that of celecoxib (SI 368.75). For Scheme 3: Thioacetohydrazide containing series (13a,b4a-d), all compounds showed SI values (SI 25473) that are practically equal or slightly higher than that of celecoxib. Introducing a degree of flexibility in between the quinazolinone scaffold plus the aryl moiety at position three led to an improvement inside the SI. Compounds with phenyl acetamide moiety (X CH2) (13 b and 14c,d) showed far better SI values compa.