- Structure guided design of potential inhibitors of human calcium-calmodulin dependent protein kinase IV containing pyrimidine scaffold
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Calmodulin dependent protein kinase IV (CAMKIV) belongs to the serine/threonine protein kinase family and considered as an encouraging target for the development of novel anticancer agents. The interaction and binding behavior of three designed inhibitors
- Naz, Huma,Jameel, Ehtesham,Hoda, Nasimul,Shandilya, Ashutosh,Khan, Parvez,Islam, Asimul,Ahmad, Faizan,Jayaram,Hassan, Md. Imtaiyaz
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Read Online
- Novel D2/5-HT receptor modulators related to cariprazine with potential implication to schizophrenia treatment
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Schizophrenia is a serious mental disorder without a fully understood pathomechanism, but which involves dysregulation of neurotransmitters and their receptors. The best option for the management of schizophrenia comprises so-called multi-target ligands, similar to the third generation of neuroleptics. Dopamine type 2 receptors (D2Rs) are the main target in the treatment of schizophrenia, in particular for mitigation of the positive symptoms. Due to the high expression of 5-hydroxytryptamine type 3 receptors (5-HT3Rs) in human brain areas responsible for emotional behavior, motivation, and cognitive function, 5-HT3Rs represent a potential target for modulating the cognitive and negative symptoms of schizophrenia. Here we present the design, synthesis, and both in vitro and in vivo biological evaluation of 1,4-disubstituted aromatic piperazines. Screening of in vitro properties revealed the two most promising drug candidates (21 and 24) which were found to be potent D2Rs and moderate 5-HT3R antagonists, and which were forwarded to in vivo studies in Wistar rats. Considering toxicity, administration of the maximal feasible dose of 21 (2 mg/kg) did not produce any side effects. By contrast, the higher solubility of 24 led to revelation of mild and temporary side effects at the dose of 20 mg/kg. Importantly, both 21 and 24 showed facile crossing of the blood-brain barrier, even exerting higher levels in the brain in comparison to plasma. In a behavioral study using the acute amphetamine model of psychosis, we showed that compound 24 ameliorated both positive and negative effects of amphetamine including hyperlocomotion, social impairments, and disruption of prepulse inhibition. The effect of the highest dose (10 mg/kg) was comparable to the effect of the reference dose of aripiprazole (1 mg/kg).
- Bojarski, Andrzej J.,Dehaen, Wim,Janousek, Jiri,Juza, Radomir,Karasova, Jana Zdarova,Kobrlova, Tereza,Korabecny, Jan,Kubacka, Monika,Mezeiova, Eva,Mogilski, Szczepan,Musilek, Kamil,Pejchal, Jaroslav,Petrasek, Tomas,Prchal, Lukas,Randakova, Alena,Satala, Grzegorz,Soukup, Ondrej,Stark, Holger,Stefkova-Mazochova, Kristyna,Svozil, Daniel,Vlcek, Premysl,Vojtechova, Iveta
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supporting information
(2022/02/17)
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- Quinoline carboxamide core moiety-based compounds inhibit P. falciparum falcipain-2: Design, synthesis and antimalarial efficacy studies
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Targeting Falcipain-2 (FP2) for the development of antimalarials is a promising and established concept in antimalarial drug discovery and development. FP2, a member of papain-family cysteine protease of the malaria parasite Plasmodium falciparum holds an important role in hemoglobin degradation pathway. A new series of quinoline carboxamide-based compounds was designed, synthesized and evaluated for antimalarial activity. We integrated molecular hybridization strategy with in-silico drug design to develop FP2 inhibitors. In-vitro results of FP2 inhibition by Qs17, Qs18, Qs20 and Qs21 were found to be in low micromolar range with IC50 4.78, 7.37, 2.14 and 2.64 μM, respectively. Among the 25 synthesized compounds, four compounds showed significant antimalarial activities. These compounds also depicted morphological and food-vacuole abnormalities much better than that of E-64, an established FP2 inhibitor. Overall these aromatic substituted quinoline carboxamides can serve as promising leads for the development of novel antimalarial agents.
- Singh, Anju,Kalamuddin, Md,Maqbool, Mudasir,Mohmmed, Asif,Malhotra, Pawan,Hoda, Nasimul
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supporting information
(2020/12/07)
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- A multifunctional therapeutic approach: Synthesis, biological evaluation, crystal structure and molecular docking of diversified 1H-pyrazolo[3,4-b]pyridine derivatives against Alzheimer's disease
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2-(piperazin-1-yl)–N-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetamides are described as a new class of selective and potent acetylcholinesterase (AChE) inhibitors and amyloid β aggregation inhibitors. Formation of synthesized compounds (P1–P9) was justified via H1 NMR, C13 NMR, mass spectra and single crystal X-Ray diffraction study. All compounds were evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activity, inhibition of self-mediated Aβ aggregation and Cu(II)-mediated Aβ aggregation. Also, docking study carried out was in concordance with in vitro results. The most potent molecule amongst the derivatives exhibited excellent anti-AChE activity (IC50 = 4.8 nM). Kinetic study of P3 suggested it to be a mixed type inhibitor. In vitro study revealed that all the compounds are capable of inhibiting self-induced β-amyloid (Aβ) aggregation with the highest inhibition percentage to be 81.65%. Potency of P1 and P3 to inhibit self-induced Aβ1-42 aggregation was ascertained by TEM analysis. Compounds were also evaluated for their Aβ disaggregation, antioxidation, metal-chelation activity.
- Umar, Tarana,Shalini, Shruti,Raza, Md Kausar,Gusain, Siddharth,Kumar, Jitendra,Seth, Prerna,Tiwari, Manisha,Hoda, Nasimul
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- Substituted indole compound and method and use thereof
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The invention provides a new indole compound, pharmaceutically acceptable salts and medicinal preparations thereof, and a use of the new indole compound in selective inhibition of 5-hydroxytryptamine reuptake and /or excitation of a 5-HT1A receptor. The invention also relates to medicinal compositions comprising the compounds, and a method for treating the central nervous system dysfunction of mammals, especially humans by using the medicinal compositions.
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Paragraph 0327; 0328; 0399; 0401; 0402; 0424; 0426; 0427
(2018/11/03)
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- Development of cyanopyridine-triazine hybrids as lead multitarget anti-Alzheimer agents
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A series of new cyanopyridine-triazine hybrids were designed, synthesized and screened as multitargeted anti-Alzheimer's agents. These molecules were designed while using computational techniques and were synthesized via a feasible concurrent synthetic ro
- Maqbool, Mudasir,Manral, Apra,Jameel, Ehtesham,Kumar, Jitendra,Saini, Vikas,Shandilya, Ashutosh,Tiwari, Manisha,Hoda, Nasimul,Jayaram
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p. 2777 - 2788
(2016/06/08)
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- Synthesis and screening of triazolopyrimidine scaffold as multi-functional agents for Alzheimer's disease therapies
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In present study a series of triazolopyrimidine-quinoline and cyanopyridine-quinoline hybrids were designed, synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs). Molecular docking and scoring was utilized for the design of inhibitors. The molecules were synthesized via an easily accessible, convergent synthetic route. Three triazolopyrimidine based compounds showed nanomolar activity towards acetylcholinesterase. Among them, Ethyl 6-fluoro-4-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)quinoline-3-carboxylate (10d), strongly inhibited AChE with IC50 value of 42 nM. Furthermore compound 10d was identified as most promising compound with 12 fold selectivity against butyrylcholinesterase (BuChE). This compound displayed a composed multitargeted profile with promising inhibition of self-induced and AChE - induced Aβ aggregation and antioxidant activity.
- Kumar, Jitendra,Meena, Poonam,Singh, Anju,Jameel, Ehtesham,Maqbool, Mudasir,Mobashir, Mohammad,Shandilya, Ashutosh,Tiwari, Manisha,Hoda, Nasimul,Jayaram
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p. 260 - 277
(2016/06/01)
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- GLYCINE COMPOUND
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[Problem] The present invention provides a compound which is useful as an active ingredient of a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases. [Means for Solution] The present inventors have conducted intensive studies on a compound having a VAP-1 inhibitory activity, and as a result, they have found that a compound of the present invention or a salt thereof exhibits an excellent VAP-1 inhibitory activity and is useful for preventing and/or treating VAP-1-related diseases, in particular, diabetic nephropathy or diabetic macular edema, thereby completing the present invention. The present invention further relates to a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases, which comprises the compound of the present invention or a salt thereof, and an excipient.
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Page/Page column 24; 77; 87
(2012/07/28)
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- Discovery and Initial SAR of Arylsulfonylpiperazine Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1)
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High-throughput screening of a small-molecule compound library resulted in the identification of a series of arylsulfonylpiperazines that are potent and selective inhibitors of human 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1). Optimization of the initial lead resulted in the discovery of compound (R)-45 (11β-HSD1 IC50 = 3 nM).
- Sun, Daqing,Wang, Zhulun,Di, Yongmei,Jaen, Juan C.,Labelle, Marc,Ma, Ji,Miao, Shichang,Sudom, Athena,Tang, Liang,Tomooka, Craig S.,Tu, Hua,Ursu, Stefania,Walker, Nigel,Yan, Xuelei,Ye, Qiuping,Powers, Jay P.
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scheme or table
p. 3513 - 3516
(2009/04/11)
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- DIKETO-PIPERAZINE AND PIPERIDINE DERIVATIVES AS ANTIVIRAL AGENTS
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This disclosure provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the disclosure is concerned with diketo piperazine and piperadine derivatives that possess unique antiviral activity. More particularly, the present disclosure relates to compounds useful for the treatment of HIV and AIDS.
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Page/Page column 35
(2008/06/13)
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- THERAPEUTIC AGENTS USEFUL FOR TREATING PAIN
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Compounds of formulae (I) and (II) where X is S or O and Ar2, R1, R2, R3, R8, n, m, and t are disclosed herein, or a pharmaceutically acceptable salt thereof (a "3-substituted Pyridyl Compound"), comp
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Page/Page column 92
(2008/06/13)
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- 4-(2-Pyridyl)piperazine-1-carboxamides: Potent vanilloid receptor 1 antagonists
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A series of 4-(2-pyridyl)piperazine-1-carboxamide analogues based on the lead compound 1 was synthesized and evaluated for VR1 antagonist activity in capsaicin-induced (CAP) and pH (5.5)-induced (pH) FLIPR assays in a rat VR1-expressing HEK293 cell line. Potent VR1 antagonists were identified through SAR studies. From these studies, 18 was found to be very potent in the in vitro assay [IC50=4.8 nM (pH) and 35 nM (CAP)] and orally available in rat (F%=15.1).
- Sun, Qun,Tafesse, Laykea,Islam, Khondaker,Zhou, Xiaoming,Victory, Sam F.,Zhang, Chongwu,Hachicha, Mohamed,Schmid, Lori A.,Patel, Aniket,Rotshteyn, Yakov,Valenzano, Kenneth J.,Kyle, Donald J.
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p. 3611 - 3616
(2007/10/03)
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- PROLINE DERIVATIVES AND USE THEREOF AS DRUGS
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The present invention aims at providing compounds having therapeutic effects due to a DPP-IV inhibitory action, and satisfactory as pharmaceutical products. The present inventors have found that derivatives having a substituent introduced into the γ-position of proline represented by the formula (I) wherein each symbol is as defined in the specification, have a potent DPP-IV inhibitory activity, and completed the present invention by increasing the stability.
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- Synthesis and anxiolytic activity of N-substituted cyclic imides (1R*,2S*3R*,4S*)-N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,3-b icyclo[2.2.1]heptanedicarboxime (Tandospirone) and related compounds
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A series of cyclic imides bearing a ω-(4-aryl and 4-heteroaryl-1-piperazinyl)alkyl moieties was synthesized and tested in vivo for anxiolytic activity. The in vitro binding affinities of these compounds were also examined for 5-HT(1A) receptor sites. Structure-activity relationships within these series are discussed. One of these compounds, (1R*,2S*,3R*,4S*)-N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,3- bicyclo[2.2.1]heptanedicarboximide (1: tandospirone), was found to be equipotent with buspirone in its anxiolytic activity and more anxio-selective than buspirone and diazepam. Tandospirone (1) is currently undergoing clinical evaluation as a selective anxiolytic agent.
- Ishizumi,Kojima,Antoku
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p. 2288 - 2300
(2007/10/02)
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- Succinimide derivatives, and their production and use
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A succinimide derivative of the formula: STR1 wherein R is a pyridyl or pyrimidinyl group substituted with at least one member selected from the group consisting of halogen, lower alkyl, lower alkoxy, cyano, benzyloxy, hydroxyl and amino, and n is an integer of 1 or 2, or a pharmaceutically acceptable acid addition salt thereof. The succinimide derivatives are useful as an anti-anxiety drugs.
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- ISOINDOLINYL-ALKYL-PIPERAZINES
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The invention is generally concerned with isoindolinyl-alkylpiperazine compounds generally characterized by the formula STR1 wherein X is halogen or trifluoromethyl; n is an integer ranging from 2 to 5; Y is STR2 in which R 1 is hydrogen, halogen, lower alkyl, lower alkoxy, trifluoromethyl, cyano; R 2 is hydrogen, halogen, lower alkyl, lower alkoxy; and R 3 is hydrogen, cyano. These compounds are useful as diuretic and/or antihypertensive agents.
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- Spirothiazolidinyl piperazine derivatives
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Piperazinyl derivatives containing a spiro-2,4-thiazolidinedione heterocyclic component with relatively selective psychotropic properties are disclosed. The compound 2-[4-[4-(7,9-dioxo-6-thia-8-azaspiro[4.4]nonan-8-yl)butyl]-1-piperazinyl]pyridine-3-carbo
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- Pyridinylpiperazines, a new class of selective α2-adrenoceptor antagonists
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A series of 1-(2-pyridinyl)piperazine derivatives was synthesized and evaluated for adrenergic activity. In vitro activity was assessed through the antagonism of clonidine's effect in the rat, isolated, field-stimulated vas deferens and by the displacemen
- Saari, Walfred S.,Halczenko, Wasyl,King, Stella W.,Huff, Joel R.,Guare, James P.,et al.
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p. 1696 - 1701
(2007/10/02)
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