- Design, synthesis and neuroprotective effects of Fenazinel derivatives
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In search of novel neuroprotective agents with higher potency and lower hERG liability, a series of novel Fenazinel derivatives were designed and synthesized, among which compounds 8m–o containing amide moiety exhibited good neuroprotective effects in vitro and in vivo. Especially, the representative compound 8o showed lower activity in a patch clamp hERG K+ ion channel screen and could be considered as a lead compound for further development. These findings provided an alternative approach to the development of drugs more potent than Fenazinel for the intervention of ischemic stroke.
- Zhang, Qing-Wei,Jiang, Ling,Wang, Guan,Li, Jian-Qi
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Read Online
- Synthesis of New 2-Halo-2-(1H-tetrazol-5-yl)-2H-azirines via a Non-Classical Wittig Reaction
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The synthesis and reactivity of tetrazol-5-yl-phosphorus ylides towards N-halosuccinimide/TMSN3 reagent systems was explored, opening the way to new haloazidoalkenes bearing a tetrazol-5-yl substituent. These compounds were obtained as single isomers, except in one case. X-ray crystal structures were determined for three derivatives, establishing that the non-classical Wittig reaction leads to the selective synthesis of haloazidoalkenes with (Z)-configuration. The thermolysis of the haloazidoalkenes afforded new 2-halo-2-(tetrazol-5-yl)-2H-azirines in high yields. Thus, the reported synthetic methodologies gave access to important building blocks in organic synthesis, vinyl tetrazoles and 2-halo-2-(tetrazol-5-yl)-2H-azirine derivatives.
- Cardoso, Ana L.,Sousa, Carmo,Henriques, Marta S.C.,Paix?o, José A.,Pinho E Melo, Teresa M.V.D.,Banert, Klaus
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- Anti-melanogenesis and anti-tyrosinase properties of aryl-substituted acetamides of phenoxy methyl triazole conjugated with thiosemicarbazide: Design, synthesis and biological evaluations
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A series of aryl phenoxy methyl triazole conjugated with thiosemicarbazides were designed, synthesized, and evaluated for their tyrosinase inhibitory activities in the presence of L-dopa and L-tyrosine as substrates. All the compounds showed tyrosinase inhibition in the sub-micromolar concentration. Among the derivatives, compound 9j bearing benzyl displayed exceptionally high potency against tyrosinase with IC50 value of 0.11 μM and 0.17 μM in the presence of L-tyrosine and L-dopa as substrates which is significantly lower than that of kojic acid as the positive control with an IC50 value of 9.28 μM for L-tyrosine and 9.30 μM for L-dopa. According to Lineweaver–Burk plot, 9j demonstrated an uncompetitive type of inhibition in the kinetic assay. Also, in vitro antioxidant activities determined by DPPH assay recorded an IC50 value of 68.43 μM for 9i. The melanin content of 9j was determined on B16F10 melanoma human cells which demonstrated a significant reduction of the melanin content. Moreover, the binding energies corresponding to the same ligand as well as computer-aided drug-likeness and pharmacokinetic studies were also carried out. Compound 9j also possessed metal chelation potential correlated to its high anti-TYR activity.
- Hosseinpoor, Hona,Moghadam Farid, Sara,Iraji, Aida,Askari, Sadegh,Edraki, Najmeh,Hosseini, Samanesadat,Jamshidzadeh, Akram,Larijani, Bagher,Attarroshan, Mahshid,Pirhadi, Somayeh,Mahdavi, Mohammad,Khoshneviszadeh, Mehdi
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- Synthesis and application of Cu(II) immobilized MCM-41 based solid Lewis acid catalyst for aminolysis reaction under solvent-free condition
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In this paper, a Cu(II) immobilized periodic mesoporous organosilica (PMOs) was synthesized and used as a reusable solid Lewis acid catalyst for the aminolysis of epoxides under solvent-free conditions. An amide-based ligand, L-propylsilyl (1) having a specific binding pocket was prepared and fabricated on mesoporous MCM-41 to produce mesoporous organosilica L-propylsilyl@MCM-41 (2). Further, it has been utilized for anchoring Cu(II) ions under controlled reaction conditions to yield solid Lewis acid catalyst Cu(II)-L-propylsilyl@MCM-41 (3). The synthesized catalyst 3 exhibits significantly higher catalytic activity for aminolysis compared to hitherto known solid Lewis acid catalysts. An extensive range of β-amino alcohols with high regio and stereoselectivity were prepared by using catalyst 3. The catalyst was recovered easily and reused eight times without any loss in its catalytic activity. Furthermore, the synthesis of clinically significant propranolol (β-blocker) from α- naphthyl glycidyl ether was attained successfully using catalyst 3 in a very decent yield.
- Chaudhary, Garima,Gupta, Neha,Singh, Amit Pratap
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supporting information
(2021/07/22)
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- Novel chromenyl-based 2-iminothiazolidin-4-one derivatives as tubulin polymerization inhibitors: Design, synthesis, biological evaluation and molecular modelling studies
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Here-in, we present molecular design, chemical synthesis and evaluation of novel chromenyl-based 2-iminothiazolidin-4-one derivatives as tubulin polymerization inhibitors. The newly synthesized compounds were evaluated for their in vitro cytotoxicities against A549 (lung cancer), MDA-MB-231 and BT-471 (breast cancer), HepG2 (liver cancer) and HCT-116 (colon cancer) cell lines by MTT assay. Among the synthesized compounds, compound 12b showed excellent anticancer activity on MDA-MB-231 cell line with IC50 value of 0.95 ± 1.88 μM and was verified to be safe in normal human bronchial epithelial cells (Beas-2B). Apoptosis induced by the lead 12b was observed using morphological observations, AO/EB and DAPI staining procedures. Further, dose-dependent increase in the depolarization of mitochondrial membrane was also observed through JC-1 staining. Annexin V-FITC/PI assay confirmed that 12b induced early apoptosis. Additionally, cell cycle analysis indicated that the MDA-MB-231 cells were arrested at sub-G2/M phase and also inhibited tubulin polymerization with IC50 value of 3.54 ± 0.2 μM. Molecular docking simulations were employed to identify the important binding modes responsible for the tubulin inhibitory activity, thus supporting their effective anticancer potential.
- Bathini, Nagendra Babu,Godugu, Chandraiah,Guggilapu, Sravanthi Devi,Kadagathur, Manasa,Pooladanda, Venkatesh,Sigalapalli, Dilep Kumar,Tangellamudi, Neelima D.,Uppu, Jaya Lakshmi
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- Synthesis, characterization and evaluation of novel ferrocenylmethylamine derivatives as cytotoxic agents
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The present report describes a new series of amide functionalized 20- and 30-aminomethylferrocene derived from ferrocenylmethylamine. The compounds 1a-5a and 1b-5b were characterized by microanalysis, 1H, 13C NMR, UV–visible, fluorescence, FTIR, thermogravimetric and crystallographic techniques. The X-ray analysis demonstrated the ability of these molecules to form various intermolecular hydrogen bonding interactions, as verified by Hirshfeld surface analysis. All the compounds were evaluated against MCF 7, IMR 32, HepG2 and immortal L132 cell lines by MTT assay and the results were compared with cisplatin. Interestingly, many compounds were very active against all the investigated cell lines and proved to be more potent as cytotoxic agents than cisplatin. The western blot, gene expression, mitochondrial membrane potential and flow cytometry study were used to investigate the mode of action of these derivatives as antitumor agents. The results showed apoptotic property of the compounds by modulating inflammatory pathway against human tumor cells of different origin. We performed the density functional theory calculations and molecular docking to rationalize the experimental results.
- Savani, Chirag J.,Roy, Hetal,Verma, Sanjay K.,Vennapu, Dushyanth R.,Singh, Vinay K.
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- Organocatalytic Cascade Reactions for the Diversification of Thiopyrano-Piperidone Fused Rings Utilizing Trienamine Activation
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An aminocatalytic privileged diversity-oriented synthesis (ApDOS) strategy utilizing trienamine catalysis for the construction of diverse and complex thiopyrans-piperidone fused rings through a thia-Diels–Alder/nucleophilic ring-closing sequence by using dithioamides as activated heterodienophiles is reported. Following this strategy, a super cascade reaction to assemble nine fused rings can be achieved by employing a bis-dithioamide. Additionally, by linking an indole moiety on the dithioamide, a Pictet–Spengler type reaction can be promoted once the cascade sequence has been achieved, leading to more complex penta- hexa- and heptacyclic fused ring derivatives in a one-pot process. This investigation opens new perspectives for the synthesis of a new class of complex and diverse thiopyrans that contribute to populate new relevant regions in the chemical space.
- Mitkari, Suhas Balasaheb,Medina-Ortíz, Alberto,Olivares-Romero, José Luis,Vázquez, Miguel A.,Pe?a-Cabrera, Eduardo,Villegas Gómez, Clarisa,Cruz Cruz, David
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supporting information
p. 618 - 621
(2020/12/11)
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- The possible effect of microRNA-155 (miR-155) and BACE1 inhibitors in the memory of patients with down syndrome and Alzheimer's disease: Design, synthesis, virtual screening, molecular modeling and biological evaluations
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MiR-155 plays main roles in several physiological and pathological mechanisms, such as Down syndrome (DS), immunity and inflammation and potential anti-AD therapeutic target. The miR-155 is one of the overexpressed miRNAs in DS patients that contribute directly and indirectly to the onset or progression of the DS. Since the miR-155 can simultaneously reduce the translation of several genes at post-transcriptional levels, targeting the miR-155 might set the stage for the treatment of DS. One of the rational strategies in providing therapeutic interventions in this respect is to design and develop novel small molecules inhibiting the miR-155 function or biogenesis or maturation. In the present study, we aim to introduce small molecule compounds with the potential to inhibit the generation of the selectively miR-155 processing by employing computational drug design approaches, as well as in vitro studies. We designed and synthesized a novel series of imidazo[1,2-a]pyridines derivatives as new nonpeptic candidates for the treatment of DS with AD. The designed compounds were investigated for their BACE1 and miR-155 binder inhibitory potential in vitro and in cell. In addition, we present a systematic computational approach that includes 3 D modeling, docking-based virtual screening, and molecular dynamics simulation to identify Small - molecule inhibitors of pre-miR-155 maturation. To confirm the inhibitory potential of compound 8k on miR-155 maturation, qRT- PCR was performed. All our results confirm that compound 8k, in addition to being a good inhibitor of BACE1, can also be a good inhibitor of miR-155. Communicated by Ramaswamy H. Sarma.
- Mahernia, Shabnam,Hassanzadeh, Malihe,Adib, Mehdi,Peytam, Fariba,Haghighijoo, Zahra,Iraji, Aida,Mahdavi, Mohammad,Edraki, Najmeh,Amanlou, Massoud
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- Effect of chirality and redox potentials on the cytotoxicity of new ferrocene functionalized chiral tertiary amines
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Optically pure enantiomeric pair viz. ferrocene functionalized chiral tertiary amines S,S-(-)-1 and R,R-(+)-2 have been synthesized from ferrocenylmethylamine to probe the influence of chirality and the redox potential on their anti-proliferative activity. Compounds were characterized by microanalysis, HPLC, 1H, 13C NMR, UV-visible, fluorescence, FTIR, thermogravimetric and crystallographic techniques. The single crystal X-ray diffraction (SCXRD) study revealed that the molecules of 1 holding S,S-chirality at benzylic carbons forms a fascinating M-helix while 2 holding R,R-chirality at benzylic carbons forms P-helix by involving intra- and intermolecular H-bonding interactions as verified by Hirshfeld surface analysis. Chirality-related influence was observed on the antiproliferative activity of enantiomeric pair and at the supramolecular level. For instance, enantiomer R,R-(+)-2 is found to be highly active against all the investigated human carcinoma cell lines MCF 7, IMR 32, HepG2, and immortal L132 cell lines. In particular, R,R-(+)-2 exhibited more than 10 folds better antiproliferation (IC 50: 6.35±0.19 μM) than other enantiomer S,S-(-)-1 (IC50: 65.96 ± 0.12 μM) and four folds better activity than highly successful anticancer drug, cisplatin (IC50: 24.3 ± 1.7 μM) against Hep G2 cell line. The electrochemical, DFT calculations and molecular docking study have been performed to justify the experimental outcomes.
- Roy, Hetal,Savani, Chirag J.,Singh, Vinay K.,Vennapu, Dushyanth R.
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- Synthesis, Characterization and Thermal Study of some new Organochalcogenide compounds containing arylamide group
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Two Series of organochalcogen compounds were prepared. The first series was prepared by the reaction of 2-chloro-N-arylacetamide (where aryl is benzyl, phenyl, o-toluene, or p-toluene) with sodium hydrogen selenide (prepared in situ) to give diorganyl selenide compounds (R2Se). The second series was prepared by reaction of N-benzyl-2-chloro-N-(2-chloroacetyl) acetamide with sodium chalcogenate, Na2E (where E= S, Se, and Te) to give the corresponding cyclic chalcogenide compounds. Diiodo derivatives of cyclic selenide and telluride were also prepared. The thermal stability of the new selenium compounds (R2Se) were decomposed at 300°C. Thermogram showed a phase transfer point between 120-150°C indicating that these compounds may act as liquid crystal compounds. All new compounds were characterized by CHN elemental analysis, UV-Visible, FT-IR and 1H NMR spectroscopic data.
- Hassan,Abdulwahid,Al-Luaibi,Al-Jadaan
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p. 5009 - 5015
(2021/08/31)
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- 3-(aminomethyl)-4-(4-fluorophenyl) piperazine-1-carboxylic acid tert-butyl ester and synthesis method thereof
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The invention belongs to the technical field of organic synthesis, and relates to 3-(aminomethyl)-4-(4-fluorophenyl) piperazine-1-carboxylic acid tert-butyl ester and a synthesis method thereof. According to the invention, the compound can be used as a medical intermediate; the synthesis method comprises the following steps: by taking benzylamine as a raw material, preparing 3-(aminomethyl)-4-(4-fluorophenyl) piperazine-1-carboxylic acid tert-butyl ester through eight steps of reactions including substitution, substitution, reduction, cyclization, substitution, esterolysis, substitution and amination; and the synthesis method is simple and high in yield.
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Paragraph 0021-0023; 0038-0040; 0055-0057
(2020/11/23)
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- Dual targeting of cholinesterase and amyloid beta with pyridinium/isoquinolium derivatives
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With the surge in the cases of Alzheimer's disease (AD) over the years, several targets have been explored to curb the disease. Cholinesterases, namely acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), remain to be the available targets that are amendable to currently approved treatments. In this study, a series of novel compounds based on tramiprosate, a highly specific amyloid beta (Aβ) inhibitor, was designed to inhibit AChE, BuChE, and Aβ aggregation. In particular, the addition of a pyridinium/isoquinolinium ring to the tramiprosate moiety (to give compounds 3a–j) led to an increase in the binding affinity for the catalytic active site of cholinesterase, which was hampered by the presence of sulfonic acid. Exclusion of the sulfonic acid moiety led to a novel but effective class of cholinesterase inhibitors (9a–w). in vitro Aβ aggregation inhibition assay indicated that compounds 3a–j, 9e–f, 9i–l, 9q, 9r, 9u–w, and 12 could inhibit over 10% Aβ aggregation at 1 mM concentration. Cholinesterase inhibition assay suggested that compounds 9g, 9h, 9o, and 9q–t exhibit over 70% inhibition on both AChE and BuChE at a concentration of 100 μM. Amongst the designed molecules, compound 9r (ca 18% at 1 mM) showed comparable inhibitory effect on the inhibition of Aβ aggregation with tramiprosate (ca 20% at 1 mM), along with impressive cholinesterase inhibitory potential (AChE IC50 = 13 μM and BuChE IC50 = 12 μM), acceptable toxicity and ability to pass through blood brain barrier, which could be used to ameliorate the phenotypes of AD in preclinical models.
- Chakravarty, Harapriya,Ju, Yaojun,Chen, Wen-Hua,Tam, Kin Y.
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p. 242 - 255
(2019/12/27)
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- Synthesis and biological evaluation of new benzimidazole-1,2,3-triazole hybrids as potential α-glucosidase inhibitors
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In this study, a series of benzimidazole-1,2,3-triazole hybrids 8a-n as new α-glucosidase inhibitors were designed and synthesized. In vitro α-glucosidase inhibition activity results indicated that all the synthesized compounds (IC50 values ranging from 25.2 ± 0.9 to 176.5 ± 6.7 μM) exhibited more inhibitory activity in comparison to standard drug acarbose (IC50 = 750.0 ± 12.5 μM). Enzyme kinetic study on the most potent compound 8c revealed that this compound was a competitive inhibitor into α-glucosidase. Moreover, the docking study was performed in order to evaluation of interaction modes of the synthesized compounds in the active site of α-glucosidase and to explain structure-activity relationships of the most potent compounds and their corresponding analogs.
- Asadi, Mehdi,Asemanipoor, Nafise,Biglar, Mahmood,Faramarzi, Mohammad Ali,Hajimiri, Mir Hamed,Hamedifar, Haleh,Larijani, Bagher,Mahdavi, Mohammad,Mohammadi-Khanaposhtani, Maryam,Moradi, Shahram,Vahidi, Mahbobeh
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- Discovery and evaluation of new compounds targeting ribosomal protein S1 in antibiotic-resistant Mycobacterium Tuberculosis
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The emergence of antibiotic-resistant Mycobacterium Tuberculosis (Mtb) infections compels new treatment strategies, of which targeting trans-translation is promising. During the trans-translation process, the ribosomal protein S1 (RpsA) plays a key role, and the Ala438 mutant is related to pyrazinamide (PZA) resistance, which shows its effects after being hydrolysed to pyrazinoic acid (POA). In this study, based on the structure of the RpsA C-terminal domain (RpsA-CTD) and POA complex, new compounds were designed. After being synthesized, the compounds were tested in vitro with saturation transfer difference (STD), fluorescence quenching titration (FQT) and chemical shift perturbation (CSP) experiments. Finally, six of the 17 new compounds have high affinity for both RpsA-CTD and its Ala438 deletion mutant. The active compounds provide new choices for targeting trans-translation in Mtb, and the analysis of the structure-activity relationships will be helpful for further structural modifications based on derivatives of 2-((hypoxanthine-2-yl)thio)acetic acid and 2-((5-hydroxylflavone-7-yl)oxy)acetamide.
- Dai, Yazhuang,Guo, Chenyun,Lin, Donghai,Lin, Kejiang,Xu, Yinqiu,Xue, Xiaowen
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- Synthesis, characterization, molecular docking, and biological activities of coumarin–1,2,3-triazole-acetamide hybrid derivatives
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Coumarins and their derivatives are receiving increasing attention due to numerous biochemical and pharmacological applications. In this study, a series of novel coumarin–1,2,3-triazole-acetamide hybrids was tested against some metabolic enzymes including α-glycosidase (α-Gly), α-amylase (α-Amy), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), human carbonic anhydrase I (hCA I), and hCA II. The new coumarin–1,2,3-triazole-acetamide hybrids showed Ki values in the range of 483.50–1,243.04 nM against hCA I, 508.55–1,284.36 nM against hCA II, 24.85–132.85 nM against AChE, 27.17–1,104.36 nM against BChE,?590.42–1,104.36 nM against α-Gly,?and 55.38–128.63 nM against α-Amy. The novel coumarin–1,2,3-triazole-acetamide hybrids had effective inhibition profiles against all tested metabolic enzymes. Also, due to the enzyme inhibitory effects of the new hybrids, they are potential drug candidates to treat diseases such as epilepsy, glaucoma, type-2 diabetes mellitus (T2DM), Alzheimer's disease (AD), and leukemia. Additionally, these inhibition effects were compared with standard enzyme inhibitors like acetazolamide (for hCA I and II), tacrine (for AChE and BChE), and acarbose (for α-Gly and α-Amy). Also, those coumarin–1,2,3-triazole-acetamide hybrids with the best inhibition score were docked into the active site of the indicated metabolic enzymes.
- Sepehri, Nima,Mohammadi-Khanaposhtani, Maryam,Asemanipoor, Nafise,Hosseini, Samanesadat,Biglar, Mahmood,Larijani, Bagher,Mahdavi, Mohammad,Hamedifar, Haleh,Taslimi, Parham,Sadeghian, Nastaran,Gulcin, Ilhami
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- Design, Synthesis, and Bioactivity of α-Ketoamide Derivatives Bearing a Vanillin Skeleton for Crop Diseases
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A series of novel α-ketoamide derivatives bearing a vanillin skeleton were designed and synthesized. Bioactivity tests on virus and bacteria were performed. The results indicated that some compounds exhibited excellent antitobacco mosaic virus (TMV) activities, such as compound 34 exhibited an inactivation activity of 90.1percent and curative activity of 51.8percent and compound 28 exhibited a curative activity of 54.8percent at 500 μg mL-1, which is equivalent to that of the commercial ningnanmycin (inactivation of 91.9percent and curative of 51.9percent). Moreover, the in vitro antibacterial activity test illustrated that compounds 2, 22, and 33 showed much higher activities than commercial thiodiazole copper, which could be used as lead compounds or potential candidates. The findings of transmission electron microscopy and molecular docking indicated that the synthesized compounds exhibited strong and significant binding affinity to the TMV coat protein and could obstruct the self-assembly and increment of TMV particles. This study revealed that α-ketoamide derivatives bearing a vanillin skeleton could be used as a novel potential pesticide for controlling the plant diseases.
- Chen, Shunhong,Dai, Ali,Guo, Shengxin,He, Feng,Luo, Dexia,Wu, Jian,Zhang, Renfeng
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p. 7226 - 7234
(2020/08/06)
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- Development of triazolothiadiazine derivatives as highly potent tubulin polymerization inhibitors: Structure-activity relationship, in vitro and in vivo study
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Based on our prior work, we reported the design, synthesis, and biological evaluation of fifty-two new triazolothiadiazine-based analogues of CA-4 and their preliminary structure-activity relationship. Among synthesized compounds, Iab was found to be the most potent derivative possessing IC50 values ranging from single-to double-digit nanomolar in vitro, and also exhibited excellent selectivity over the normal human embryonic kidney HEK-293 cells (IC50 > 100 μM). Further mechanistic studies revealed that Iab significantly blocked tubulin polymerization and disrupted the intracellular microtubule network of A549 cells. Moreover, Iab induced G2/M cell cycle arrest by regulation of p-cdc2 and cyclin B1 expressions, and caused cell apoptosis through up-regulating cleaved PARP and cleaved caspase-3 expressions, and down-regulating of Bcl-2. Importantly, in vivo, Iab effectively suppressed tumor growth of A549 lung cancers in a xenograft mouse model without obvious signs of toxicity, confirming its potential as a promising candidate for cancer treatment.
- Ma, Weifeng,Chen, Peng,Huo, Xiansen,Ma, Yufeng,Li, Yanhong,Diao, Pengcheng,Yang, Fang,Zheng, Shengquan,Hu, Mengjin,You, Wenwei,Zhao, Peiliang
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- Sequence-Defined Dithiocarbamate Oligomers via a Scalable, Support-free, Iterative Strategy
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Precise control over the monomeric sequence on natural sequence-defined polymers (SDPs) leads to their structural diversity and functions. However, absolute control over the monomeric sequence on a synthetic polymer remains a challenging process. Herein, we describe a support-free, protection-deprotection-free, cost-effective, and fast iterative strategy for multigram production of a new class of SDP with a unique functional group, dithiocarbamate, a potential group for material and biomedical applications. The strategy is based on a unique monomer, named as amine-hydroxyl monomer, and a three-component reaction between the monomer, CS2, and terminal chloro group of the growing chain. The fast strategy allows us to synthesize a 5-mer sequence-defined oligomer in 6 h. For a proof of concept, a range of aliphatic and aromatic groups have been incorporated at different sequences in the sequence-defined oligomer. This SDP platform has further been advanced by two ways: (i) multiple approaches for postsynthetic modification of SDP and (ii) increasing the chain length in a single step.
- Nanjan, Pandurangan,Jose, Anna,Thurakkal, Liya,Porel, Mintu
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p. 11019 - 11026
(2020/12/22)
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- Facile amidation of esters with aromatic amines promoted by lanthanide tris (amide) complexes
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The development of catalysts capable of catalyzing amidation of esters with amines to construct amides under mild conditions is of great importance. Compared to aliphatic amines, the direct catalytic amidation of esters with less nucleophilic aromatic amines is rather difficult. Employing simple lanthanide tris (amide) complexes Ln[N (SiMe3)2]3(μ-Cl)Li (THF)3 as the catalysts, it was found a broad range of aromatic amines and esters were efficiently converted into various amides in good yields under mild conditions. A plausible mechanism for this transformation was experimentally supported as starting from an amide exchange reaction between the lanthanide tris (amide) complex and the substrate amine.
- Li, Zhao,Guo, Chenjun,Chen, Jue,Yao, Yingming,Luo, Yunjie
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- Antidiabetic compounds
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Compounds for the treatment of hyperglycemia and/or diabetes are provided. The compounds, which inhibit the enzyme dipeptidyl peptidase (DPP-4), are based on the structure where X may be present or absent an may be OH, Ar is an aryl group; and n ranges from 0 to 5.
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Page/Page column 13-14
(2020/06/16)
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- Rad51/BRCA2 disruptors inhibit homologous recombination and synergize with olaparib in pancreatic cancer cells
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Olaparib is a PARP inhibitor (PARPi). For patients bearing BRCA1 or BRCA2 mutations, olaparib is approved to treat ovarian cancer and in clinical trials to treat breast and pancreatic cancers. In BRCA2-defective patients, PARPi inhibits DNA single-strand break repair, while BRCA2 mutations hamper double-strand break repair. Recently, we identified a series of triazole derivatives that mimic BRCA2 mutations by disrupting the Rad51-BRCA2 interaction and thus double-strand break repair. Here, we have computationally designed, synthesized, and tested over 40 novel derivatives. Additionally, we designed and conducted novel biological assays to characterize how they disrupt the Rad51-BRCA2 interaction and inhibit double-strand break repair. These compounds synergized with olaparib to target pancreatic cancer cells with functional BRCA2. This supports the idea that small organic molecules can mimic genetic mutations to improve the profile of anticancer drugs for precision medicine. Moreover, this paradigm could be exploited in other genetic pathways to discover innovative anticancer targets and drug candidates.
- Roberti, Marinella,Schipani, Fabrizio,Bagnolini, Greta,Milano, Domenico,Giacomini, Elisa,Falchi, Federico,Balboni, Andrea,Manerba, Marcella,Farabegoli, Fulvia,De Franco, Francesca,Robertson, Janet,Minucci, Saverio,Pallavicini, Isabella,Di Stefano, Giuseppina,Girotto, Stefania,Pellicciari, Roberto,Cavalli, Andrea
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supporting information
p. 80 - 92
(2019/01/23)
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- Cink4T, a quinazolinone-based dual inhibitor of Cdk4 and tubulin polymerization, identified via ligand-based virtual screening, for efficient anticancer therapy
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Inhibition of cyclin dependent kinase 4 (Cdk4) prevents cancer cells from entering the early G0/G1 phase of the cell division cycle whereas inhibiting tubulin polymerization blocks cancer cells’ ability to undergo mitosis (M) late in the cell cycle. We had reported earlier that two non-planar and relatively non-toxic fascaplysin derivatives, an indole and a tryptoline, inhibit Cdk4 with IC50 values of 6.2 and 10 μM, respectively. Serendipitously, we had also found that they inhibited tubulin polymerization. The molecules were efficacious in mouse tumor models. We have now identified Cink4T in a 59-compound quinazolinone library, designed on the basis of ligand-based virtual screening, as a compound that inhibits Cdk4 and tubulin. Its IC50 value for Cdk4 inhibition is 0.47 μM and >50 μM for inhibition of Cdk1, Cdk2, Cdk6, Cdk9. Cink4T inhibits tubulin polymerization with an IC50 of 0.6 μM. Molecular modelling studies on Cink4T with Cdk4 and tubulin crystal structures lend support to these observations. Cancer cell cycle analyses confirm that Cink4T blocks cells at both G0/G1 and M phases as it should if it were to inhibit both Cdk4 and tubulin polymerization. Our results show, for the very first time, that virtual screening can be used to design novel inhibitors that can potently block two crucial phases of the cell division cycle.
- Sonawane, Vinay,Mohd Siddique, Mohd Usman,Jadav, Surender Singh,Sinha, Barij Nayan,Jayaprakash, Venkatesan,Chaudhuri, Bhabatosh
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p. 115 - 132
(2019/01/23)
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- Efficient synthesis, spectroscopic characterization and DFT based studies of novel 1-amide 4-sulfonamide-1,2,3-triazole derivatives
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In the present study, for the first time 1-amide 4-sulfonamide-1,2,3-triazole scaffolds were synthesized by using an azide-alkyne Huisgen cycloaddition reaction. The target products were obtained in moderate to good yields (45–75%) by using catalytic CuI and green system H2O/EtOH. The easy availability of the inexpensive starting materials, avoiding isolation and handling of hazardous organic azides and mild reaction conditions make this method a valuable tool for generating functionalized 1,2,3-triazole derivatives. The unambiguous characterization of synthesized compounds was accomplished by using various spectroscopic techniques such as 1H NMR, 13C NMR, and FT-IR. The information regarding optimized geometry, were obtained by applying DFT/B3LYP-6-31G(d) method. The electrophilicity index, 1H and 13C chemical shift values, lithium and sodium ion affinities of the desired product 3b have been also calculated by the mentioned method. As a whole, the calculated results were found in close agreement to that of experimental data. The studies revealed that the compound 3b possesses good Li+ and Na+ affinity and cation π interaction plays a vital role in the complexation of 3b. For the first time, nucleus–independent chemical shift index was used to confirm the cation π interaction of 3b.
- Bonyad, Sarvenaz Rouhi,Mirjafary, Zohreh,Saeidian, Hamid,Rouhani, Morteza
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p. 164 - 170
(2019/07/18)
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- Discovery of certain benzyl/phenethyl thiazolidinone-indole hybrids as potential anti-proliferative agents: Synthesis, molecular modeling and tubulin polymerization inhibition study
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A series of certain benzyl/phenethyl thiazolidinone-indole hybrids were synthesized for the study of anti-proliferative activity against A549, NCI-H460 (lung cancer), MDA-MB-231 (breast cancer), HCT-29 and HCT-15 (colon cancer) cell lines by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). We found that compound G37 displayed highest cytotoxicity with IC50 value of 0.92 ± 0.12 μM towards HCT-15 cancer cell line among all the synthesized compounds. Moreover, compound G37 was also tested on normal human lung epithelial cells (L132) and was found to be safe in contrast to HCT-15 cells. The lead compound G37 showed significant G2/M phase arrest in HCT-15 cells. Additionally, compound G37 significantly inhibited tubulin polymerization with IC50 value of 2.92 ± 0.23 μM. Mechanistic studies such as acridine orange/ethidium bromide (AO/EB) dual staining, DAPI nuclear staining, annexinV/propidium iodide dual staining, clonogenic growth inhibition assays inferred that compound G37 induced apoptotic cell death in HCT-15 cells. Moreover, loss of mitochondrial membrane potential with elevated intracellular ROS levels was observed by compound G37. These compounds bind at the active pocket of the α/β-tubulin with higher number of stable hydrogen bonds, hydrophobic and arene-cation interactions confirmed by molecular modeling studies.
- Sigalapalli, Dilep Kumar,Pooladanda, Venkatesh,Singh, Priti,Kadagathur, Manasa,Guggilapu, Sravanthi Devi,Uppu, Jaya Lakshmi,Tangellamudi, Neelima D.,Gangireddy, Pavan Kumar,Godugu, Chandraiah,Bathini, Nagendra Babu
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supporting information
(2019/08/26)
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- Ether acetamide derivative containing alpha-carbonyl amide structure and application of ether acetamide derivative
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The invention discloses application of an ether acetamide derivative containing an alpha-carbonyl amide structure in an aspect of resisting plant diseases. The structure is shown in a general formulaI. Limitation of groups such as R and R is shown as the specification. A compound shown in the general formula I has a function of preventing and treating the plant diseases, and TMV, rice bacterial blight, citrus canker, ralstonia solanacearum and other plant virus diseases can be prevented and treated.
- -
-
Paragraph 0033; 0035
(2019/11/12)
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- Coumarin and 3,4-dihydroquinolinone derivatives: Synthesis, antidepressant activity, and molecular docking studies
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Background: Coumarin and 3,4-dihydroquinolinone nuclei are two heterocyclic rings that are important and widely exploited for the development of bioactive molecules. Here, we designed and synthesized a series of 3,4-dihydroquinolinone and coumarin derivatives (Compounds 8, 9, 11, 14, 15, 18-20, 23, 24 and 28 are new compounds) and studied their antidepressant activities. Methods: Forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant activity of the target compounds. The most active compound was used to evaluate the exploratory activity of the animals by the open-field test. 5-HT concentration was estimated to evaluate if the compound has an effect on the mouse brain, by using ELISA. A 5-HT1A binding assay was also performed. The biological activities of the compounds were verified by molecular docking studies. The physicochemical and pharmacokinetic properties of the target compounds were predicted by Discovery Studio and ChemBioDraw Ultra. Results: Of all the compounds tested, compound 7 showed the best antidepressant activity, which decreased the immobility time by 65.52 s in FST. However, in the open-field test, compound 7 did not affect spontaneous activity. The results of 5-HT concentration estimation in vivo showed that compound 7 may have an effect on the mouse brain. Molecular docking results indicated that compound 7 showed significant interactions with residues at the 5-HT1A receptor using homology modeling. The results show that compound 7 exhibits good affinity for the 5-HT1A receptor. Conclusion: Coumarin and 3,4-dihydroquinolinone derivatives synthesized in this study have a significant antidepressant activity. These findings can be useful in the design and synthesis of novel antidepressants.
- Wang, Shi-Ben,Liu, Hui,Li, Guang-Yong,Li, Jun,Li, Xiao-Jing,Lei, Kang,Wei, Li-Chao,Quan, Zhe-Shan,Wang, Xue-Kun,Liu, Ren-Min
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p. 1244 - 1252
(2019/11/02)
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- Application of RhoGDI inhibitor to preparation of drugs for treating nasopharynx cancer
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The invention discloses application of a RhoGDI inhibitor to the preparation of drugs for treating nasopharynx cancer. The invention further discloses application of a RhoGDI inhibitor to the preparation of nasopharynx cancer radiotherapy sensitizer. The invention further discloses a drug for treating nasopharynx cancer, which adopts a preparation prepared from the RhoGDI inhibitor taken as an active component and pharmaceutically acceptable auxiliary materials. The RhoGDI inhibitor achieves the effects of tumor growth resistance, tumor metastasis resistance and radiotherapy sensitivity through specific inhibition of RhoGDI expression and activation of a JNK-1 pathway at the downstream (namely the activation of the expression of downstream p-JNK-1, c-Jun, inhibition the expression of p-AKT, enhancement the conversion of pro-caspase-3 to cleaved-caspase-3), and has a good clinical application prospect.
- -
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Paragraph 0035; 0036; 0037
(2018/07/06)
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- Synthesis, antiproliferative evaluation, and structure–activity relationships of novel triazole–isoindoline hybrids bearing 3,4,5-trimethoxyphenyl moiety
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As an aspect of our ongoing research on developing novel antiproliferative agents, 31 new triazole–isoindoline hybrids bearing 3,4,5-trimethoxyphenyl moiety were synthesized and evaluated for their antiproliferative activity against four cancer cell lines (HepG2, HeLa, PC-3, and HCT116). Some compounds showed excellent potency, and compared to fluorouracil, the most promising compound 6s exhibited 5.8-, 4.3-, and 1.3- fold increase in activities against HeLa, HepG2, and PC-3 cell lines with IC50 values of 9.7, 10.7, and 16.8?μM, respectively. Moreover, structure–activity relationship studies indicated that a much shorter amide linkage and electron-withdrawing groups at phenyl ring of the acetamide fragment contribute to the antitumour activity.
- Li, Qiu,Chen, Peng,Yang, Haikui,Luo, Miaolan,You, Wenwei,Zhao, Peiliang
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p. 651 - 659
(2018/02/28)
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- Synthesis and acaricidal activities of scopoletin phenolic ether derivatives: Qsar, molecular docking study and in silico Adme predictions
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Thirty phenolic ether derivatives of scopoletin modified at the 7-hydroxy position were synthesized, and their structures were confirmed by IR,1H-NMR,13C-NMR, MS and elemental analysis. Preliminary acaricidal activities of these compounds against female adults of Tetranychus cinnabarinus (Boisduval) were evaluated using the slide-dip method. The results indicated that some of these compounds exhibit more pronounced acaricidal activity than scopoletin, especially compounds 32, 20, 28, 27 and 8 which exhibited about 8.41-, 7.32-, 7.23-, 6.76-, and 6.65-fold higher acaricidal potency. Compound 32 possessed the the most promising acaricidal activity and exhibited about 1.45-fold higher acaricidal potency against T. cinnabarinus than propargite. Statistically significant 2D-QSAR model supports the observed acaricidal activities and reveals that polarizability (HATS5p) was the most important parameter controlling bioactivity. 3D-QSAR (CoMFA: q2 = 0.802, r2 = 0.993; CoMSIA: q2 = 0.735, r2 = 0.965) results show that bulky substituents at R4, R1, R2 and R5 (C6, C3, C4, and C7) positions, electron positive groups at R5 (C7) position, hydrophobic groups at R1 (C3) and R2 (C4), H-bond donors groups at R1 (C3) and R4 (C6) will increase their acaricidal activity, which provide a good insight into the molecular features relevant to the acaricidal activity for further designing novel acaricidal agents. Molecular docking demonstrates that these selected derivatives display different bide modes with TcPMCA1 from lead compound and they interact with more key amino acid residues than scopoletin. In silico ADME properties of scopoletin and its phenolic ether derivatives were also analyzed and showed potential to develop as good acaricidal candidates.
- Luo, Jinxiang,Lai, Ting,Guo, Tao,Chen, Fei,Zhang, Linli,Ding, Wei,Zhang, Yongqiang
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- Design, synthesis, docking study, α-glucosidase inhibition, and cytotoxic activities of acridine linked to thioacetamides as novel agents in treatment of type 2 diabetes
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A novel series of acridine linked to thioacetamides 9a–o were synthesized and evaluated for their α-glucosidase inhibitory and cytotoxic activities. All the synthesized compounds exhibited excellent α-glucosidase inhibitory activity in the range of IC50 = 80.0 ± 2.0–383.1 ± 2.0 μM against yeast α-glucosidase, when compared to the standard drug acarbose (IC50 = 750.0 ± 1.5 μM). Among the synthesized compounds, 2-((6-chloro-2-methoxyacridin-9-yl)thio)-N-(p-tolyl) acetamide 9b displayed the highest α-glucosidase inhibitory activity (IC50 = 80.0 ± 2.0 μM). The in vitro cytotoxic assay of compounds 9a–o against MCF-7 cell line revealed that only the compounds 9d, 9c, and 9n exhibited cytotoxic activity. Cytotoxic compounds 9d, 9c, and 9n did not show cytotoxic activity against the normal human cell lines HDF. Kinetic study revealed that the most potent compound 9b is a competitive inhibitor with a Ki of 85 μM. Furthermore, the interaction modes of the most potent compounds 9b and 9f with α-glucosidase were evaluated through the molecular docking studies.
- Mohammadi-Khanaposhtani, Maryam,Rezaei, Sepideh,Khalifeh, Reza,Imanparast, Somaye,Faramarzi, Mohammad Ali,Bahadorikhalili, Saeed,Safavi, Malihe,Bandarian, Fatemeh,Nasli Esfahani, Ensieh,Mahdavi, Mohammad,Larijani, Bagher
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p. 288 - 295
(2018/07/06)
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- COMPOSITONS AND METHODS FOR MODULATING UBA5
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Disclosed herein, inter alia, are compositions and methods useful for inhibiting ubiquitin-like modifier activating enzyme 5.
- -
-
Paragraph 0633; 0635; 0638; 0704
(2018/08/26)
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- COMPOSITIONS AND METHODS FOR MODULATING PPP2R1A
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Disclosed herein, inter alia, are compositions and methods useful for modulating PPP2R1 A and for the treatment of cancer.
- -
-
Paragraph 0599; 0600; 0601; 0683
(2018/08/26)
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- COMPOSITIONS AND METHODS FOR INHIBITING RETICULON 4
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Disclosed herein, inter alia, are compositions and methods useful for inhibiting reticulon 4(RTN4).
- -
-
Paragraph 0646; 0649; 0719
(2018/08/26)
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- A study of diketopiperazines as electron-donor initiators in transition metal-free haloarene-arene coupling
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Several diketopiperazines have been shown to promote carbon-carbon coupling between benzene and aryl halides in the presence of potassium tert-butoxide and without the assistance of a transition metal catalyst. The structure of the diketopiperazine has an influence on its reductive potential and can help to promote the coupling of the more challenging aryl bromides with benzene.
- Cumine, Florimond,Zhou, Shengze,Tuttle, Tell,Murphy, John A.
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p. 3324 - 3336
(2017/04/21)
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- Chemoproteomics-enabled covalent ligand screen reveals a cysteine hotspot in reticulon 4 that impairs ER morphology and cancer pathogenicity
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Chemical genetics has arisen as a powerful approach for identifying novel anti-cancer agents. However, a major bottleneck of this approach is identifying the targets of lead compounds that arise from screens. Here, we coupled the synthesis and screening of fragment-based cysteine-reactive covalent ligands with activity-based protein profiling (ABPP) chemoproteomic approaches to identify compounds that impair colorectal cancer pathogenicity and map the druggable hotspots targeted by these hits. Through this coupled approach, we discovered a cysteine-reactive acrylamide DKM 3-30 that significantly impaired colorectal cancer cell pathogenicity through targeting C1101 on reticulon 4 (RTN4). While little is known about the role of RTN4 in colorectal cancer, this protein has been established as a critical mediator of endoplasmic reticulum tubular network formation. We show here that covalent modification of C1101 on RTN4 by DKM 3-30 or genetic knockdown of RTN4 impairs endoplasmic reticulum and nuclear envelope morphology as well as colorectal cancer pathogenicity. We thus put forth RTN4 as a potential novel colorectal cancer therapeutic target and reveal a unique druggable hotspot within RTN4 that can be targeted by covalent ligands to impair colorectal cancer pathogenicity. Our results underscore the utility of coupling the screening of fragment-based covalent ligands with isoTOP-ABPP platforms for mining the proteome for novel druggable nodes that can be targeted for cancer therapy.
- Bateman,Nguyen,Roberts,Miyamoto,Ku,Huffman,Petri,Heslin,Contreras,Skibola,Olzmann,Nomura
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supporting information
p. 7234 - 7237
(2017/07/11)
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- Carbamylmethyl Mercaptoacetate Thioether: A Novel Scaffold for the Development of L1 Metallo-β-lactamase Inhibitors
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Given the clinical importance of metallo-β-lactamases (MβLs), a new scaffold, N-substituted carbamylmethyl mercaptoacetate thioether, was constructed. The obtained molecules 1-16 inhibited MβLs from all three subclasses, but preferentially L1 from subclass B3. Compound 9 with a p-carboxyphenyl substituent exhibited the broadest spectrum with at least 70% inhibition of enzymes from all subclasses at 100 μM, while compound 5 with a p-methylphenyl substituent was the most potent inhibitor of any individual enzyme, with 97% inhibition at 100 μM and an IC50 value of 0.41 μM against L1. Isothermal titration calorimetry assays corroborate findings from UV-vis spectrophotometric assays that the inhibition of L1 by 5 is dose-dependent. Docking studies suggest that the carboxyl group, the sulfide atom, and the carbonyl group of the carbamyl coordinate Zn2 in a chelating fashion. Using E. coli cells expressing L1, 6 and 8 were able to decrease cefazolin minimum inhibitory concentration 8-fold.
- Chang, Ya-Nan,Xiang, Yang,Zhang, Yue-Juan,Wang, Wen-Ming,Chen, Cheng,Oelschlaeger, Peter,Yang, Ke-Wu
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supporting information
p. 527 - 532
(2017/05/19)
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- 1,3-dimethyl-7-substituted-quinazolinyl-2,4-diones, and synthesis method and application thereof
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The invention discloses 1,3-dimethyl-7-substituted-quinazolinyl-2,4-diones. The structural general formula of the compounds is disclosed in the specification, wherein R1 is hydrogen or ethyl; and R2 is a benzene ring, benzene ring derivative, heterocyclic ring or aliphatic hydrocarbon. Part of compounds have favorable inhibiting activities for Candida albicans, Aspergillus flavus, Torula histolytica and Aspergillus fumigatus. The compounds have obvious inhibiting activities for chitin synthetase, have favorable antibacterial effects, and can be used for preparing drugs for anti-pathogenic microorganisms.
- -
-
Paragraph 0056; 0057; 0058; 0059; 0060; 0079; 0080
(2017/07/31)
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- DOPAMINE D3 RECEPTOR ANTAGONISTS COMPOUNDS
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The disclosure is directed to novel dopamine D3 receptor antagonists, processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, including treating drug dependency and psychosis.
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Page/Page column 318
(2016/05/19)
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- Design, synthesis and biological evaluation of novel dicarbonylalkyl piperazine derivatives as neuroprotective agents
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In the search of novel neuroprotective agents with higher potency than our previously identified anti-ischemic stroke drug candidate 1, a series of novel dicarbonyl piperazine derivatives were synthesized and evaluated on their neuroprotective activity via oxygen-glucose deprivation test in the neuron-like PC12 cells, hypoxia tolerance model in mice and focal cerebral ischemia model in rats. The result obtained indicated that compounds 7f, 7k and 7o, exhibited neuroprotective activity. Particularly, compound 7o containing 2,5-dimethylpiperazin moiety, showed prolonged life time of mice and reduced cerebral infarction of rats, which provided a potential candidate for the development of neuroprotective agents.
- Wang, Wen-Ya,Shen, Cheng-Wu,Weng, Zhi-Jie,Wang, Tie-Chuang,Zhang, Chuang,Jin, Xun-Qi,Li, Jian-Qi
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supporting information
p. 387 - 390
(2016/03/16)
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- TRIAZOLE DERIVATIVES AND THEIR USE AS PDE4 ACTIVATORS
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Compounds of Formula (I), which are activators of long form cyclic nucleotide phosphodiesterase-4 (PDE4) enzymes, are provided. Methods and uses of these compounds for the treatment or prevention of disorders requiring a reduction of second messenger responses mediated by cyclic 3',5'-adenosine monophosphate (cAMP) are also described.
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Page/Page column 56
(2016/10/11)
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- Hafnium-catalyzed direct amide formation at room temperature
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Herein, the first example of a metal-catalyzed protocol for direct amidation of nonactivated carboxylic acids at ambient temperature (26 °C) is presented. The mild reaction conditions give rise to high yields of a range of amides in reaction times as short as 90 min, employing a commercial hafnium complex, [Hf(Cp)2Cl2], as catalyst. Amino acids are transformed into their corresponding amides without racemization, and the catalyst displays full selectivity for the amidation of carboxylic acids over esters. Electronic properties of the carboxylic acids were found to have a strong influence on the rate of the amidation reaction, and the need for a balanced amount of molecular sieves was observed to be highly important for optimal reaction outcome.
- Lundberg, Helena,Adolfsson, Hans
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p. 3271 - 3277
(2015/06/16)
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- Azolylthioacetamide: A highly promising scaffold for the development of metallo-β-lactamase inhibitors
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A new scaffold, azolylthioacetamide, was constructed and assayed against metallo-β-lactamases (MβLs). The obtained molecules specifically inhibited MβL ImiS, and 1c was found to be the most potent inhibitor, with a Ki = 1.2 μM using imipenem as substrate. Structure-activity relationships reveal that the aromatic carboxyl improves inhibitory activity of the inhibitors, but the aliphatic carboxyl does not. Compounds 1c-d and 1h-i showed the best antibacterial activities against E. coli BL21(DE3) cells producing CcrA or ImiS, resulting in 32- and 8-fold reduction in MIC values, respectively; 1c and 1f-j resulted in a reduction in MIC against P. aeruginosa. Docking studies revealed that 1a, 1c, and 1d fit tightly into the substrate binding site of CphA as a proxy for ImiS with the aromatic carboxylate forming interactions with Lys224, the Zn(II) ion, the backbone of Asn233, and hydrophobic portions of the inhibitors aligning with hydrophobic patches of the protein surface.
- Yang, Shao-Kang,Kang, Joon S.,Oelschlaeger, Peter,Yang, Ke-Wu
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supporting information
p. 455 - 460
(2015/04/27)
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- Synthesis and in vitro kinetic study of novel mono-pyridinium oximes as reactivators of organophosphorus (OP) inhibited human acetylcholinesterase (hAChE)
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A series of mono pyridinium oximes linked with arenylacetamides as side chains were synthesized and their in vitro reactivation potential was evaluated against human acetylcholinesterase (hAChE) inhibited by organophosphorus inhibitors (OP) such as sarin, VX and tabun. The reactivation data of the synthesized compounds were compared with those obtained with standard reactivators such as 2-PAM and obidoxime. The dissociation constant (KD) and specific reactivity (kr) of the oximes were also determined by performing reactivation kinetics against OP inhibited hAChE. Among the synthesized compounds, oximes 1-(2-(4-cyanophenylamino)-2-oxoethyl)-4-((hydroxyimino)methyl)pyridinium chloride (12a) and 4-((hydroxyimino)methyl)-1-(2-(4-methoxyphenylamino)-2-oxoethyl)pyridinium chloride (2a) were found most potent reactivators for hAChE inhibited by sarin. In case of VX inhibited hAChE majority of the oximes have shown good reactivation efficacies. Among these oximes 1-(2-(benzylamino)-2-oxoethyl)-4-((hydroxyimino)methyl)pyridinium chloride (18a), 4-((hydroxyimino)methyl)-1-(2-(4-(methoxycarbonyl)phenylamino)-2-oxoethyl)pyridinium-chloride (14a) and 12a were found to surpass the reactivation potential of 2-PAM and obidoxime. However, the synthesized oximes showed marginal reactivation efficacies in case of tabun inhibited hAChE. The pKa value of the oximes were determined and correlated with their observed reactivation potential.
- Valiveti, Aditya Kapil,Bhalerao, Uma M.,Acharya, Jyotiranjan,Karade, Hitendra N.,Gundapu, Raviraju,Halve, Anand K.,Kaushik, Mahabir Parshad
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p. 125 - 132
(2015/06/25)
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- Discovery, synthesis and biological evaluation of 2-(4-(N-phenethylsulfamoyl)phenoxy)acetamides (SAPAs) as novel sphingomyelin synthase 1 inhibitors
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Sphingomyelin synthase (SMS) has been proved to be a potential drug target for the treatment of atherosclerosis. However, few SMS inhibitors have been reported. In this paper, structure-based virtual screening was performed on hSMS1. SAPA 1a was discovered as a novel SMS1 inhibitor with an IC50 value of 5.2 μM in enzymatic assay. A series of 2-(4-(N-phenethylsulfamoyl)phenoxy)acetamides (SAPAs) were synthesized and their biological activities toward SMS1 were evaluated. Among them, SAPA 1j was found to be the most potent SMS1 inhibitor with an IC50 value of 2.1 μM in in vitro assay. The molecular docking studies suggested the interaction modes of SMS1 inhibitors and PC with the active site of SMS1. Site-directed mutagenesis validated the involvement of residues Arg342 and Tyr338 in enzymatic sphingomyelin production. The discovery of SAPA derivatives as a novel class of SMS1 inhibitors would advance the development of more effective SMS1 inhibitors.
- Li, Ya-Li,Qi, Xiang-Yu,Jiang, Hui,Deng, Xiao-Dong,Dong, Yan-Ping,Ding, Ting-Bo,Zhou, Lu,Men, Peng,Chu, Yong,Wang, Ren-Xiao,Jiang, Xian-Cheng,Ye, De-Yong
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p. 6173 - 6184
(2015/09/15)
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- A simple method for the synthesis of furfuryl ketones and furylacetic acid derivatives
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A simple preparative method has been developed for the synthesis of aryl(furfuryl) ketones, amides, and furylacetic acid esters, based on radical alkylation of furan derivatives at the α-position with O-ethyl(phenacyl)xanthogenates and phenacyl iodides in the presence of Fenton's reagent (H2O2/FeSO4·7H2O) in DMSO. The range of applicability and mechanisms for the formation of major and side products have been considered.
- Chalikidi, Petrakis N.,Nevolina, Tatyana A.,Uchuskin, Maxim G.,Abaev, Vladimir T.,Butin, Alexander V.
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p. 621 - 629
(2015/10/12)
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- Promiscuity and selectivity in covalent enzyme inhibition: A systematic study of electrophilic fragments
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Covalent ligand-target interactions offer significant pharmacological advantages. However, off-target reactivity of the reactive groups, which usually have electrophilic properties, must be minimized, and the selectivity of irreversible inhibitors is a crucial requirement. We therefore performed a systematic study to determine the selectivity of several electrophilic groups that can be used as building blocks for covalently binding ligands. Six reactive groups with modulated electrophilicity were combined with 11 nonreactive moieties, resulting in a small combinatorial library of 72 fragment-like compounds. These compounds were screened against a group of 11 enzyme targets to assess their selectivity and their potential for promiscuous binding to proteins. The assay results showed a considerably lower degree of promiscuity than initially expected, even for those members of the screening collection that contain supposedly highly reactive electrophiles.
- J?st, Christian,Nitsche, Christoph,Scholz, Therese,Roux, Lionel,Klein, Christian D.
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supporting information
p. 7590 - 7599
(2014/12/11)
-
- Design, synthesis and evaluation of novel quinazoline-2,4-dione derivatives as chitin synthase inhibitors and antifungal agents
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A series of novel 1-methyl-3-substituted quinazoline-2,4-dione derivatives were designed, synthesized, and characterized by 1H NMR, 13C NMR and MS spectral data. Their inhibition against chitin synthase (CHS) and antifungal activities were evaluated in vitro. Results showed compounds 5b, 5c, 5e, 5f, 5j, 5k, 5l, and 5o had strong inhibitory potency against CHS. Compound 5c, which has the highest potency among these compounds, had a half-inhibition concentration (IC50) of 0.08 mmol/L, while polyoxin B as positive drug had IC50 of 0.18 mmol/L. These IC 50 values of compounds 5i, 5m, 5n, and 5s were greater than 0.75 mmol/L, which revealed that those compounds had weak inhibition activity against CHS. Moreover, most of these compounds exhibited moderate to excellent antifungal activities. In detail, to Candida albicans, the activities of compound 5g and 5k were 8-fold stronger than that of fluconazole and 4-fold stronger than that of polyoxin B; to Aspergillus flavus, the activities of 5g, 5l and 5o were16-fold stronger than that of fluconazole and 8-fold stronger than that of polyoxin B; to Cryptococcus neoformans, the minimum-inhibition- concentration (MIC) values of compounds 5c, 5d, 5e and 5l were comparable to those of fluconazole and polyoxin B. The antifungal activities of these compounds were positively correlated to their IC50 values against CHS. Furthermore, these compounds had negligible actions to bacteria. Therefore, these compounds were promising selective antifungal agents.
- Ji, Qinggang,Yang, Dan,Wang, Xin,Chen, Chunyan,Deng, Qiao,Ge, Zhiqiang,Yuan, Lvjiang,Yang, Xiaolan,Liao, Fei
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p. 3405 - 3413
(2014/06/23)
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- The synthesis of 4,7-disubstituted-2H-benzo[b][1,4]-oxazin-3(4H)-ones using Smiles rearrangement and their in vitro evaluation as platelet aggregation inhibitors
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A series of novel benzo[b][1,4]oxazin-3(4H)-one derivatives were synthesized as platelet aggregation inhibitors for structure-activity relationships (SAR) analysis. The synthetic pattern, involved Smiles rearrangement for the preparation of benzoxazine, was proven to be more efficient than the conventional methods. Biological evaluation demonstrated that among all the synthesized compounds, compound 9u (IC50 = 9.20 μM) exhibited the most potent inhibition activity compared with aspirin, the positive control (IC50 = 7.07 μM). Molecular docking revealed that these set of compounds could be the GPIIb/IIIa antagonist for that they could be situated in the binding site of GPIIb/IIIa receptor quite well.
- Xia, Shuai,Liu, Ji-Qiang,Wang, Xiu-Hua,Tian, Ye,Wang, Yu,Wang, Jing-Huan,Fang, Liang,Zuo, Hua
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supporting information
p. 1479 - 1483
(2014/03/21)
-
- In silico and experimental identification of non ulcerogenic antiinflammatory agents: 3-Thio substituted-4,5-diaryl-4H-1,2,4-triazoles
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A new series of 4,5 diaryl-1,2,4-triazole-3-thione substituted carboxamides have been designed, synthesized and tested for their analgesic and antiinflammatory potential. All the tested compounds exhibit antiinflammatory activity comparable to that of standard drugs rofecoxib and diclofenac. Some compounds demonstrate significant analgesic activity in contrast to reference drugs. Compound 9c has emerged as a highly potent lead compound. Ulcerogenic studies of synthesized compounds and rofecoxib show nil or negligible ulcerogenic effect compared to diclofenac. In silico analysis (docking studies) of the most active compound 9c has revealed hypothetical binding mode of the target compound to the cyclooxygenase isoenzyme (COX-2). Docking study has anticipated stereoselective binding mode for the most active compound 9c.
- Khatale, Pravin N.,Sivakumar,Mahajan, Niranjan S.,Jawarkar, Rahul D.,Kedar, Chakor K.
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p. 890 - 899
(2014/08/05)
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- Lanthanum(III) triflate catalyzed direct amidation of esters
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Lanthanum trifluoromethanesulfonate is an effective single-component catalyst for synthesizing a variety of amides directly from esters and amines under mild conditions. Highly selective amidation of esters and amines, as well as catalyst-controlled amidation of esters, demonstrated the effectiveness of the catalyst system.
- Morimoto, Hiroyuki,Fujiwara, Risa,Shimizu, Yuhei,Morisaki, Kazuhiro,Ohshima, Takashi
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supporting information
p. 2018 - 2021
(2014/05/06)
-
