title: Quantitative structure-activity relationships of 1,3,4-thiadiazol-2(3H)-ones and 1,3,4-oxadiazol-2(3H)-ones as human protoporphyrinogen oxidase inhibitors.
abstract: Protoporphyrinogen oxidase (Protox, EC 1.3.3.4) has attracted great interest during the last decades due to its unique biochemical characteristics and biomedical significance. As a continuation of our research work on the development of new PPO inhibitors, 23 new 1,3,4-thiadiazol-2(3H)-ones bearing benzothiazole substructure were designed and synthesized. The in vitro assay indicated that the newly synthesized compounds 1a-w displayed good inhibition activity against human PPO (hPPO) with K(i) values ranging from 0.04μM to 245μM. To the knowledge, compound 1a, O-ethyl S-(5-(5-(tert-butyl)-2-oxo-1,3,4-thiadiazol-3(2H)-yl)-6-fluorobenzothiazol-2-yl)carbonothioate, with the K(i) value of 40nM, is so far known as the most potent inhibitor against hPPO. Based on the molecular docking and modified molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) calculations, the quantitative structure-activity relationships of 1,3,4-thiadiazol-2(3H)-ones and 1,3,4-oxadiazol-2(3H)-one derivatives were established with excellent correlation relationships (r(2)=0.81) between the calculated and experimental binding free energies. Some important insights were also concluded for guiding the future rational design of new hPPO inhibitors with improved potency.
authors: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China.
authors: Yang
authors: Y
authors: Zuo
authors: Sheng-Gang
authors: SG
authors: Yang
authors: Li-Li
authors: LL
authors: Jiang
authors: Ge-Fei
authors: GF
authors: Hao
authors: Zhi-Fang
authors: ZF
authors: Wang
authors: Qiong-You
authors: QY
authors: Wu
authors: Zhen
authors: Z
authors: Xi
authors: Guang-Fu
authors: GF
authors: Yang
mesh_terms: D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008968:Molecular Conformation; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D050768:Protoporphyrinogen Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D013816:Thermodynamics; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D052160:Benzothiazoles; D004791:Enzyme Inhibitors; C571600:O-ethyl S-(5-(5-(tert-butyl)-2-oxo-1,3,4-thiadiazol-3(2H)-yl)-6-fluorobenzo-thiazol-2-yl)carbonothioate; D010069:Oxadiazoles; D013830:Thiadiazoles; D050768:Protoporphyrinogen Oxidase