N-(benzo[d]thiazol-2-yl)-1,2,3,4-tetrahydro-4-(3-hydroxy-4-methoxyphenyl)-6-methyl-2-thioxopyrimidine-5-carboxamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 酚类
• 英文名称: N-(benzo[d]thiazol-2-yl)-1,2,3,4-tetrahydro-4-(3-hydroxy-4-methoxyphenyl)-6-methyl-2-thioxopyrimidine-5-carboxamide
• 英文别名: N-(1,3-benzothiazol-2-yl)-4-(3-hydroxy-4-methoxy-phenyl)-6-methyl-2-thioxo-3,4-dihydro-1H-pyrimidine-5-carboxamide；N-(1,3-benzothiazol-2-yl)-4-(3-hydroxy-4-methoxyphenyl)-6-methyl-2-sulfanylidene-3,4-dihydro-1H-pyrimidine-5-carboxamide
• 化学式: C₂₀H₁₈N₄O₃S₂
• 分子量: 426.52
• InChiKey: PDUXLLCBAAUBDO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  156
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  苯基硫脲 在 溴 、 对甲苯磺酸 、 sodium hydroxide 作用下， 以 甲醇 、 甲苯 为溶剂， 反应 30.0h， 生成 N-(benzo[d]thiazol-2-yl)-1,2,3,4-tetrahydro-4-(3-hydroxy-4-methoxyphenyl)-6-methyl-2-thioxopyrimidine-5-carboxamide
  参考文献：
  名称：

  Development of selective DprE1 inhibitors: Design, synthesis, crystal structure and antitubercular activity of benzothiazolylpyrimidine-5-carboxamides

  摘要：

  Decaprenylphosphoryl-b-D-ribose 20-epimerase (DprE1) is a potential drug target for development of antitubercular agents. Structure based drug discovery approach yielded twenty novel derivatives of benzothiazolylpyrimidine-5-carboxamides (7a-t) which were synthesised by three component one pot reaction involving benzothiazolyl oxobutanamide, thiourea and substituted 'aromatic benzaldehydes. These derivatives were evaluated for antituberculat activity to determine MIC and compound 7a, 7e, 7f and 7o were found to be potentially active against Mycobacterium tuberculosis (H(37)Rv). Log P of these compounds was found to be between 2.0 and 3.0 maldng.them suitable for oral dosing. DprE1 selectivity and pharmacokinetic studies were carried out for these compounds of which 7a and 7o were found to be highly selective and bioavailability was found to be above 52% by oral dose. Crystal structure of 7a was studied and molecular packing was determined, it exhibited a triclinic crystal lattice arrangement having hydrogen bonded dimeric arrangement. Drug receptor interactions were studied which exhibited docking in the active site of receptor with hydrogen bonding, hydrophobic interactions, vdW interactions with amino acid residues such as Cys387, Asn385, Lys418, Tyr314, Gln334 and Lys367 respectively. 3D QSAR analysis was carried out by kNN-MFA method to determine and develop theoretical model, best suitable model was found to be based on Simulated Annealing k-Neariest Neighbour Molecular Field Analysis (SA kNN-MFA). The model provided with hydrophobic descriptors in positive side indicating the need of bulky groups, steric and electronegative descriptors in negative coordinates hints with contribution by the electronegative substitutions as favourable and desirable moieties for enhancing the activity. The q(2), q(2)_se and Pred_r(2)se were found to be 0.5000, 0.6404 and 1.0094 respectively. A pharmacophore model was generated which suggested for necessity of aromatic, aliphatic carbon centre and hydrogen bond donor for development of newer DprE1 selective inhibitors. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.04.011

文献信息

• Development of selective DprE1 inhibitors: Design, synthesis, crystal structure and antitubercular activity of benzothiazolylpyrimidine-5-carboxamides
  作者：Rupesh Chikhale、Sunil Menghani、Ramavath Babu、Ratnadeep Bansode、G. Bhargavi、Nazira Karodia、M.V. Rajasekharan、Anant Paradkar、Pramod Khedekar

  DOI：10.1016/j.ejmech.2015.04.011

  日期：2015.5

  Decaprenylphosphoryl-b-D-ribose 20-epimerase (DprE1) is a potential drug target for development of antitubercular agents. Structure based drug discovery approach yielded twenty novel derivatives of benzothiazolylpyrimidine-5-carboxamides (7a-t) which were synthesised by three component one pot reaction involving benzothiazolyl oxobutanamide, thiourea and substituted 'aromatic benzaldehydes. These derivatives were evaluated for antituberculat activity to determine MIC and compound 7a, 7e, 7f and 7o were found to be potentially active against Mycobacterium tuberculosis (H(37)Rv). Log P of these compounds was found to be between 2.0 and 3.0 maldng.them suitable for oral dosing. DprE1 selectivity and pharmacokinetic studies were carried out for these compounds of which 7a and 7o were found to be highly selective and bioavailability was found to be above 52% by oral dose. Crystal structure of 7a was studied and molecular packing was determined, it exhibited a triclinic crystal lattice arrangement having hydrogen bonded dimeric arrangement. Drug receptor interactions were studied which exhibited docking in the active site of receptor with hydrogen bonding, hydrophobic interactions, vdW interactions with amino acid residues such as Cys387, Asn385, Lys418, Tyr314, Gln334 and Lys367 respectively. 3D QSAR analysis was carried out by kNN-MFA method to determine and develop theoretical model, best suitable model was found to be based on Simulated Annealing k-Neariest Neighbour Molecular Field Analysis (SA kNN-MFA). The model provided with hydrophobic descriptors in positive side indicating the need of bulky groups, steric and electronegative descriptors in negative coordinates hints with contribution by the electronegative substitutions as favourable and desirable moieties for enhancing the activity. The q(2), q(2)_se and Pred_r(2)se were found to be 0.5000, 0.6404 and 1.0094 respectively. A pharmacophore model was generated which suggested for necessity of aromatic, aliphatic carbon centre and hydrogen bond donor for development of newer DprE1 selective inhibitors. (C) 2015 Elsevier Masson SAS. All rights reserved.