Xi:Irritant;7479-05-2Relevant academic research and scientific papers
Harmine-based dual inhibitors targeting histone deacetylase (HDAC) and DNA as a promising strategy for cancer therapy
Lu, Dehua,Qu, Lailiang,Wang, Cheng,Luo, Heng,Li, Shang,Yin, Fucheng,Liu, Xingchen,Chen, Xinye,Luo, Zhongwen,Cui, Ningjie,Peng, Wan,Ji, Limei,Kong, Lingyi,Wang, Xiaobing
, (2022/01/20)
Overexpression of histone deacetylases (HDACs) are observed in different types of cancers, but histone deacetylase inhibitors (HDACIs) have not shown significant efficacy as monotherapy against solid tumors. Recently, studies demonstrated that it is promi
Stereoretentive N-Arylation of Amino Acid Esters with Cyclohexanones Utilizing a Continuous-Flow System
Ichitsuka, Tomohiro,Komatsuzaki, Shingo,Masuda, Koichiro,Koumura, Nagatoshi,Sato, Kazuhiko,Kobayashi, Shū
supporting information, p. 10844 - 10848 (2021/05/31)
The N-arylation of chiral amino acid esters with minimal racemization is a challenging transformation because of the sensitivity of the α-stereocenter. A versatile synthetic method was developed to prepare N-arylated amino acid esters using cyclohexanones as aryl sources under continuous-flow conditions. The designed flow system, which consists of a coil reactor and a packed-bed reactor containing a Pd(OH)2/C catalyst, efficiently afforded the desired N-arylated amino acids without significant racemization, accompanied by only small amounts of easily removable co-products (i. e., H2O and alkanes). The efficiency and robustness of this method allowed for the continuous synthesis of the desired product in very high yield and enantiopurity with high space-time yield (74.1 g L?1 h?1) and turnover frequency (5.9 h?1) for at least 3 days.
Inhibition of acetylcholinesterase by coumarin-linked amino acids synthetized via triazole associated with molecule partition coefficient
De Sousa, Bianca L.,Leite, Jo?o P.V.,Mendes, Tiago A.O.,Varej?o, Eduardo V.V.,Chaves, Anna C.S.,da Silva, Júnio G.,Agrizzi, Ana P.,Ferreira, Priscila G.,Pilau, Eduardo J.,Silva, Evandro,dos Santos, Marcelo H.
, p. 652 - 664 (2021/02/16)
A previous study for the identification of acetylcholinesterase (AChE) inhibitors demonstrated that the hybrid between tyrosol, the 1,2,3-triazole nucleus, and the coumarin group, namely 7-({1-[2-(4-hydroxyphenyl)ethyl]-1H-1,2,3-triazol-4-yl}methoxy)-4-methyl-2H-chromen-2-one (10), has a high enzyme inhibitory activity. Here, we synthesized analogues of 10 via triazole with pharmacophoric groups represented by tyrosine, phenylalanine, tryptophan, and glycine in addition to evaluating the impact of coumarin-linked amino acids on AChE inhibition. We obtained eight triazoles, six of which are undescribed. In general, the presence of carboxylic acid decreased the inhibitory activity, while aromatic amino acids increased enzymatic inhibition compared to glycine. The derivative containing tyrosine, structurally most similar to 10, presented the lowest inhibition percentage, indicating that phenolic hydroxyl is not the preponderant factor for inhibition. Molecular docking was not enough to explain in vitro experiments. On the other hand, MlogP (logP calculated by the Moriguchi method) was related positively to enzymatic inhibition. To increase the hydrophobicity of the molecules, we tested the esterified triazole derivatives comparatively with the enzyme. The compound ethyl 2-(4-(((4-methyl-2-oxo-2H-chromen-7-yl)oxy)methyl)- 1H-1,2,3-triazol-1-yl)acetate (6) presented an increment of inhibitory activity of 46.97 ± 1.75% at 100 μmol L-1. We also associated the best activity with the lowest van der Waals volume and molar mass values.
Design, synthesis and evaluation of novel β-carboline ester analogues as potential anti-leishmanial agents
Adinarayana, Nandikolla,Balana Fouce, Rafael,Chandra Sekhar, K. V. G.,Faheem,Karan Kumar, Banoth,Melcon-Fernandez, Estela,Murugesan, Sankaranarayan,Perez-Pertejo Yolanda, Yolanda,Reguera, Rosa M.,Vanaparthi, Satheeshvarma
, (2021/09/03)
Leishmaniasis is one of today's most neglected diseases. The emergence of new anti-leishmanial therapies emphasizes several study groups funded by the World Health Organization. The present investigation will focus on the research to determine a few new potential derivatives of β-carboline ester derivatives against leishmaniasis. The in-silico predicted ADMET properties of most of the titled compounds are in an acceptable range and having drug like properties. Among all the tested analogs, compound ES-3 (EC50 3.36 μM; SI > 29.80) showed comparable and equipotent anti-leishmanial activity as that of standard drug miltefosine (EC50 4.80 μM; SI > 20.80) against amastigote forms of the tested L. infantum strain. Two compounds ES-6 and ES-10 exhibited significant activity with EC50 10.16, 13.56 μM; SI > 4.90, 7.37, respectively. In-silico based molecular docking and dynamics study of the significantly active analog also performed to study the putative binding mode, interaction pattern at the active site of the target leishmanial trypanothione reductase enzyme as well as stability of the target-ligand complex. The changes in the conformation of molecules during MD (frame wise trajectory analysis) provided new insights for the development of novel potent molecules. These findings will further give insight that will help modify the compound ES-3 for better potency and the design of novel inhibitors for leishmaniasis. Communicated by Ramaswamy H. Sarma.
Solvent free three-component synthesis of 2,4,5-trisubstituted-1H-pyrrol-3-ol-type Compounds from L-tryptophan: DFT-B3LYP calculations for the reaction mechanism and 3H-pyrrol-3-one?1H-pyrrol-3-ol tautomeric equilibrium
Becerra, Lili Dahiana,Coy-Barrera, Ericsson,Quiroga, Diego
, (2020/10/12)
In this paper, we describe the solvent-free three-component synthesis of 2,4,5-trisubstituted-1H-pyrrol-3-ol-type compounds from L-tryptophan. The first step of the synthetic methodology involved the esterification of L-tryptophan in excellent yields (93–98%). Equimolar mixtures of alkyl 2-aminoesters, 1,3-dicarbonyl compounds, and potassium hydroxide (0.1 eq.) were heated under solvent-free conditions. The title compounds were obtained in moderate to good yields (45%–81%). Density functional theory using “Becke, 3-parameter, Lee–Yang–Parr” correlational functional (DFT-B3LYP) calculations were performed to understand the molecular stability of the synthesized compounds and the tautomeric equilibrium from 3H-pyrrol-3-one type intermediates to 1H-pyrrol-3-ol type aromatized rings.
A class of DL-tryptophan compounds, preparation method and applications thereof
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Paragraph 0175-0178, (2020/06/17)
The invention provides a DL-tryptophan compound represented by a general formula I or a pharmaceutically acceptable salt thereof, a preparation method and applications thereof, especially applicationsin preparation of RANKL inhibitors. According to the DL-tryptophan compound or the pharmaceutically acceptable salt thereof, an OPG-RANKL-RANK signal system can be intervened by inhibiting the interaction of RANKL-RANK, and the activity of RANKL in osteoclast precursor cells is regulated and controlled, so that formation of osteoclasts is inhibited, and bone resorption is reduced; and the DL-tryptophan compound or the pharmaceutically acceptable salt thereof is expected to play a role in preventing and treating bone metabolic diseases, and brings good news to bone metabolic disease patients.
ZnO-NP assisted synthesis of fluorescent β-carboline C-1 tethered benzimidazole/benzothiazole/benzoxazole derivatives and assessment of their photophysical properties
Kumar, Vipin,Singh, Dharmender,Paul, Avijit Kumar,Shrivastava, Rahul,Singh, Virender
supporting information, p. 18304 - 18315 (2019/12/02)
A facile transformation of 1-formyl β-carboline into fluorescent β-carboline C-1 tethered benzazole derivatives is described under the catalysis of ZnO nanoparticles. The reaction proceeded with the reaction of 1-formyl β-carboline and substituted o-diaminobenzene/2-aminobenzenethiol/2-aminophenol, which results in formation of a Schiff base, followed by an intramolecular cylization reaction to generate β-carboline linked benzimidazole, benzothiazole and benzoxazole derivatives. This appraoch displayed a wide substrate scope and high regioselectivity to yield the desired products in moderate to good yields. The photophysical properties of the synthesized derivatives were also evaluated and they exhibited excellent fluorescence properties. Among these β-carboline substituted azoles, the benzothiazole derivative displayed the maximum quantum yield (ΦF up to 28%).
Development of Small-Molecules Targeting Receptor Activator of Nuclear Factor-κB Ligand (RANKL) - Receptor Activator of Nuclear Factor-κB (RANK) Protein-Protein Interaction by Structure-Based Virtual Screening and Hit Optimization
Jiang, Min,Peng, Lei,Yang, Kai,Wang, Tianqi,Yan, Xueming,Jiang, Tao,Xu, Jianrong,Qi, Jin,Zhou, Hanbing,Qian, Niandong,Zhou, Qi,Chen, Bo,Xu, Xing,Deng, Lianfu,Yang, Chunhao
supporting information, p. 5370 - 5381 (2019/06/24)
Targeting RANKL/RANK offers the possibility of developing novel therapeutic approaches to treat bone metabolic diseases. Multiple efforts have been made to inhibit RANKL. For example, marketed monoclonal antibody drug Denosumab could inhibit the maturation of osteoclasts by binding to RANKL. This study is an original approach aimed at discovering small-molecule inhibitors impeding RANKL/RANK protein interaction. We identified compound 34 as a potent and selective RANKL/RANK inhibitor by performing structure-based virtual screening and hit optimization. Disruption of the RANKL/RANK interaction by 34 effectively inhibits RANKL-induced osteoclastogenesis and bone resorption. The expression of osteoclast marker genes was also suppressed by treatment of 34. Furthermore, 34 markedly blocked the NFATc1/c-fos pathway. Thus, our current work demonstrates that the chemical tractability of the difficult PPI (RANKL/RANK) target by a small-molecule compound 34 offers a potential lead compound to facilitate the development of new medications for bone-related diseases.
Biological evaluation and structure activity relationship of 9-methyl-1-phenyl-9H-pyrido[3,4-b]indole derivatives as anti-leishmanial agents
Ashok, Penta,Chander, Subhash,Smith, Terry K.,Prakash Singh, Rajnish,Jha, Prabhat Nath,Sankaranarayanan, Murugesan
, p. 98 - 105 (2018/11/30)
A series of piperazinyl-β-carboline-3-carboxamide derivatives were designed through a molecular hybridization approach. Designed analogues were synthesized, characterized and evaluated for anti-leishmanial activity against Leishmania infantum and Leishmania donovani. In L. infantum inhibition assay, compounds 7d, 7g and 7c displayed potent inhibition of promastigotes (EC50 1.59, 1.47 and 3.73 μM respectively) and amastigotes (EC50 1.4, 1.9 and 2.6 μM respectively). SAR studies revealed that, para substitution of methoxy, chloro groups and methyl group on ortho position favored anti-leishmanial activity against L. infantum. Among these analogues 7d, 7h, 7n and 7g exhibited potent inhibition against L. donovani promastigotes (EC50 0.91, 4.0, 4.57 and 5.02 μM respectively), axenic amastigotes (EC50 0.9, 3.5, 2.2 and 3.8 μM respectively) and intracellular amastigotes (EC50 1.3, 7.8, 5.6 and 6.3 μM respectively). SAR studies suggested that, para substitution of methoxy group, para and meta substitution of chloro groups and benzyl replacement recommended for significant anti-leishmanial against L. donovani.
Design, synthesis and biological evaluation of piperazinyl-β-carbolinederivatives as anti-leishmanial agents
Ashok, Penta,Chander, Subhash,Smith, Terry K.,Sankaranarayanan, Murugesan
, p. 559 - 566 (2018/03/21)
Molecular hybridization is a ligand based drug design approach is well known recent medicinal chemistry to design anti-parasitic agents. In the present study, we have designed a series of (1-phenyl-9H-pyrido [3,4-b]indol-3-yl) (4-phenylpiperazin-1-yl)methanone derivatives using molecular hybridization approach. Designed analogues were evaluated for cytotoxicity and inhibition activity against Leishmania infantum and Leishmania donovani. Among these reported analogues 7b, 7d, 7e, 7f and 7m displayed potent inhibition of both L. infantum and L. donovani. Compounds 7i and 7k exhibited selective potent inhibition of L. donovani. Especially, compounds 7e and 7k showed most potent anti-leishmanial activity against L. infantum and L. donovani respectively. Anti-leishmanial activity of these compounds is comparable with standard drugs miltefosine and pentamidine. SAR studies revealed that, electron donating group substitution on phenyl ring recommended for potent anti-leishmanial activity.
