Chemical Space Exploration around Thieno[3,2-d]pyrimidin-4(3H)-one Scaffold Led to a Novel Class of Highly Active Clostridium difficile Inhibitors

Shao Xuwei; AbdelKhalek Ahmed; Abutaleb Nader S.; Velagapudi Uday Kiran; Yoganathan Sabesan; Seleem Mohamed N.; Talele Tanaji T.

首页> 外文期刊>Journal of Medicinal Chemistry >Chemical Space Exploration around Thieno[3,2-d]pyrimidin-4(3H)-one Scaffold Led to a Novel Class of Highly Active Clostridium difficile Inhibitors

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Chemical Space Exploration around Thieno[3,2-d]pyrimidin-4(3H)-one Scaffold Led to a Novel Class of Highly Active Clostridium difficile Inhibitors

机译：Thieno [3,2-D]嘧啶-4（3H）周围的化学空间探索-NOTO脚手架导致了一种新型高活性梭菌艰难梭菌抑制剂

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Clostridium difficile infection (CDI) is the leading cause of healthcare-associated infection in the United States. Therefore, development of novel treatments for CDI is a high priority. Toward this goal, we began in vitro screening of a structurally diverse in-house library of 67 compounds against two pathogenic C. difficile strains (ATCC BAA 1870 and ATCC 43255), which yielded a hit compound, 2-methyl-8-nitroquinazolin-4(3H)-one (2) with moderate potency (MIC = 312/156 mu M). Optimization of 2 gave lead compound 6a (2-methyl-7-nitrothieno[3,2-d]pyrimidin-4(3H)-one) with improved potency (MIC = 19/38 mu M), selectivity over normal gut microflora, CC(50)s > 606 mu M against mammalian cell lines, and acceptable stability in simulated gastric and intestinal fluid. Further optimization of 6a at C2-, N3-, C4-, and C7-positions resulted in a library of >50 compounds with MICs ranging from 3 to 800 mu M against clinical isolates of C. difficile. Compound 8f (MIC = 3/6 mu M) was identified as a promising lead for further optimization.

机译：Clostridium艰难的感染（CDI）是美国医疗保健相关感染的主要原因。因此，开发CDI的新型治疗是一种高优先级。对此目的，我们开始体外筛选67个化合物的结构多样化的内部文库，其针对两种致病性C.艰难型菌株（ATCC Baa 1870和ATCC 43255），其产生了麦芽化合物，2-甲基-8-硝基喹唑啉 - 4（3h） - 具有中等效力的（2）（MIC = 312/156 mu m）。用改善的效力（MIC = 19/38 mu m），优化2给出铅化合物6a（2-甲基-7-裸硫酸[3,2-d]嘧啶-4（3h） - 酮），在正常肠道微生物中选择性， CC（50）S>606μm对哺乳动物细胞系，以及模拟胃和肠液中可接受的稳定性。在C2-，N3-，C4-和C7位置进一步优化6A，导致具有麦克风3至800μm的MICS的30种化合物库中，对抗C.艰难梭菌的临床分离物。将化合物8F（MIC =3/6μm）鉴定为有前途的铅，以进一步优化。

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《Journal of Medicinal Chemistry》 |2019年第21期|共20页
作者
Shao Xuwei; AbdelKhalek Ahmed; Abutaleb Nader S.; Velagapudi Uday Kiran; Yoganathan Sabesan; Seleem Mohamed N.; Talele Tanaji T.;
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St Johns Univ Coll Pharm &

Hlth Sci Dept Pharmaceut Sci Queens NY 11439 USA;

Purdue Univ Coll Vet Med Dept Comparat Pathobiol W Lafayette IN 47907 USA;

Purdue Univ Coll Vet Med Dept Comparat Pathobiol W Lafayette IN 47907 USA;

St Johns Univ Coll Pharm &

Hlth Sci Dept Pharmaceut Sci Queens NY 11439 USA;

St Johns Univ Coll Pharm &

Hlth Sci Dept Pharmaceut Sci Queens NY 11439 USA;

Purdue Univ Coll Vet Med Dept Comparat Pathobiol W Lafayette IN 47907 USA;

St Johns Univ Coll Pharm &

Hlth Sci Dept Pharmaceut Sci Queens NY 11439 USA;

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1. Chemical Space Exploration around Thieno[3,2-d]pyrimidin-4(3H)-one Scaffold Led to a Novel Class of Highly Active Clostridium difficile Inhibitors [J] . Shao Xuwei, AbdelKhalek Ahmed, Abutaleb Nader S., Journal of Medicinal Chemistry . 2019,第21期

机译：Thieno [3,2-D]嘧啶-4（3H）周围的化学空间探索-NOTO脚手架导致了一种新型高活性梭菌艰难梭菌抑制剂
2. SYNTHESIS AND ANALGESIC ACTIVITY OF 2-ARYLAMINO-3-ARYL-5-PHENYL-THIENO [2,3-d] PYRIMIDIN-4(3H)-ONES AND 2-ARYLAMINO-3-ARYL-7-PHENYL-THIENO [3,2-d] PYRIMIDIN-4(3H)-ONES [J] . Ishwarsinh S.Rathod, Harsha U.Patel Indian Journal of Heterocyclic Chemistry. (Text in English) . 2005,第3期

机译：2-ARYLAMINO-3-ARYL-5-PHENYL-THIENO [2,3-d] PYRIMIDIN-4（3H）-ones and 2-ARYLAMINO-3-ARYL-7-Phenyl-Thieno [3，3的合成和止痛活性[3， 2-d] PYRIMIDIN-4（3H）-ONES
3. Synthesis and Antiobesity Properties of 6-(4-Chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (BMS-814580): A Highly Efficacious Melanin Concentrating Hormone Receptor 1 (MCHR1) Inhibitor [J] . Ahmad Saleem, Washburn William N., Hernandez Andres S., Journal of Medicinal Chemistry . 2016,第19期

机译：6-（4-氯苯基）-3-（4-（（（3,3-二氟-1-羟基环丁基）甲氧基）-3-甲氧基苯基）噻吩并[3,2-d]嘧啶-4（3H）的合成和抗肥胖性）-一（BMS-814580）：一种高效的黑色素浓缩激素受体1（MCHR1）抑制剂
4. Scaffold-based chemical space exploration [C] . Hoksza David, Skoda Petr IEEE International Conference on Bioinformatics and Biomedicine . 2014

机译：基于支架的化学空间探索
5. Chemical Space Exploration Around Thieno[3,2-d]Pyrimidin-4(3H)-One Scaffold Led to a Novel Class of Highly Active Clostridium difficile Inhibitors [D] . Shao, Xuwei. 2020

机译：Thieno [3,2-D]嘧啶-4（3H）周围的化学空间探索-NE脚手架导致了一种新型高活性梭菌艰难梭菌抑制剂
6. Synthesis of Novel Analogs of Thieno23-d Pyrimidin-4(3H)-ones as Selective Inhibitors of Cancer Cell Growth [O] . Sheng Zhang, Feize Liu, Xueling Hou, 2019

机译：Thieno 23-d Pyrimidin-4（3H）-ones作为癌细胞生长的选择性抑制剂的新型类似物的合成。
7. Chemical Space Exploration around Thieno3,2dpyrimidin-4(3H)one Scaffold Led to a Novel Class of Highly Active Clostridium difficile Inhibitors [O] . -1

机译：Thieno附近的化学空间探索3,2d嘧啶-4（3h）一个脚手架导致了一种新型高活性梭菌艰难梭菌抑制剂

Chemical Space Exploration around Thieno[3,2-d]pyrimidin-4(3H)-one Scaffold Led to a Novel Class of Highly Active Clostridium difficile Inhibitors

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