- Arylazolyl(azinyl)thioacetanilides: Part 19: Discovery of Novel Substituted Imidazo[4,5-b]pyridin-2-ylthioacetanilides as Potent HIV NNRTIs Via a Structure-based Bioisosterism Approach
-
With the continuation of our unremitting efforts toward the discovery of potent HIV-1 NNRTIs, a series of novel imidazo[4,5-b]pyridin-2-ylthioacetanilides were designed, synthesized, and evaluated for their antiviral activities through combining bioisosteric replacement and structure-based drug design. Almost all of the title compounds displayed moderate to good activities against wild-type (wt) HIV-1 strain with EC50 values ranging from 0.059 to 1.41 μm in a cell-based antiviral assay. Thereinto, compounds 12 and 13 were the most active two analogues possessing an EC50 value of 0.059 and 0.073 μm against wt HIV-1, respectively, which was much more effective than the control drug nevirapine (EC50 = 0.26 μm) and comparable to delavirdine (EC50 = 0.038 μm). In addition, one selected compound showed a remarkable reverse transcriptase inhibitory activity compared to nevirapine and etravirine. In the end of this manuscript, preliminary structure–activity relationships (SARs) and molecular modeling studies were detailedly discussed, which may provide valuable insights for further optimization.
- Li, Xiao,Huang, Boshi,Zhou, Zhongxia,Gao, Ping,Pannecouque, Christophe,Daelemans, Dirk,De Clercq, Erik,Zhan, Peng,Liu, Xinyong
-
-
Read Online
- Arylazolyl(azinyl)thioacetanilides. Part 20: Discovery of novel purinylthioacetanilides derivatives as potent HIV-1 NNRTIs via a structure-based bioisosterism approach
-
By means of structure-based bioisosterism approach, a series of novel purinylthioacetanilide derivatives were designed, synthesized and evaluated as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Some of the tested compounds were found to be active against wild-type (WT) HIV-1(IIIB) with EC50in the range of 0.78–4.46?μM. Among them, LAD-8 displayed the most potent anti-HIV activity (EC50?=?0.78?μM, SI?=?24). In addition, LBD-6 showed moderate activity against L100I mutant (EC50?=?5.64?μM) and double mutant strain RES056 (EC50?=?22.24?μM). Preliminary structure–activity relationships (SARs) were discussed in detail. Molecular modeling study was used to predict the optimal conformation in the NNRTI binding site, which may play a guiding role in further rational optimization.
- Lu, Xueyi,Li, Xiao,Yang, Jiapei,Huang, Boshi,Kang, Dongwei,Zhao, Fabao,Zhou, Zhongxia,De Clercq, Erik,Daelemans, Dirk,Pannecouque, Christophe,Zhan, Peng,Liu, Xinyong
-
-
Read Online
- Thienopyrimidone acyl sulfonamide derivative as well as preparation method and application thereof
-
The invention relates to a thienopyrimidone acyl sulfonamide derivative as well as a preparation method and application thereof. The thienopyrimidone acyl sulfonamide derivative has a structure as shown in a formula I. The invention also relates to a preparation method of the compound with the structure as shown in the general formula I and a pharmaceutical composition. The invention also provides application of the compound in preparation of anti-gout drugs.
- -
-
Paragraph 0032-0036
(2021/09/04)
-
- Thienopyrimidinone mercaptoacetic acid derivative as well as preparation method and application thereof
-
The invention relates to an imidazopyridine mercaptoacetic acid derivative as well as a preparation method and application thereof. The compound has a structure shown as a formula I or a formula II which is described in the specification. The invention also relates to a preparation method and a pharmaceutical composition of the compound containing the structure shown in the formula I or II. The invention also provides application of the compound in preparation of anti-gout drugs.
- -
-
Paragraph 0044; 0045; 0046; 0047
(2020/10/21)
-
- Novel Human Urate Transporter 1 Inhibitors as Hypouricemic Drug Candidates with Favorable Druggability
-
Lesinurad, a human urate transporter 1 (URAT1) inhibitor approved as a medication for the treatment of hyperuricemia associated with gout in 2015, can cause liver and renal toxicity. Here, we modified all three structural components of lesinurad by applying scaffold hopping, bioisosterism, and substituent-decorating strategies. In a mouse model of acute hyperuricemia, 21 of the synthesized compounds showed increased serum uric acid (SUA)-reducing activity; SUA was about 4-fold lower in animals treated with 44, 54, and 83 compared with lesinurad or benzbromarone. In the URAT1 inhibition assay, 44 was over 8-fold more potent than lesinurad (IC50: 1.57 μM vs 13.21 μM). Notably, 83 also displayed potent inhibitory activity (IC50 = 31.73 μM) against GLUT9. Furthermore, we also preliminarily explored the effect of chirality on the potency of the promising derivatives 44 and 54. Compounds 44, 54, and 83 showed favorable drug-like pharmacokinetics and appear to be promising candidates for the treatment of hyperuricemia and gout.
- Zhao, Tong,Meng, Qing,Sun, Zhuosen,Chen, Yanyu,Ai, Wei,Zhao, Zean,Kang, Dongwei,Dong, Yue,Liang, Ruipeng,Wu, Ting,Pang, Jianxin,Liu, Xinyong,Zhan, Peng
-
p. 10829 - 10854
(2020/11/09)
-
- Preparation method of 4-cyclopropyl-1-naphthylamine
-
The invention relates to a novel preparation method of 4-cyclopropyl-1-naphthylamine. The raw materials needed for the preparation method are cheap in price and easy to obtain, the reaction step operation is simple, and the total yield is better than that of the prior art level. Moreover, the nitrification, hydrogenation reduction, Suzuki coupling and other reactions are avoided to use, and thus the production difficulty and production cost is greatly reduced. A relatively economical, efficient, safe and environment-friendly synthetic route is provided for the preparation of 4-cyclopropyl-1-naphthylamine.
- -
-
Paragraph 0022-0026
(2019/07/16)
-
- Preparation method of naphthylamine drug intermediate
-
The invention discloses a preparation method of a naphthylamine drug intermediate. The preparation method of the naphthylamine drug intermediate comprises the steps of: in a solvent, and under the action of the catalyst FeO(OH), carrying out the following reduction reaction on a compound I and hydrazine hydrate to obtain a compound II. The method has the advantages of high purity and yield of product, simple and safe process, and easy operation, and is suitable for large-scale industrial production.
- -
-
Paragraph 0022-0045
(2019/01/24)
-
- Lesinurad analogue and its preparation method and medical use
-
The invention relates to a lesinurad analog as shown in the general formula (I), its preparation method, a pharmaceutical composition containing the derivative and an application of the pharmaceutical composition used as a therapeutic agent, especially as a medicine for treating hyperuricemia and gout, wherein definition of each substituent group in the general formula (I) is as the same as definition in the specification.
- -
-
Paragraph 0046; 0047; 0048; 0053; 0054
(2019/05/28)
-
- Imidazole [4, 5 - b] pyridine qiu acetyl amine derivative and its preparation method and application
-
The invention relates to an imidazole [4,5-b] pyridine mercaptoacetamide derivative represented in a formula I and pharmaceutically acceptable salt, ester or prodrug of the derivative, a preparation method of the derivative and an application of composition containing one or more of the compound to preparation of a drug for treating and preventing HIV (human immunodeficiency virus) infection and anti-leukemia or anti-tumor drugs.
- -
-
Paragraph 0040
(2017/12/28)
-
- 2-(5-bromo-4-(4-cyclopropyl naphthalen-1-yl)-4H-1,2,4-triazol-3-yl thio)acetic acid intermediates
-
Lesinurad key intermediate compounds (L-4) and (L-5) are prepared; a preparation method is simple in postprocessing of reaction, the product is relatively high in purity and relatively good in stability, the preparation method is suitable for industrialized production, and a new simple and feasible method is provided for preparation of 2-(5-bromo-4-(4-cyclopropyl naphthalen-1-yl)-4H-1,2,4-triazol-3-yl thio)acetic acid key intermediate compound (L-6) and a final finished product raw material medicine thereof; the pollution to the environment is reduced, the product yield and quality of the prepared raw material medicine are improved to a great extent, and medicine industrialization costs are reduced.
- -
-
Paragraph 0028; 0035
(2017/07/05)
-
- Preparing method of triazole thioglycolic acid compound for curing metabolic arthritis
-
The invention discloses a preparing method of a triazole thioglycolic acid compound for curing metabolic arthritis. According to the method, compound II and compound III are utilized as initial materials and are generated into intermediate compound IV through Suzuki reaction; then nucleophilic substitution happens between the intermediate compound IV and 1,1minute-thiocarbonyl polypyridobisinudazole to generate intermediate compound V; the compound V generates intermediate compound VI through cyclization reaction, and then nucleophilic substitution happens between the compound VI and methyl chloroacetate to generate intermediate compound VII; the intermediate compound VII generates intermediate compound VIII through bromination reaction; and a target product 2-((5-bromine-4-(4-cyclopropyl naphthalene-1-yl)-4H-1,2,4-triazole-3-yl)sulfenyl) acetic acid (I) is generated through hydrolysis reaction. The preparing method is high in selectivity and simple to operate and avoids poisonous reagents and rigorous reacting conditions. Compared with an original synthetic method, the reacting time of the preparing method is shortened, the energy consumption is reduced, and the reaction yield is improved.
- -
-
Paragraph 0060; 0061; 0062
(2016/10/09)
-
- Imidazopyridine thioglycolic acid derivative and preparation method and application thereof
-
The invention relates to an imidazopyridine thioglycolic acid derivative and a preparation method and application thereof. The compound has the structure as shown in a formula I or a formula II or a formula III. The invention further relates to a preparation method of the compound with the structure as shown in the formula I or the formula II or the formula III and pharmaceutical compositions. The invention further provides application of the compound in preparation of drugs for resisting gout. Please see the formula in the description.
- -
-
Paragraph 0133; 0134; 0170; 0171
(2017/01/02)
-
- Method for producing lesinurad intermediate 4-cyclopropyl-1-naphthylamine
-
The invention discloses a synthetic method which can be applied to produce gout treating drug lesinurad intermediate 4-cyclopropyl-1-naphthylamine 2. The method adopts metal or low-price salt as a reducing agent, to provide a production technique which can avoid the application of hydrogen and precious metal catalysts without producing a by-product 3. The present technique has the characteristics of high purity products, good security and low cost.
- -
-
Paragraph 0025-0026
(2017/02/24)
-
- Optically pure thioacetic compound
-
The invention belongs to the field of pharmacy and relates to an optically pure thioacetic compound and application thereof to medicine. The optically pure thioacetic compound comprises levorotatory 2-(5-bromo-4-(4-cyclopropyl-naphthalene-1-base)-4H-1,2,4-triazole-3-based sulfenyl) acetic acid and dextral 2-(5-bromo-4-(4-cyclopropyl-naphthalene-1-base)-4H-1,2,4-triazole-3-based sulfenyl) acetic acid.
- -
-
Paragraph 0045; 0046; 0047
(2016/12/26)
-
- THIO-1,2,4-TRIAZOLE DERIVATIVES AND METHOD FOR PREPARING THE SAME
-
Provided is a process for preparing a compound shown as formula (I), comprising a step of contacting a compound shown as formula (II) or a salt thereof with a brominating agent, wherein R1is OR2 or NR3R4; R2 is C1-C6 alkyl or phenyl; each R3, R4 is independently H, C1-C6 alkyl or cycloalkyl, wherein C1-C6 alkyl, cycloalkyl, or phenyl is optionally further substituted by F, Cl, Br, CH3 or CF3. A process for preparing a compound shown as formula (II), a process for preparing a compound shown as formula (V), a process for preparing a compound shown as formula (III), and an intermediate compound as shown as formula (IIa) or formula (Ib) are also provided.
- -
-
Paragraph 065-066
(2015/01/09)
-
- MANUFACTURE OF 2- (5- BROMO-4 (-CYCLOPROPYLNAPHTHALEN-1-YL) -4H-1,2,4-TRIAZOL-3-YLTHIO) ACETIC ACID
-
Described herein are certain processes for the synthesis of compounds of Formula (I):
- -
-
Paragraph 0345-0348
(2014/01/18)
-
- POLYMORPHIC, CRYSTALLINE AND MESOPHASE FORMS OF SODIUM 2-(5-BROMO-4-(4-CYCLOPROPYLNAPHTHALEN-1-YL)-4H-1,2,4-TRIAZOL-3-YLTHIO)ACETATE, AND USES THEREOF
-
Crystalline polymorphs and solid mesophase forms of sodium 2-(5-bromo-4- (4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-ylthio)acetate are described. In addition, pharmaceutical compositions and uses of such compositions for the treatment of a variety of diseases and conditions are provided.
- -
-
Page/Page column 36-37
(2011/08/03)
-
- NOVEL COMPOUNDS AND COMPOSITIONS AND METHODS OF USE
-
Described herein are compounds useful in the modulation of blood uric, acid levels, formulations containing them and methods of using them. In some embodiments, the compounds described herein are used in the treatment or prevention of disorders relafed to aberrant levels of uric acid
- -
-
Page/Page column 89-90
(2009/07/03)
-
- S-TRIAZOLYL α-MERCAPTOACETANILDES AS INHIBITORS OF HIV REVERSE TRANSCRIPTASE
-
A series of S-triazolyl α-mercaptoacetanilides having general structure (1) are provided, where Q is CO2H, CONR2, SO3H, or SO2NR2. The compounds inhibit several variants of the reverse transcriptase of HIV, and are useful in the treatment of HIV infections.
- -
-
Page/Page column 35-36
(2010/10/20)
-