14733-73-4Relevant articles and documents
Multifunctional agents based on benzoxazolone as promising therapeutic drugs for diabetic nephropathy
Zhang, Xin,Chen, Huan,Lei, Yanqi,Zhang, Xiaonan,Xu, Long,Liu, Wenchao,Fan, Zhenya,Ma, Zequn,Yin, Zhechang,Li, Lingyun,Zhu, Changjin,Ma, Bing
, (2021)
Diabetic nephropathy (DN) is resulted from activations of polyol pathway and oxidative stress by abnormal metabolism of glucose, and no specific medication is available. We designed a novel class of benzoxazolone derivatives, and a number of individuals were found to have significant antioxidant activity and inhibition of aldose reductase of the key enzyme in the polyol pathway. The outstanding compound (E)-2-(7-(4-hydroxy-3-methoxystyryl)-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid was identified to reduce urinary proteins in diabetic mice suggesting an alleviation in the diabetic nephropathy, and this was confirmed by kidney hematoxylin-eosin staining. Further investigations showed blood glucose normalization, declined in the polyol pathway and lipid peroxides, and raised glutathione and superoxide dismutase activity. Thus, we suggest a therapeutic function of the compound for DN which could be attributed to the combination of hypoglycemic, aldose reductase inhibition and antioxidant.
Design, synthesis and biological evaluation of methyl-2-(2-(5-bromo benzoxazolone)acetamido)-3-(1H-indol-3-yl)propanoate: TSPO ligand for SPECT
Srivastava, Pooja,Kaul, Ankur,Ojha, Himanshu,Kumar, Pravir,Tiwari, Anjani K.
, p. 114491 - 114499 (2016)
The translator protein (TSPO, 18 kDa), a transmembrane mitochondrial protein, has been explored as an important biomarker by researchers because of its involvement in inflammation, immune modulation and cell proliferation. Recently, our group has explored a modified benzoxazolone derivative for diagnostic applications that has overcome few problems of first and second generation TSPO PET ligands. In this study, a new skeleton acetamidobenzoxazolone-indole, a conjugation of two TSPO pharmacophoric moieties benzoxazolone and indole, has been designed, synthesized and evaluated for TSPO targeting for SPECT. The methyl-2-(2-(5-bromo benzoxazolone)acetamido)-3-(1H-indol-3-yl)propanoate (MBIP) ligand was designed on the basis of pharmacophore modeling done on benzoxazolone based TSPO ligands which was then validated computationally for TSPO binding through docking studies (PDB ID: 4RYO, 4RYQ, and 4UC1) which showed a comparable Glide Gscore as compared to known ligands like PK11195, PBR28, and FGIN-127. MBIP was synthesized by amidation reaction of 2-(5-bromo-benzoxazolone)acetic acid with tryptophan methyl ester hydrochloride (yield 62%). The compound was synthesized and characterized using spectroscopic techniques like 1H-NMR, 13C-NMR, and mass spectroscopy. Purification was carried out by column chromatography and analytical HPLC (purity > 97%). The purified compound was labelled with 99mTc (radiochemical yield > 96%). The radiolabelled compound showed >94% stability in solution and >91% stability in serum after 24 h indicating the stable nature of the radio complex. A biodistribution study on BALB/c mice showed uptake of 99mTc-MBIP in TSPO rich organs and appropriate pharmacokinetics of excretion and release for a SPECT agent. Further evaluation of the 99mTc-MBIP may prove it as a potential candidate for TSPO targeting using SPECT.
Design, Synthesis, and In Silico Evaluation of Methyl 2-(2-(5-Bromo/chloro-2-oxobenzoxazol-3(2H)-yl)-acetamido)-3-phenylpropanoate for TSPO Targeting
Kumar, P.,Srivastava, P.,Tiwari, Anjani Kumar
, p. 107 - 118 (2020/04/02)
The high expression of the translocator protein (TSPO) makes it an ideal target for imaging and therapy. The present study is aimed at optimizing acetamidobenzoxazolone-based TSPO ligands by structural modification to overcome the limitations of TSPO ligands of the first two generations such as nonspecificity and polymorphism. Three different TSPO proteins, 2MGY, 4RYQ, and 4UC1, in the native and mutated form were chosen. Acetamidobenzoxazolones modified with phenylalanine methyl ester (methyl 2-(2-(5-bromo/chloro-2-oxobenzooxazol-3(2H)-yl)acetamido)-3-phenylpropanoate, ABPO-Br, ABPO-Cl) through better or comparable docking scores than the known TSPO ligands such as MBMP, FEBMP, FPBMP, and PK11195 are identified as potential TSPO ligands. ABPO-Cl and ABPO-Br were synthesized using phenylalanine methyl ester as a moiety for incorporation of the desired pharmacophoric feature. All the intermediates and final compounds were purified using column chromatography and analytical HPLC (purity > 97%). The purified compounds were characterized by 1H, 13C NMR and mass spectroscopy. Drug likeliness and comparative bioactivity analysis were performed using QikProp through prediction of various properties. Both analogs follow all the five Lipinski rules and three Jogersen’s rules predicting their drug likeliness. The other important aspects related to TSPO ligands such as blood-brain barrier penetration and better contrast have been predicted through lipophilicity (QP log P = 2.76 and 2.74 for ABPO-Br and ABPO-Cl, respectively) and serum binding (QP log Khsa = ?0.18 and ?0.25 for ABPO-Br and ABPO-Cl, respectively). The selectivity and distribution of these TSPO ligands were confirmed by 99mTc-ABPO-Br dynamic image in New Zealand rabbit. These results have shown that the ABPO analogs have the potential to act as better ligands as compared to known acetamidobenzoxazolone derivatives and would be of interest as a promising starting point for designing compounds for TSPO targeting.
Comparative evaluation of 99mTc-MBIP-X/11[C] MBMP for visualization of 18 kDa translocator protein
Srivastava, Pooja,Kumari, Neelam,Kakkar, Dipti,Kaul, Ankur,Kumar, Pravir,Tiwari, Anjani K.
, p. 11288 - 11295 (2019/07/22)
An elevated translocator protein (18 kDa, TSPO) density is observed during inflammation in the brain and peripheral organs making it a viable target for imaging. Recently, our group has explored a pharmacophore skeleton acetamidobenzoxazolone for positron emission tomography (PET) and single photon emission computed tomography (SPECT) applications to target TSPO. 2-(2-(5-Bromo/chloro benzoxazolone)acetamide)-3-(1H-indol-3-yl)propionate (MBIP-Br/Cl) were synthesized by using tryptophan methyl ester and compared with 2-[5-(4-methoxyphenyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]-N-methyl-N-phenyl acetamide (MBMP) through tracer techniques. Computational docking showed similar results for MBIP-Br/Cl in comparison to MBMP. Their ex vivo and in vivo biodistributions were assessed in TSPO-rich organs as well as their release kinetics 0-120 min post injection. The ex vivo biodistribution showed a 7 fold higher uptake (5.16%ID per g vs. 0.72%ID per g) in the heart and a 2.5 fold higher uptake (12.91%ID per g vs. 4.69%ID per g) in the lungs for 99mTc-MBIP-Cl compared to that of 99mTc-MBIP-Br at 15 min. These findings demonstrated that 99mTc-MBIP-Cl has improved pharmacokinetic properties compared to 99mTc-MBIP-Br for SPECT application and is comparable to [11C]MBMP.
