Evaluation of new thiadiazoles and benzothiazoles as potential radioprotectors: free radical scavenging activity in vitro and theoretical studies (QSAR, DFT).
Thiol and aminothiol compounds are among the most efficient chemical radioprotectors. To increase their efficiency, we synthesized two new classes of thiol and aminothiol compounds derived from benzothiazole (T1, T2, AM1, AM2) and thiadiazole (T3, T4, AM3) structures. We examined them for their ability to scavenge free radicals (DPPH*, ABTS(*+), *OH). Thiol derivatives with a thiadiazole structure are the most active compounds scavenging DPPH* and ABTS(*+) free radicals, with an IC(50) of 0.053+/-0.006 and 0.023+/-0.002 mM, respectively, for the derivative T3. Moreover, compounds T1, T2, and T3 at 60 microM gave 83% protection against 2-deoxyribose degradation by *OH. The ability of these compounds to protect DNA against *OH produced by a Fenton reaction and gamma-irradiation (15 Gy)-induced strand breaks was also evaluated on pBR322 plasmid DNA. In both tests thiol derivatives were the most efficient compounds. Derivatives T2 and T3 totally inhibit DNA strand breaks at the concentration of 50 microM. The protection afforded by these derivatives was comparatively higher than that of the radioprotectors WR-2721 and WR-1065. Our data indicate that these two compounds are free radical scavengers and potential antioxidant agents. Finally, DFT and QSAR studies were performed to support the experimental observations.
Université de Toulouse, UPS, LHFA, Toulouse Cedex 9, France.
Caroline
C
Prouillac
Patricia
P
Vicendo
Jean-Christophe
JC
Garrigues
Romuald
R
Poteau
Ghassoub
G
Rima
D004999:Amifostine; D001419:Bacteria / Q000235:genetics; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D001713:Biphenyl Compounds; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004269:DNA, Bacterial / Q000032:analysis* / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000494:pharmacology*; D017665:Hydroxyl Radical; D008624:Mercaptoethylamines; D008962:Models, Theoretical; D016571:Neural Networks, Computer; D018384:Oxidative Stress; D010851:Picrates; D021281:Quantitative Structure-Activity Relationship; D011839:Radiation, Ionizing; D011837:Radiation-Protective Agents / Q000138:chemical synthesis / Q000494:pharmacology; D013451:Sulfonic Acids; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D013844:Thiazoles
D052160:Benzothiazoles; D001713:Biphenyl Compounds; D004269:DNA, Bacterial; D016166:Free Radical Scavengers; D008624:Mercaptoethylamines; D010851:Picrates; D011837:Radiation-Protective Agents; D013451:Sulfonic Acids; D013830:Thiadiazoles; D013844:Thiazoles; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; C002502:2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid; D017665:Hydroxyl Radical; C004931:1,1-diphenyl-2-picrylhydrazyl; D004999:Amifostine