- An analysis of structural, spectroscopic, quantum chemical and in silico studies of ethyl 3-[(pyridin-2-yl)amino]propanoate: A potential thrombin inhibitor
-
In the present investigation, we report an analysis of the structural, spectroscopic characterization, reactivity parameters, topological studies, and molecular docking studies of the synthesized ethyl 3-[(pyridin-2-yl)amino]propanoate (abbreviated to EPYAPP), C10H14N2O2. The molecular and crystal structure was determined by using the single-crystal X-ray diffraction technique. The whole molecule is planar with r.m.s.d. of all the non-hydrogen atoms being 0.041(2) ?. Further, the dihedral angle between the planes of the aromatic ring and the side chain is 1.6(1)o. The crystal structure features a pair of N-H…N hydrogen-bonded dimers connected via two C-H…π (π electrons of the aromatic ring) interactions to form a two-dimensional zig-zag sheet propagating parallel to the bc plane. The qualitative and quantitative estimation of close contacts in the solid phase of the title compound was performed through the 3D-Hirshfeld surface analysis and 2D-finger print plots. The quantum chemical calculations of the EPYAPP compound were performed at DFT/B3LYP/6-311++G(d,p) method at the ground state in the gas phase. The detailed investigation of each vibrational wave number was carried out by using the VEDA4 package, and theoretical results showed an excellent mutual agreement with the experimental spectral data. The HOMO-LUMO orbital energy calculations, chemical reactivity descriptors, and natural bond orbital analysis were also performed. Prone reactive sites of the title compound have been identified by the molecular electrostatic surface potential and Fukui functions, which are mapped to the electron density surfaces. Hydrogen bond dissociation energies and bond dissociation energies for all other single bonds were further calculated for the EPYAPP molecule in order to examine the autoxidation mechanism and degradation properties. The title compound forms a stable complex with human alpha thrombin (PDB code: 1PPB) (binding energy -7.03 kcal/mol)) antagonist and could be a lead compound for developing new thrombin inhibitor or anti-thrombotic drugs.
- Pillai, Renjith Raveendran,Poojith, Nuthalapati,Potla, Krishna Murthy,Rani, Nannapaneni Usha,Rose, J. John,Suchetan, P. A.,Vankayalapati, Suneetha
-
-
Read Online
- Synthesis and biological evaluation of some new 2,5-Substituted 1-Ethyl-1H-benzoimidazole fluorinated derivatives as direct thrombin Inhibitors
-
A new series of fluorinated 2,5-substituted 1-ethyl-1H-benzimidazole derivatives were synthesized from starting compounds 3a-i, which were prepared from acrylic acid ethyl ester and the appropriate amines using trifluoromethanesulfonic acid as a catalyst. A total of 9 novel derivatives were synthesized through 9 steps. All of them were evaluated for thrombin inhibition activity in vitro for the first time. We have altered their structures using different substituents on the amines to assess their structure-activity relationships as direct thrombin inhibitors. All the compounds were effective thrombin inhibitors, with IC50 values ranging from 3.39 to 23.30nM. Among the compounds synthesized, compounds 14a, 14b, 14d, 14e, and 14h exhibited greater anticoagulant activity than argatroban (IC50=9.36nM). Furthermore, compound 14h synthesized starting with 2-amino-pyridine was the most potent thrombin inhibitor with an IC50 value of 3.39nM. Molecular modeling studies were performed to determine the probable interactions of the most potent compounds 14a, 14e, and 14h with their protein receptor (PDB ID: 1KTS). Docking data show that the active compounds inhibit thrombin in a similar mode to that of the potent anticoagulant dabigatran. A new series of fluorinated derivatives were evaluated for their in vitro thrombin inhibition activities. 3-({2-[(4-Carbamimidoyl-2-fluoro-phenylamino)-methyl]-1-ethyl-1H-benzoimidazole-5-carbonyl}-pyridin-2-yl-amino)-propionic acid 14h shows the most potent antithrombin activity (IC50=3.39nM). Molecular docking revealed that its inhibition mode was similar to that of dabigatran.
- Li, Meilin,Ren, Yujie
-
-
Read Online
- Michael addition reaction catalyzed by imidazolium chloride to protect amino groups and construct medium ring heterocycles
-
An effective approach for amino protection and construction of a seven-membered ring has been developed. The method uses imidazolium chloride to carry out the Michael addition reaction at low temperatures and perform amino deprotection or construction of a seven-membered ring at high temperatures.
- Dai, Zeshu,Li, Dan,Li, Yanwu,Li, Zhiyao,Luo, Wen,Shang, Suqin,Tian, Qingqiang,Wang, Xuetong,Yuan, Jianyong,Zhang, Ying
-
supporting information
(2019/12/04)
-
- Method for catalyzing amino protection by imidazole hydrochloride
-
The invention provides an amino protection method which realizes multi-substituted amino protection by using imidazole hydrochloric acid as an accelerator to push derivatives of primary amine, secondary amine and acrylamide to perform Michael addition at a relatively low temperature, wherein the imidazole hydrochloric acid promotes a carbon-nitrogen bond to crack back to the derivatives of primaryamine and acrylamide at a high temperature. The method provided by the invention is simple and economical, high in practicability, free of any other catalysts or additives, capable of protecting amino to have good functional group tolerance and excellent yield and purity, short in reaction time, free from harsh reaction conditions and suitable for industrial production.
- -
-
Paragraph 0039-0043
(2019/08/01)
-
- Multi-substituted 4-methyl ester derivative of amino benzonitrile trunk and its preparation and use
-
The invention provides new ester derivatives with a general formula (I) shown in the specification of multi-substituted 4-methylamino-benzamidine or pharmaceutically acceptable salts, wherein A1, A2, A3 and A4 in the formula are as defined in the specification. The compounds have an anticoagulant effect and can be used for preparing medicaments for preventing and treating thromboembolic diseases.
- -
-
Paragraph 0096; 0099-0101
(2018/01/19)
-
- Triflic acid as efficient catalyst for the hydroamination of ethyl acrylate with 2-aminopyridines
-
Triflic acid (5mol%) is an efficient catalyst, which firstly applied to the anti-Markovnikov intermolecular hydroamination of ethyl acrylate with 2-aminopyridines, sharply improves yields as high as 96%, reduces reaction times as short as 12h. Moreover, the post-reaction process involves simple recrystallization in petroleum ether to obtain products in purity as high as 99%. The reaction mechanism is verified by crossover experiments, based on the catalytic mechanism of triflic acid previously proposed. The triflic acid is used for the reaction of a series of 2-aminopyridines with ethyl acrylate, and all the derivatives of ethyl 3-[(pyridine-2-yl)amino]propionate are characterized by 1H/13C NMR and HR-MS. The effect of electron-withdrawing/-donating substituent on the reaction is established by the reaction of substituted aminopyridines with ethyl acrylate. The reactivity of 5-methyl-2-aminopyridine is higher than those of other positional isomers of the same substituent. The reactivity of 2-aminopyridine with an electron-donating group is higher than that with an electron-withdrawing group at the same position. 2-Aminopyridines with weak electron-withdrawing substituent reacted more efficiently that those with strong electron-withdrawing substituents.
- Xu, Wen Qian,Ren, Yu Jie,Wang, Qing Wei,Sun, Ying Xin
-
p. 146 - 152
(2015/06/22)
-
- A PROCESS FOR PREPARATION OF DABIGATRAN ETEXILATE MESYLATE AND INTERMEDIATES THEREOF
-
The present invention relates to an improved process for the preparation of Dabigatran etexilate and its acid addition salts thereof, wherein the said process substantially eliminates the potential impurities. The present invention also relates to an intermediate of Dabigatran etexilate and process for preparation thereof.
- -
-
Page/Page column 41
(2015/09/28)
-
- Process For The Preparation Of Benzimidazole Derivatives And Salts Thereof
-
Provided are novel salts of benzimidazole derivatives, preferably salts of benzimidazole derivatives which are useful intermediates in the synthesis of pure 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide and its salts.
- -
-
Paragraph 0215
(2015/03/31)
-
- Dabigatran etexilate and related substances, processes and compositions, and use of the substances as reference standards and markers
-
The present invention relates to dabigatran etexilate and related substances and use of the substances as reference standards and markers. There are also provided processes of detecting the substances in samples of dabigatran etexilate, or pharmaceutically acceptable salts or solvates thereof, and also for analyzing the purity of samples of dabigatran etexilate, or pharmaceutically acceptable salts or solvates thereof. There are still further provided processes of preparing dabigatran etexilate and related substances, and pharmaceutical compositions containing the same.
- -
-
Page/Page column 19
(2012/12/13)
-
- DABIGATRAN ETEXILATE AND RELATED SUBSTANCES, PROCESSES AND COMPOSITIONS, AND USE OF THE SUBSTANCES AS REFERENCE STANDARDS AND MARKERS
-
The present invention relates to dabigatran etexilate and related substances and use of the substances as reference standards and markers. There are also provided processes of detecting the substances in samples of dabigatran etexilate, or pharmaceutically acceptable salts or solvates thereof, and also for analyzing the purity of samples of dabigatran etexilate, or pharmaceutically acceptable salts or solvates thereof.There are still further provided processes of preparing dabigatran etexilate and related substances, and pharmaceutical compositions containing the same.
- -
-
Page/Page column 34; 35
(2012/12/13)
-