N-(4-methyl-1,3-thiazol-2-yl)imidazole-1-carbothioamide | 149486-47-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: N-(4-methyl-1,3-thiazol-2-yl)imidazole-1-carbothioamide
• CAS: 149486-47-5
• 化学式: C₈H₈N₄S₂
• 分子量: 224.31
• InChiKey: YVWCXSMGAHCAFY-UHFFFAOYSA-N

物化性质

• 沸点：
  405.3±38.0 °C(Predicted)
• 密度：
  1.47±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  14
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  103
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (R)-2-苯基-1-丙胺 、 N-(4-methyl-1,3-thiazol-2-yl)imidazole-1-carbothioamide 以 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 生成 1-(4-methylthiazol-2-yl)-3-[(2R)-2-phenylpropyl]thiourea
  参考文献：
  名称：

  Effect of stereo and regiochemistry towards wild and multidrug resistant HIV-1 virus: viral potency of chiral PETT derivatives

  摘要：

  Chiral derivatives of several substituted halopyridyl and thiazolyl PETT compounds were synthesized as non-nucleoside inhibitors of the reverse transcriptase (RT) enzyme of the human immunodeficiency virus (HIV- 1). Molecular modeling studies indicated that because of the asymmetric geometry of the non-nucleoside inhibitors (NNRTI) binding pocket, the 'R' stercoisomers would fit the NNRTI binding pocket of the HIV-1 RT much better than the corresponding 'S' stereoisomers, as reflected by their 10(4)-fold lower K-i values. The 'R' stereoisomers of several PETT derivatives inhibited the recombinant RT in vitro with lower IC50 values than their enantiomers. The active compounds were further evaluated for their ability to inhibit HIV-1 replication in human peripheral blood mononuclear cells (PBMCs). All the 'R' isomers again showed potent anti-HIV activity and inhibited the replication of the HIV-1 strains HTLVIIIB in PBMCs at nanomolar concentrations whereas their enantiomers were less potent. The lead compounds for the respective groups were further tested against A17 (NNRTI-resistant, Y181C mutant RT), and A17Var (NNI-resistant Y181C +/- K103N mutant RT) as well as multidrug resistant viral strains. The results indicated that the lead compounds were several logs more potent than the standard NNRTI drug nevirapine. Structure-activity relationship among the derivatives showed preference of pyridyl unit with halo substitutions primarily at 5-position demonstrating the importance of both the stereochemistry as well as regiochemistry. Our data provides experimental evidence that the stereochemistry and the regiochemistry of non-nucleoside inhibitors can profoundly affect their anti-HIV activity. (C) 2004 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2004.01.019
• 作为产物：
  描述：

  2-氨基-4-甲基噻唑 、 N,N'-硫羰基二咪唑 以 乙腈 为溶剂， 反应 15.0h， 生成 N-(4-methyl-1,3-thiazol-2-yl)imidazole-1-carbothioamide
  参考文献：
  名称：

  Effect of stereochemistry on the anti-HIV activity of chiral thiourea compounds

  摘要：

  Chiral derivatives of several substituted halopyridyl and thiazolyl PETT compounds were synthesized as non-nucleoside inhibitors of the reverse transcriptase (RT) enzyme (NNRTI) of the human immunodeficiency virus (HIV-1). Molecular modeling studies indicated that because of the asymmetric geometry of the NNRTI binding pocket, the R stereoisomers would fit the NNRTI binding pocket of the HIV-1 RT much better than the corresponding S stereoisomers, as reflected by their 10(4)-fold lower K-i values. The R stereoisomers of several PETT derivatives inhibited recombinant RT in vitro with lower IC50 values than their enantiomers. The active compounds were further evaluated for their ability to inhibit HIV-1 replication in human peripheral blood mononuclear cells (PBMC). All the R isomers once again showed potent anti-HIV activity and inhibited the replication of the HIV-1 strain HTLVIIIB in peripheral blood mononuclear cells (PBMC) at nanomolar concentrations whereas their enantiomers were substantially less potent. The lead compounds in the respective groups were further tested against the NNRTI-resistant HIV strains, A17 (Y181C mutant), and A17Var (YISIC+K103N mutant) and RT MDR (V106N). The results showed that the lead compounds were several logs more potent than the standard NNRTI nevirapine. Structure-activity relationship studies also revealed a preference for the pyridyl unit with halo substitutions primarily at 5-position demonstrating the importance of regiochemistry. Our data provides experimental evidence that the stereochemistry as well as regiochemistry of NNRTI can profoundly affect their anti-HIV activity. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2004.04.050

文献信息

• Compounds and methods for inhibition of HIV and related viruses
  申请人：Medivir Aktiebolag

  公开号：EP0540143A2

  公开（公告）日：1993-05-05

  Treatment of Aids, inhibition of the replication of HIV and related viruses, and formulations using thiourea derivative compounds or salts thereof are disclosed. Also disclosed are novel thiourea compounds.

  公开了治疗艾滋病、抑制 HIV 和相关病毒复制以及使用硫脲衍生物化合物或其盐的制剂。还公开了新型硫脲化合物。
• Effect of stereochemistry on the anti-HIV activity of chiral thiourea compounds
  作者：T.K Venkatachalam、C Mao、Fatih.M Uckun

  DOI：10.1016/j.bmc.2004.04.050

  日期：2004.8.1

  Chiral derivatives of several substituted halopyridyl and thiazolyl PETT compounds were synthesized as non-nucleoside inhibitors of the reverse transcriptase (RT) enzyme (NNRTI) of the human immunodeficiency virus (HIV-1). Molecular modeling studies indicated that because of the asymmetric geometry of the NNRTI binding pocket, the R stereoisomers would fit the NNRTI binding pocket of the HIV-1 RT much better than the corresponding S stereoisomers, as reflected by their 10(4)-fold lower K-i values. The R stereoisomers of several PETT derivatives inhibited recombinant RT in vitro with lower IC50 values than their enantiomers. The active compounds were further evaluated for their ability to inhibit HIV-1 replication in human peripheral blood mononuclear cells (PBMC). All the R isomers once again showed potent anti-HIV activity and inhibited the replication of the HIV-1 strain HTLVIIIB in peripheral blood mononuclear cells (PBMC) at nanomolar concentrations whereas their enantiomers were substantially less potent. The lead compounds in the respective groups were further tested against the NNRTI-resistant HIV strains, A17 (Y181C mutant), and A17Var (YISIC+K103N mutant) and RT MDR (V106N). The results showed that the lead compounds were several logs more potent than the standard NNRTI nevirapine. Structure-activity relationship studies also revealed a preference for the pyridyl unit with halo substitutions primarily at 5-position demonstrating the importance of regiochemistry. Our data provides experimental evidence that the stereochemistry as well as regiochemistry of NNRTI can profoundly affect their anti-HIV activity. (C) 2004 Elsevier Ltd. All rights reserved.
• Substituted heterocyclic thiourea compounds as a new class of anti-allergic agents inhibiting IgE/FcεRI receptor mediated mast cell leukotriene release
  作者：T.K Venkatachalam、S Qazi、P Samuel、F.M Uckun

  DOI：10.1016/s0968-0896(02)00531-x

  日期：2003.3

  Mast cell derived leukotrienes (LT's) play a vital role in pathophysiology of allergy and asthma. We synthesized various analogues of indolyl, naphthyl and phenylethyl substituted halopyridyl, thiazolyl and benzothiazolyl thioureas and examined their in vitro effects on the high affinity IgE receptor/FcepsilonRI-mediated mast cell leukotriene release. Of the 22 naphthylethyl thiourea compounds tested, there were 7 active compounds and N-[1-(1-naphthyl)ethyl]-N'-[2-(ethyl-4-acetylthiazolyl)]thiourea (17 and 16) (IC50=0.002 muM) and N-[1-(1R)-naphthylethyl]-N'-[2-(5-methylpyridyl)]thiourea (compound 5) (IC50 = 0.005 muM) were identified as the lead compounds. Among the 1l indolylethyl thiourea compounds tested, there were seven active compounds and the halopyridyl compounds N-[2-(3-indolylethyl)]-N'-[2-(5-chloropyridyl)lthiourea (24) and N-[2-(3-indolylethyl)]-N'-[2-(5-bromopyridyl)]thiourea (25) were the most active agents and inhibited the LTC4 release with low micromolar IC50 values of 4.9 and 6.1 PM, respectively. The hydroxylphenyl substituted compounds N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(5-chloropyridyl)]thiourea (37; IC50 = 12.6muM), N-[2-(4-hydroxyphenyl)ethyll-AT-[2-(5-bromopyridyl)]thiourea (50; IC50 16.8 muM) and N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(pyridyl)]thiourea (35; IC50 = 8.5muM) were the most active pyridyl thiourea agents. Notably, the introduction of electron withdrawing or donating groups had a marked impact on the biological activity of these thiourea derivatives and the Hammett sigma values of their substituents were identified as predictors of their potency. In contrast, experimentally determined partition coefficient values did not correlate with the biological activity of the thiourea compounds which demonstrates that their liphophilicity is not an important factor controlling their mast cell inhibitory effects. These results establish the substituted halopyridyl, indolyl and naphthyl thiourea compounds as a new chemical class of anti-allergic agents inhibiting IgE receptor/FcepsilonRI-mediated mast cell LTC4 release. Further lead optimization efforts may provide the basis for new and effective treatment as well as prevention programs for allergic asthma in clinical settings. (C) 2003 Elsevier Science Ltd. All rights reserved.
• Inhibition of mast cell leukotriene release by thiourea derivatives
  作者：Taracad K Venkatachalam、Sanjive Qazi、Peter Samuel、Fatih M Uckun

  DOI：10.1016/s0960-894x(02)00992-7

  日期：2003.2

  Mast cell derived leukotrienes (LT's) play a vital role in pathophysiology of allergy and asthma. We synthesized various analogues of indolyl, naphthyl and phenylethyl substituted halopyridyl, thiazolyl and benzothiazolyl thioureas and examined their in vitro effects on the high affinity IgE receptor/FcERI-mediated mast cell leukotriene release. Of the 22 naphthylethyl thiourea compounds tested, there were seven active compounds and N-[1-(1-naphthyl)ethyl]-N'-[2-(ethyl-4-acetylthiazolyl)]thiourea (17 and 16) (IC50 = 0.002 muM) and N-[1-(1R)-naphthylethyl]-N'-[2-(5-methylpyridyl)]thiourea (5) (IC50 = 0.005 muM) were identified as the lead compounds. Among the I I indolylethyl thiourea compounds tested, there were seven active compounds and the halopyridyl compounds N-[2-(3-indolylethyl)]-N'-[2-(5-chloropyridyl)]thiourea and N-[2-(3-indolylethyl)]-N'-[2-(5-bromopyridyl)]thiourea were the most active agents and inhibited the LTC4 release with low micromolar IC50 values of 4.9 muM and 6.1 muM, respectively. The hydroxylphenyl substituted compounds N-[2-(4-hydroxyphenyl)ethyl]- N'-[2-(5-chloropyridyl)] thiourea (IC50 = 12.6 muM), N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(5-bromopyridyl)]thiourea (IC50 = 16.8 muM) and N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(pyridyl)]thiourea (IC50 = 8.5 muM) were the most active pyridyl thiourea agents. Notably, the introduction of electron withdrawing or donating groups had a marked impact on the biological activity of these thiourea derivatives and the Hammett sigma values of their substituents were identified as predictors of their potency. In contrast, experimentally determined partition coefficient values did not correlate with the biological activity of the thiourea compounds which demonstrates that their liphophilicity is not an important factor controlling their mast cell inhibitory effects. (C) 2002 Elsevier Science Ltd. All rights reserved.
• Regiospecific synthesis, X-ray crystal structure and biological activities of 5-bromothiophenethyl thioureas
  作者：Taracad K Venkatachalam、Elise A Sudbeck、Fatih M Uckun

  DOI：10.1016/s0040-4039(01)01290-4

  日期：2001.9

  The regiospecific synthesis of 5-bromothiophenethyl thioureas was accomplished in four steps with an overall yield of 40-60%. The requisite regioselectivity for bromination of the thiophene ring was achieved using bromine in acetic acid at low temperatures. The resulting 5-bromothiophenethylamine hydrobromide is an important precursor for the preparation of substituted thioureas. The X-ray crystal structure demonstrates that the bromine atom is indeed located at the 5-position of the thiophene ring. (C) 2001 Elsevier Science Ltd. All rights reserved.