- Analgesic and anticancer activity of benzoxazole clubbed 2-pyrrolidinones as novel inhibitors of monoacylglycerol lipase
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Ten benzoxazole clubbed 2-pyrrolidinones (11–20) as human monoacylglycerol lipase inhibitors were designed on the criteria fulfilling the structural requirements and on the basis of previously reported inhibitors. The designed, synthesized, and characterized compounds (11–20) were screened against monoacylglycerol lipase (MAGL) in order to find potential inhibitors. Compounds 19 (4-NO2 derivative) and 20 (4-SO2 NH2 derivative), with an IC50 value of 8.4 and 7.6 nM, were found most active, respectively. Both of them showed micromolar potency (IC50 value above 50 μM) against a close analogue, fatty acid amide hydrolase (FAAH), therefore considered as selective inhibitors of MAGL. Molecular docking studies of compounds 19 and 20 revealed that carbonyl of 2-pyrrolidinone moiety sited at the oxyanion hole of catalytic site of the enzyme stabilized with three hydrogen bonds (~2 ?) with Ala51, Met123, and Ser122, the amino acid residues responsible for the catalytic function of the enzyme. Remarkably, the physiochemical and pharmacokinetic properties of compounds 19 and 20, computed by QikProp, were found to be in the qualifying range as per the proposed guideline for good orally bioactive CNS drugs. In formalin-induced nociception test, compound 20 reduced the pain response in acute and late stages in a dose-dependent manner. They significantly demonstrated the reduction in pain response, having better potency than the positive control gabapentin (GBP), at 30 mg/kg dose. Compounds 19 and 20 were submitted to NCI, USA, for anticancer activity screening. Compounds 19 (NSC: 778839) and 20 (NSC: 778842) were found to have good anticancer activity on SNB-75 cell line of CNS cancer, exhibiting 35.49 and 31.88% growth inhibition (% GI), respectively.
- Afzal, Obaid,Altamimi, Abdulmalik Saleh Alfawaz,Hassan, Md Quamrul,Riadi, Yassine,Shahroz, Mir Mohammad,Sharma, Hemant Kumar
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- Pyrrolidin-2-one linked benzofused heterocycles as novel small molecule monoacylglycerol lipase inhibitors and antinociceptive agents
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Eighteen pyrrolidin-2-one linked benzothiazole, and benzimidazole derivatives (10–27) were designed and synthesized. The structure of the compounds was confirmed by elemental and spectral (IR, 1H-NMR and MS) data analysis. All the compounds wer
- Altamimi, Abdulmalik Saleh Alfawaz,Bawa, Sandhya,Athar, Fareeda,Hassan, Md Quamrul,Riadi, Yassine,Afzal, Obaid
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p. 1418 - 1432
(2020/07/13)
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- Synthesis of a novel and potent small-molecule antagonist of PAC1 receptor for the treatment of neuropathic pain
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We recently identified novel small-molecule antagonists of the PACAP type I (PAC1) receptor using docking-based in silico screening followed by in vitro/vivo pharmacological assays. In the present study, we synthesized 18 novel derivatives based on the structure of PA-9, a recently developed antagonist of the PAC1 receptor, with a view to obtain a panel of compounds with more potent antagonistic and analgesic activities. Among them, compound 3d showed improved antagonistic activities. Intrathecal injection of 3d inhibited both pituitary adenylate cyclase-activating polypeptide (PACAP) and spinal nerve ligation-induced mechanical allodynia. The effects were more potent than PA-9. Compound 3d also showed anti-allodynic effects following oral administration. Hence, our results suggest that 3d may become an orally available analgesic in the treatment of the neuropathic pain.
- Takasaki, Ichiro,Ogashi, Haruna,Okada, Takuya,Shimodaira, Ayaka,Hayakawa, Daichi,Watanabe, Ai,Miyata, Atsuro,Kurihara, Takashi,Gouda, Hiroaki,Toyooka, Naoki
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- The discovery of new plant activators and scaffolds with potential induced systemic resistance: From jasmonic acid to pyrrolidone
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Plants can develop multifaceted system resistance as a result of infection with pathogens, insects, and some specific microbes or after treatment with specific chemicals.1 Among them, systemic acquired resistance (SAR) and induced systemic resi
- Chang, Kang,Shi, Yanxia,Chen, Jianqin,He, Zenghui,Xu, Zheng,Zhao, Zhenjiang,Zhu, Weiping,Li, Honglin,Xu, Yufang,Li, Baoju,Qian, Xuhong
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p. 1849 - 1857
(2016/09/23)
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- N-Aryl pyrrolidinonyl oxadiazoles as potent mGluR5 positive allosteric modulators
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A novel series of N-aryl pyrrolidinonyl oxadiazoles were identified as mGluR5 positive allosteric modulators (PAMs). Optimization of the initial lead compound 6a led to the identification of the 12c (-) enantiomer as a potent compound with acceptable in vitro clearance, CYP, hERG and PK properties. Para substituted N-aryl pyrrolidinonyl oxadiazoles are mGluR5 PAMs while the meta and ortho substituted N-aryl pyrrolidinonyl oxadiazoles are negative allosteric modulators (NAMs). Para fluoro substitution on the N-aryl group and meta chloro or methyl substituents on the aryl oxadiazole moiety are optimal for mGluR5 PAM efficacy. The existence of an exquisitely sensitive 'PAM to NAM switch' within this chemotype making it challenging for simultaneous optimization of potency and drug-like properties.
- Packiarajan, Mathivanan,Mazza Ferreira, Christine G.,Hong, Sang-Phyo,White, Andrew D.,Chandrasena, Gamini,Pu, Xiaosui,Brodbeck, Robbin M.,Robichaud, Albert J.
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scheme or table
p. 5658 - 5662
(2012/09/22)
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- Sodium borohydride-iodine mediated reduction of γ-lactam carboxylic acids followed by DDQ mediated oxidative aromatisation: a simple approach towards N-aryl-formylpyrroles and 1,3-diaryl-formylpyrroles
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A simple methodology for the conversion of substituted N-aryl-γ-lactam 2/3-carboxylic acids to substituted N-aryl-2/3-formyl-pyrroles has been developed. Several N-aryl-γ-lactam 2/3-carboxylic acids were reduced to substituted (N-aryl-pyrroliden-2/3-yl)-m
- Haldar, Pranab,Barman, Gopa,Ray, Jayanta K.
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p. 3049 - 3056
(2007/10/03)
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- Synthesis of 4-methyloxybenzoic acids and related compounds, and their inhibitory capacities toward fatty-acid and sterol biosynthesis
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The synthesis of a series of 4-methyloxybenzoic acids and related compounds, and their evaluation for inhibitory capacity toward fatty-acid and sterol biosyntheses using rats' liver slices in vitro and rabbits
- Watanabe, S.,Ogawa, K.,Ohno, T.,Yano, S.,Yamada, H.,Shirasaka, T.
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p. 675 - 686
(2007/10/02)
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