- Synthesis and evaluation of potent and selective MGL inhibitors as a glaucoma treatment
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Monoacylglycerol lipase (MGL) inhibition provides a potential treatment approach to glaucoma through the regulation of ocular 2-arachidonoylglycerol (2-AG) levels and the activation of CB1 receptors. Herein, we report the discovery of new series of carbamates as highly potent and selective MGL inhibitors. The new inhibitors showed potent nanomolar inhibitory activity against recombinant human and purified rat MGL, were selective (>1000-fold) against serine hydrolases FAAH and ABHD6 and lacked any affinity for the cannabinoid receptors CB1 and CB2. Protein-based 1H NMR experiments indicated that inhibitor 2 rapidly formed a covalent adduct with MGL with a residence time of about 6 h. This interconversion process “intrinsic reversibility” was exploited by modifications of the ligand's size (length and bulkiness) to generate analogs with “tunable’ adduct residence time (τ). Inhibitor 2 was evaluated in a normotensive murine model for assessing intraocular pressure (IOP), which could lead to glaucoma, a major cause of blindness. Inhibitor 2 was found to decrease ocular pressure by ～4.5 mmHg in a sustained manner for at least 12 h after a single ocular application, underscoring the potential for topically-administered MGL inhibitors as a novel therapeutic target for the treatment of glaucoma.
- Alapafuja, Shakiru O.,Malamas, Michael S.,Shukla, Vidyanand,Zvonok, Alexander,Miller, Sally,Daily, Laura,Rajarshi, Girija,Miyabe, Christina Yume,Chandrashekhar, Honrao,Wood, JodiAnne,Tyukhtenko, Sergiy,Straiker, Alex,Makriyannis, Alexandros
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- Design, synthesis, and molecular docking study of new piperazine derivative as potential antimicrobial agents
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Herein, we describe the successful design and synthesis of seventeen new 1,4-diazinanes, compounds commonly known as piperazines. This group of piperazine derivatives (3a-q) were fully characterized by 1H NMR, 13C NMR, FT-IR, and LCMS spectral techniques. The molecular structure of piperazine derivative (3h) was further established by single crystal X-ray diffraction analysis. All reported compounds were evaluated for their antibacterial and antifungal potential against five bacterial (Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa) and two fungal strains (Candida albicans and Cryptococcus neoformans). The complete bacterial screening results are provided. As documented, piperazine derivative 3e performed the best against these bacteria. Additionally, data obtained during molecular docking studies are very encouraging with respect to potential utilization of these compounds to help overcome microbe resistance to pharmaceutical drugs, as explicitly noted in this manuscript.
- Patil, Mahadev,Noonikara Poyil, Anurag,Joshi, Shrinivas D.,Patil, Shivaputra A.,Patil, Siddappa A.,Bugarin, Alejandro
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supporting information
(2019/09/06)
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- Synthesis, molecular docking studies, and antimicrobial evaluation of new structurally diverse ureas
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A series of new urea derivatives (3a-p) have been synthesized from readily available isocyanates and amines in good to high yields. All synthesized compounds were fully characterized using 1H NMR, 13C NMR, IR, and mass spectrometry. Additionally, the structure of the compound (3n) was confirmed by single-crystal X-ray diffraction. Furthermore, all compounds were evaluated for antimicrobial activity against five bacteria and two fungi. Last but not the least, molecular docking studies with Candida albicans dihydropteroate synthetase were performed and the results are presented herein.
- Patil, Mahadev,Poyil, Anurag Noonikara,Joshi, Shrinivas D.,Patil, Shivaputra A.,Patil, Siddappa A.,Bugarin, Alejandro
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supporting information
p. 302 - 311
(2019/03/26)
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- Synthesis, crystal structure, Hirshfeld surfaces analysis and anti-ischemic activity of cinnamide derivatives
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Two cinnamide derivatives, namely, (E)-1-(4-(bis(4-methylphenyl)- methyl)piperazin-1-yl)-3-(3,4-diethoxyphenyl)prop-2-en-1-one (5) and (E)-1-(4-(bis- (4-fluorophenyl)methyl)piperazin-1-yl)-3-(4-methoxyphenyl)prop-2-en-1-one (6), have been synthesized and characterized by IR spectra, High resolution mass spectra, 1H NMR spectra, 13C NMR spectra. The compound 5 is a novel compound and has never been reported in the literature. Their crystal structures were studied by single-crystal X-ray diffraction. They all crystallize in the monoclinic system. The single-crystal X-ray revealed that compound 5 has infinite X-shaped 1-D polymeric chains structure and compound 6 has a layered 3-D structure by intermolecular interactions. Hirshfeld surface analysis demonstrated the presence of H?H, O?H, C?H, F?H, C[sbnd]H?π and π?π intermolecular interactions. In addition, the MTT assay results indicated that the compounds 5 and 6 display effective activities against neurotoxicity which is induced by glutamine in PC12 cells. The in vivo experiment indicated that the compound 6 has a good protective effect on cerebral infarction.
- Zhong, Jian-gang,Han, Jia-pei,Li, Xiao-feng,Xu, Yi,Zhong, Yan,Wu, Bin
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- Synthesis and biological evaluation of aryloxyacetamide derivatives as neuroprotective agents
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A series of new aryloxyacetamide derivatives 10a-s and 14a-m are designed and synthesized. Their protective activities against the glutamate-induced cell death were investigated in differentiated rat pheochromocytoma cells (PC12 cells). Most compounds exhibited neuroprotective effects, especially for 10m, 10r, 14b and 14c, which showed potential protection of PC12 cells at three doses (0.1, 1.0, 10 μM). MTT assay, Hoechst 33342/PI double staining, and high content screening (HCS) revealed that pretreatment of the cells with 10m, 10r, 14b and 14c has significantly decreased the extent of cell apoptosis in a dose-dependent manner. The results of western blot analysis demonstrated these compounds suppressed apoptosis of glutamate-induced PC12 cells via caspase-3 pathway. These compounds can be lead compounds for further discovery of neuroprotective agents for treating cerebral ischemic stroke. Basic structure-activity relationships are also presented.
- Zhong, Yan,Xu, Yi,Zhang, Ai-Xia,Li, Xiao-Feng,Xu, Zhao-Ying,Li, Ping,Wu, Bin
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supporting information
p. 2526 - 2530
(2016/07/07)
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- (4-(Bis(4-Fluorophenyl)Methyl)Piperazin-1-yl)(Cyclohexyl) methanone hydrochloride (LDK1229): A new cannabinoid CB1 receptor inverse agonist from the class of benzhydryl piperazine analogs
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Some inverse agonists of cannabinoid receptor type 1 (CB1) have been demonstrated to be anorectic antiobesity drug candidates. However, the first generation of CB1 inverse agonists, represented by rimonabant (SR141716A), otenabant, and taranabant, are centrally active, with a high level of psychiatric side effects. Hence, the discovery of CB1 inverse agonists with a chemical scaffold distinct from these holds promise for developing peripherally active CB1 inverse agonists with fewer side effects. We generated a new CB1 inverse agonist, (4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)(cyclohexyl)methanone hydrochloride (LDK1229), from the class of benzhydryl piperazine analogs. This compound binds to CB1 more selectively than cannabinoid receptor type 2, with a Ki value of 220 nM. Comparable CB1 binding was also observed by analogs 1-[bis(4-fluorophenyl)methyl]-4-cinnamylpiperazine dihydrochloride (LDK1203) and 1-[bis(4-fluorophenyl)methyl]-4-tosylpiperazine hydrochloride (LDK1222), which differed by the substitution on the piperazine ring where the piperazine of LDK1203 and LDK1222 are substituted by an alkyl group and a tosyl group, respectively. LDK1229 exhibits efficacy comparable with SR141716A in antagonizing the basal G protein coupling activity of CB1, as indicated by a reduction in guanosine 59-O-(3-thio)triphosphate binding. Consistent with inverse agonist behavior, increased cell surface localization of CB1 upon treatment with LDK1229 was also observed. Although docking and mutational analysis showed that LDK1229 forms similar interactions with the receptor as SR141716A does, the benzhydryl piperazine scaffold is structurally distinct from the first-generation CB1 inverse agonists. It offers new opportunities for developing novel CB1 inverse agonists through the optimization of molecular properties, such as the polar surface area and hydrophilicity, to reduce the central activity observed with SR141716A.
- Mahmoud, Mariam M.,Olszewska, Teresa,Liu, Hui,Shore, Derek M.,Hurst, Dow P.,Lu, Dai,Kendall, Debra A.
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p. 197 - 206
(2015/02/19)
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- Synthesis of 1-benzhydryl piperazine derivatives and evaluation of their ACE inhibition and antimicrobial activities
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This study presents the synthesis of 14 new 1,4-disubstituted piperazine derivatives from allyl bromides of Baylis-Hillman adduct and 4,4-disubstituted benzhydryl piperazines. All the synthesized compounds were further screened for in vitro ACE inhibitor and antimicrobial activities. Among the synthesized piperazine derivatives, compound 12h showed moderate ACE inhibitor activity as compared to the standard, angiotensin-converting enzyme inhibitor (Sigma). The kinetic data (K m, K i and V max values) of enzyme inhibition for compound 12h and ACE inhibitor standard were also determined. Similarly, all compounds were screened against different bacterial strains. Compounds 12a, 12b, 12d, 12h and 12i showed excellent to moderate activity against various tested bacterial strains. Compounds 12b and 12i showed broad spectrum of antibacterial activity against Pseudomonas aeruginosa, Staphylococcus aureus, S. aureus MLS 16, Escherichia coli, Bacillus subtilis and Klebsiella planticola, while compounds 12a, 12d and 12i showed promising activity against P. aeruginosa (MIC value of 8.96 μM), S. aureus (MIC value of 42.2 μM) and S. aureus MLS 16 (MIC value of 81.3 μM), respectively. The remaining compounds showed activity at a concentration of >491 μM.
- Santhoshi, Amlipur,Kumar, Singam Naveen,Sujitha, Pombala,Poornachandra, Yedla,Sadhu, Partha Sarathi,Kumar, C. Ganesh,Rao, Vaidya Jayathirtha
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p. 3207 - 3219
(2014/05/06)
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- Synthesis and cytotoxicity studies of novel benzhydrylpiperazine carboxamide and thioamide derivatives
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Synthesis and cytotoxic activities of 32 benzhydrylpiperazine derivatives with carboxamide and thioamide moieties were reported. In vitro cytotoxic activities of compounds were screened against hepatocellular (HUH-7), breast (MCF-7) and colorectal (HCT-116) cancer cell lines by sulphorhodamine B assay. In general, 4-chlorobenzhydrylpiperazine derivatives were more cytotoxic than other compounds. In addition, thioamide derivatives (6a-g) have higher growth inhibition than their carboxamide analogs.
- Gurdal, Enise Ece,Durmaz, Irem,Cetin-Atalay, Rengul,Yarim, Mine
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p. 205 - 214
(2014/04/03)
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- Stereoselective synthesis of (z)-1-benzhydryl-4-cinnamylpiperazines via the wittig reaction
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A synthetic method of producing (E)- and (Z)-isomers of 1-benzhydryl-4-cinnamylpiperazines in a specific ratio from corresponding benzhydrylpiperazine is described. Of the three compounds synthesized (5a-c), the ratio of E/Z-isomers remained around 15:85. The key intermediates, 1-benzhydryl-4-(2,2-dimethoxyethyl)piperazine derivatives (3a-c), were prepared by nucleophilic substitution reaction of benzhydrylpiperazines (2a-c) with chloroacetaldehyde dimethylacetal in good yield (up to 88%). Hydrolysis of 3a-c gave the corresponding aldehydes 4a-c, which when subjected to the Wittig reaction followed by column purification to afford 1a-c (E-isomers) and 6a-c (Z-isomers) in pure form. The isolated compounds were characterized by NMR and mass spectral analysis. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.] Copyright
- Shivprakash,Reddy, G. Chandrasekara
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supporting information
p. 600 - 609
(2014/01/17)
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- Development of small-molecule probes that selectively kill cells induced to express mutant RAS
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Synthetic lethal screening is a chemical biology approach to identify small molecules that selectively kill oncogene-expressing cell lines with the goal of identifying pathways that provide specific targets against cancer cells. We performed a high-throughput screen of 303,282 compounds from the National Institutes of Health-Molecular Libraries Small Molecule Repository (NIH-MLSMR) against immortalized BJ fibroblasts expressing HRASG12V followed by a counterscreen of lethal compounds in a series of isogenic cells lacking the HRASG12V oncogene. This effort led to the identification of two novel molecular probes (PubChem CID 3689413, ML162 and CID 49766530, ML210) with nanomolar potencies and 4-23-fold selectivities, which can potentially be used for identifying oncogene-specific pathways and targets in cancer cells.
- We?wer, Michel,Bittker, Joshua A.,Lewis, Timothy A.,Shimada, Kenichi,Yang, Wan Seok,MacPherson, Lawrence,Dandapani, Sivaraman,Palmer, Michelle,Stockwell, Brent R.,Schreiber, Stuart L.,Munoz, Benito
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supporting information; experimental part
p. 1822 - 1826
(2012/04/04)
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- A simple and efficient synthesis of the antimigraine drug lomerizine
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The synthesis of the antimigraine drug 1-[bis(4-fluorophenyl)methyl]-4-(2, 3,4-trimethoxybenzyl)piperazine has been carried out in very good yields. The five-step synthesis started from bis(4-fluorophenyl)methanone. This route can be applied for large-scale preparation of lomerizine. Georg Thieme Verlag Stuttgart.
- Narsaiah, A. Venkat,Kumar, J. Kranthi
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experimental part
p. 1989 - 1991
(2010/08/13)
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- Amino acid derivative having anti-CCK activity
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A compound represented by the formula (1): STR1 wherein, m is an integer of 1 to 3; n is an integer 0 or 1; A represents CH or N atom, and forms together with the N atom bonded to the carbonyl group a piperidine ring or a piperazine ring; R1 independently represents a straight or branched chain alkyl group having 1 to 4 carbon atoms; a cycloalkyl group having 3 to 8 carbon atoms; a phenyl group, unsubstituted or substituted with a halogen atom or with an alkoxy group having 1 to 4 carbon atoms; or a pyridyl group; or two R1, together with the group >CH-- to which they bind, form a dibenzo cycloheptenyl group or a fluorenyl group; R2 represents a phenyl group substituted with a carboxyl or substituted carboxyl group; a pyridyl group substituted with a carboxyl or substituted carboxyl group, a pyrazyl group substituted with a carboxyl or substituted carboxyl group, an oxazolyl substituted with a carboxyl or substituted carboxyl group, a triazolyl substituted with one or two carboxyl or substituted carboxyl groups, or a phosphonopyridyl group; and R3 represents an indolyl group unsubstituted or substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms and methoxycarbonyl ethyl group and the pharmaceutically acceptable salts thereof.
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- Structure-activity relationship of newly synthesized quinoline derivatives for reversal of multidrug resistance in cancer
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The effect of 24 newly synthesized quinoline derivatives on tumor cell multidrug resistance (MDR) was examined in vitro. At low concentrations, these compounds enhanced the accumulation of [3H]vincristine in K562/ADM cells and reversed tumor cell MDR. The results of the structure-activity relationship analysis indicate that in highly active compounds the two aryl rings in the hydrophobic moiety deviate from a common plane, so they are capable of interacting with hydrogen bond donors of P-170 glycoprotein (P- gp) via π-hydrogen-π interactions. Other major structural features which influence the MDR-reversing activities of these compounds are a quinoline nitrogen atom and a basic nitrogen atom in piperazine. Furthermore, in highly active compounds, the distance between the hydrophobic moiety and the basic nitrogen atom (an atom connected to 2-hydroxypropoxyquinoline) must be at least 5 A?. Several compounds were found to reverse vincristine resistance in K562/ADM cells in vitro, and compound 16 (MS-209) was selected for clinical studies.
- Suzuki, Tsuneji,Fukazawa, Nobuyuki,San-nohe, Kunio,Sato, Wakao,Yano, Osamu,Tsuruo, Takashi
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p. 2047 - 2052
(2007/10/03)
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- POTENTIAL NOOTROPIC AGENTS: SYNTHESIS OF SOME 1,4-DISUBSTITUTED 2-OXOPYRROLIDINES AND SOME RELATED COMPOUNDS
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4-(Aminomethyl)-1-benzyl-2-oxopyrrolidine (VI) was transformed by treatment with (4-benzhydrylpiperazin-1-yl)carbonyl chlorides IIIb-IIId and with (4-methylpiperazin-1-yl)carbonyl chloride (IIIa) to the carboxamides IVa-IVd.Heating of 1-(ethoxycarbonylmethyl)-2,4-dioxopyrrolodine (XIX) in acetonitrile in the presence of water afforded XVIIIa.Treatment with ammonia led to the diamide XVIIIc, while alkaline hydrolysis of XVIIIa gave the dicarboxylic acid XVIIIb. 4-(Aminomethyl)-1-(4-methylthiobenzyl)-2-oxopyrrolidine (XII) was prepared by the reaction of 4-(methylthio)benzylamine with itaconic acid and the following sequence of reaction ...
- Valenta, Vladimir,Urban, Jiri,Taimr, Jan,Polivka, Zdenek
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p. 1126 - 1136
(2007/10/02)
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- New xanthine derivatives with potent and long lasting anti-bronchoconstrictive activity
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Twenty eight new derivatives of 8-aminoalkyl substituted xanthine have been synthesized.They all have demonstrated a potent anti-bronchoconstrictive effect in the guinea pig and some of them have a very long duration of action (>48 h).Among them, one compound: 1-methyl 3-isobutyl 8-(4-benzhydryl piperazino ethyl)xanthine (57) (S 9795) has been selected for clinical trials in asthmatic patients because of its long duration of action, its lack of CNS stimulating effects and its inhibiting action on mast cell degranulation and phosphodiesterase activity.Keywords - 8-aminoalkyl substituted xanthines / benzhydryl piperazine / piperidine / ethylenediamine / anti-bronchoconstrictors / phosphodiesterase inhibitors / asthma
- Regnier, Gilbert L.,Guillonneau, Claude G.,Duhault, Jacques L.,Tisserand, Francoise P.,Saint-Romas, Guy,Holstorp, Sophie M.
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p. 243 - 250
(2007/10/02)
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