ortho-Halogen naphthaleins as specific inhibitors of Lactobacillus casei thymidylate synthase. Conformational properties and biological activity

摘要: Abstract Thymidylate synthase (TS) (EC 2.1.1.45), an enzyme involved in the DNA synthesis of both prokaryotic and eukaryotic cells, is a potential target for development anticancer antinfective agents. Recently, we described series phthalein naphthalein derivatives as TS inhibitors. These compounds have structures unrelated to folate (Non-Analogue Antifolate Inhibitors, NAAIs) were selective bacterial versus human (hTS). In particular, halogen-substituted molecules most interesting. present paper halogen variously substituted 3,3-bis(4-hydroxyphenyl)-1H,3H-naphtho[2,3- c ]furan-1-one ( 1 – 5 ) 3,3-bis(4-hydroxyphenyl)-1H,3H-naphtho[1,8-c,d]pyran-1-one 6 14 synthesized investigate biological effect substitution on inhibition selectivity enzymes. Conformational properties explored order highlight possible differences between that show species-specific profile with respect non ones. With this aim, conformational investigated by NMR, various solvents at different temperatures, computational analysis. The apparent constants K i Lactobacillus casei (LcTS) found range from 0.7 7.0 μM, exception weakly active iodo-derivatives 4 , 10 13 ); all] poorly against hTS. di-halogenated 7 8 showed highest specificity towards LcTS, their index (SI) ranging 40 >558. 1,8-naphthalein exhibited tetra-haloderivatives. Though clear explanation observed means analysis difficult find, some interesting effects are discussed context recognition LcTS enzyme.