Design, synthesis, and evaluation of bitopic arylpiperazine-phthalimides as selective dopamine D3 receptor agonists.


:The dopamine D3 receptor (D3R) is a proven therapeutic target for the treatment of neurological and neuropsychiatric disorders. In particular, D3R-selective ligands that can eliminate side effects associated with dopamine D2 receptor (D2R) therapeutics have been validated. However, the high homology in signaling pathways and the sequence similarity between D2R and D3R have rendered the development of D3R-selective ligands challenging. Herein, we designed and synthesized a series of piperazine-phthalimide bitopic ligands based on a fragment-based and molecular docking inspired design. Compound 9i was identified as the most selective D3R ligand among these bitopic ligands. Its selectivity was improved compared to reference compounds 1 and 2 by 9- and 2-fold, respectively, and it was 21-fold more potent than compound 2. Molecular docking demonstrated that the orientation of Leu2.64 and Phe7.39 and the packing at the junction of helices may affect the specificity for D3R over D2R. Functional evaluation revealed that D3R-selective ligand 9i displayed a subpicomolar agonist activity at D3R with a 199-fold increase in potency compared to quinpirole. These results may be useful for the fragment-based design of bitopic compounds as selective D3R ligands.






Cao Y,Sun N,Zhang J,Liu Z,Tang YZ,Wu Z,Kim KM,Cheon SH




Has Abstract


2018-06-14 00:00:00














  • Synthesis of dihydronaphthalene analogues inspired by combretastatin A-4 and their biological evaluation as anticancer agents.

    abstract::The natural products colchicine and combretastatin A-4 (CA4) have provided inspiration for the discovery and development of a wide array of derivatives and analogues that inhibit tubulin polymerization through a binding interaction at the colchicine site on β-tubulin. A water-soluble phosphate prodrug salt of CA4 (ref...


    pub_type: 杂志文章


    authors: Maguire CJ,Chen Z,Mocharla VP,Sriram M,Strecker TE,Hamel E,Zhou H,Lopez R,Wang Y,Mason RP,Chaplin DJ,Trawick ML,Pinney KG

    更新日期:2018-08-24 00:00:00

  • Toxicity of tryptophan manganese(i) carbonyl (Trypto-CORM), against Neisseria gonorrhoeae.

    abstract::The potential for carbon monoxide-releasing molecules (CO-RMs) as antimicrobials represents an exciting prospective in the fight against antibiotic resistance. Trypto-CORM, a tryptophan-containing manganese(i) carbonyl, is toxic against E. coli following photo-activation. Here, we demonstrate that Trypto-CORM is toxic...


    pub_type: 杂志文章


    authors: Ward JS,Morgan R,Lynam JM,Fairlamb IJS,Moir JWB

    更新日期:2016-12-06 00:00:00

  • Novel sphingosine-containing analogues selectively inhibit sphingosine kinase (SK) isozymes, induce SK1 proteasomal degradation and reduce DNA synthesis in human pulmonary arterial smooth muscle cells.

    abstract::Sphingosine 1-phosphate (S1P) is involved in hyper-proliferative diseases such as cancer and pulmonary arterial hypertension. We have synthesized inhibitors that are selective for the two isoforms of sphingosine kinase (SK1 and SK2) that catalyze the synthesis of S1P. A thiourea adduct of sphinganine (F02) is selectiv...


    pub_type: 杂志文章


    authors: Byun HS,Pyne S,Macritchie N,Pyne NJ,Bittman R

    更新日期:2013-01-01 00:00:00

  • Deciphering the role of hydrophobic and hydrophilic bile acids in angiogenesis using in vitro and in vivo model systems.

    abstract::Bile acids have emerged as strong signaling molecules capable of influencing various biological processes like inflammation, apoptosis, cancer progression and atherosclerosis depending on their chemistry. In the present study, we investigated the effect of major hydrophobic bile acids lithocholic acid (LCA) and deoxyc...


    pub_type: 杂志文章


    authors: Kundu S,Bansal S,Muthukumarasamy KM,Sachidanandan C,Motiani RK,Bajaj A

    更新日期:2017-10-31 00:00:00

  • Rational design and optimization of selenophenes with basic side chains as novel potent selective estrogen receptor modulators (SERMs) for breast cancer therapy.

    abstract::To increase the diversity of estrogen receptor (ER) ligands having novel structures and activities, series of selenophene derivatives with a basic side chain (BSC) were synthesized and their biological activity as subtype-selective antagonists for the ER was explored. Compared with the selenophenes without a BSC, most...


    pub_type: 杂志文章


    authors: Luo J,Hu Z,Xiao Y,Yang T,Dong C,Huang J,Zhou HB

    更新日期:2017-05-24 00:00:00

  • Design, synthesis and initial biological evaluation of a novel pladienolide analog scaffold.

    abstract::A novel and simplified synthetic scaffold based on pladienolide was designed using a consensus pharmacophore hypothesis. An initial target was synthesized and evaluated to examine the role of the 3-hydroxy group and the methyl groups present at positions 10, 16, 20, 22 in 1, on biological activity. We report the first...


    pub_type: 杂志文章


    authors: Gundluru MK,Pourpak A,Cui X,Morris SW,Webb TR

    更新日期:2011-01-01 00:00:00

  • Recent advances in combretastatin based derivatives and prodrugs as antimitotic agents.

    abstract::The dynamic and crucial role of tubulin in different cellular functions rendered it a promising target in anticancer drug development. Combretastatin A-4 (CA-4), an inhibitor of tubulin polymerization isolated from natural sources, is a lead molecule with significant cytotoxicity against tumour cells. Owing to its non...


    pub_type: 杂志文章,评审


    authors: Seddigi ZS,Malik MS,Saraswati AP,Ahmed SA,Babalghith AO,Lamfon HA,Kamal A

    更新日期:2017-07-04 00:00:00

  • Effect of antimalarial drug primaquine and its derivatives on the ionization potential of hemoglobin: A QM/MM study.

    abstract::We used quantum mechanics/molecular mechanics calculations to test if antimalarial primaquine (PQ) and its derivatives aid the conversion of hemoglobin to methemoglobin by binding to hemoglobin and merely lowering hemoglobin's ionization potential (IP). Our results showed that PQ and its derivatives do not significant...


    pub_type: 杂志文章


    authors: Liu H,Ding Y,Walker LA,Doerksen RJ

    更新日期:2013-08-01 00:00:00

  • Synthesis of DNA-coupled isoquinolones and pyrrolidines by solid phase ytterbium- and silver-mediated imine chemistry.

    abstract::DNA-encoded libraries of chemically synthesized compounds are an important small molecule screening technology. The synthesis of encoded compounds in solution is currently restricted to a few DNA-compatible and water-tolerant reactions. Encoded compound synthesis of short DNA-barcodes covalently connected to solid sup...


    pub_type: 杂志文章


    authors: Potowski M,Kunig VBK,Losch F,Brunschweiger A

    更新日期:2019-02-26 00:00:00

  • Synthesis, molecular docking, and biological evaluation of novel 2-pyrazoline derivatives as multifunctional agents for the treatment of Alzheimer's disease.

    abstract::A novel series of 2-pyrazoline derivatives were designed, synthesized, and evaluated for cholinesterase (ChE) inhibitory, Aβ anti-aggregating and neuroprotective activities. Among these, 3d, 3e, 3g, and 3h were established as the most potent and selective BChE inhibitors (IC50 = 0.5-3.9 μM), while 3f presented dual in...


    pub_type: 杂志文章


    authors: Unsal-Tan O,Tüylü Küçükkılınç T,Ayazgök B,Balkan A,Ozadali-Sari K

    更新日期:2019-05-09 00:00:00

  • Correction: Recent updates in the discovery and development of novel antimalarial drug candidates.

    abstract::[This corrects the article DOI: 10.1039/C7MD00637C.]. ...


    pub_type: 杂志文章,已发布勘误


    authors: Okombo J,Chibale K

    更新日期:2018-03-02 00:00:00

  • Synthesis and antitumor mechanism of a new iron(iii) complex with 5,7-dichloro-2-methyl-8-quinolinol as ligands.

    abstract::A new iron(iii) complex with 5,7-dichloro-2-methyl-8-quinolinol (HClMQ) as ligands, i.e., [Fe(ClMQ)2Cl] (1), was synthesized and evaluated for its anticancer activity. Compared to the HClMQ ligand, complex 1 showed a higher cytotoxicity towards a series of tumor cell lines, including Hep-G2, BEL-7404, NCI-H460, A549, ...


    pub_type: 杂志文章


    authors: Zou BQ,Qin QP,Bai YX,Cao QQ,Zhang Y,Liu YC,Chen ZF,Liang H

    更新日期:2017-02-01 00:00:00

  • Preparation and evaluation of 99mTc-labeled porphyrin complexes prepared using PNP and HYNIC cores: studying the effects of core selection on pharmacokinetics and tumor uptake in a mouse model.

    abstract::Porphyrins are tetrapyrrolic macrocyclic ligands known for their affinity towards neoplastic tissues and once radiolabeled with a suitable diagnostic radioisotope could potentially be used for the imaging of tumorous lesions. In the present study, an unsymmetrically substituted porphyrin derivative namely 5-(p-amino-p...


    pub_type: 杂志文章


    authors: Guleria M,Das T,Vats K,Amirdhanayagam J,Mathur A,Sarma HD,Dash A

    更新日期:2019-02-22 00:00:00

  • High affinity rigidified AT2 receptor ligands with indane scaffolds.

    abstract::Rigidification of the isobutyl side chain of drug-like AT2 receptor agonists and antagonists that are structurally related to the first reported selective AT2 receptor agonist 1 (C21) delivered bioactive indane derivatives. Four enantiomer pairs were synthesized and the enantiomers were isolated in an optical purity >...


    pub_type: 杂志文章


    authors: Wallinder C,Sköld C,Sundholm S,Guimond MO,Yahiaoui S,Lindeberg G,Gallo-Payet N,Hallberg M,Alterman M

    更新日期:2019-11-18 00:00:00

  • Design, Synthesis and Preliminary Antimicrobial Evaluation of N-Alkyl Chain Tethered C-5 Functionalized Bis-Isatins.

    abstract::A series of N-alkyl tethered C-5 functionalized bis-isatins were synthesized and evaluated for antimicrobial activity against pathogenic microorganisms. The preliminary evaluation studies revealed the compound 4t, with an optimal combination of bromo-substituent at the C-5 position of isatin ring along with propyl cha...


    pub_type: 杂志文章


    authors: Singh A,Nisha,Bains T,Hahn HJ,Liu N,Tam C,Cheng LW,Kim J,Debnath A,Land KM,Kumar V

    更新日期:2017-01-01 00:00:00

  • Exploring eukaryotic versus prokaryotic ribosomal RNA recognition with aminoglycoside derivatives.

    abstract::New derivatives of aminoglycosides containing 6'-carboxylic acid or 6'-amide on their ring I were designed, synthesized and their ability to readthrough nonsense mutations was examined in vitro, along with the protein translation inhibition in prokaryotic and eukaryotic systems. The observed structure-activity relatio...


    pub_type: 杂志文章


    authors: Sabbavarapu NM,Pieńko T,Zalman BH,Trylska J,Baasov T

    更新日期:2018-02-02 00:00:00

  • Biochemical and microbiological evaluation of N-aryl urea derivatives against mycobacteria and mycobacterial hydrolases.

    abstract::A focused library of 24 N-aryl urea derivatives was prepared and evaluated against serine esterases of Mycobacterium tuberculosis (Mtb) Rv3802c and Mtb Ag85C. The members of the library were evaluated for both selectivity and mode of inhibition. Furan-based urea derivative 6c was found to be the most potent non-covale...


    pub_type: 杂志文章


    authors: Vartak A,Goins C,de Moura VCN,Schreidah CM,Landgraf AD,Lin B,Du J,Jackson M,Ronning DR,Sucheck SJ

    更新日期:2019-06-04 00:00:00

  • Synthesis and biological evaluation against Leishmania donovani of novel hybrid molecules containing indazole-based 2-pyrone scaffolds.

    abstract::A series of novel indazole-pyrone hybrids were synthesized by a one pot reaction between N-alkyl-6(5)-nitroindazoles and 2-pyrone (4-hydroxy-6-methyl-2H-pyran-2-one) using indium or stannous chloride as the reducing system in the presence of acetic acid in tetrahydrofuran. The hybrid molecules were obtained in good to...


    pub_type: 杂志文章


    authors: El Ghozlani M,Bouissane L,Berkani M,Mojahidi S,Allam A,Menendez C,Cojean S,Loiseau PM,Baltas M,Rakib EM

    更新日期:2018-11-19 00:00:00

  • Repositioning Salirasib as a new antimalarial agent.

    abstract::Malaria is a serious tropical disease that kills thousands of people every year, mainly in Africa, due to Plasmodium falciparum infections. Salirasib is a promising cancer drug candidate that interferes with the post-translational modification of Ras. This S-farnesyl thiosalicylate inhibits isoprenylcysteine carboxyl ...


    pub_type: 杂志文章


    authors: Porta EOJ,Bofill Verdaguer I,Perez C,Banchio C,Ferreira de Azevedo M,Katzin AM,Labadie GR

    更新日期:2019-06-21 00:00:00

  • Design, synthesis and bioactivity investigation of tetrandrine derivatives as potential anti-cancer agents.

    abstract::Twenty-four 14-sulfonamide-tetrandrine derivatives as potential anti-cancer agents were synthesized. The synthetic derivatives were investigated for their cytotoxic activity against human cancer cell lines MDA-MB-231, PC3, WM9, HEL and K562. Initially, the IC50 values (50% inhibitory concentrations) of all of the comp...


    pub_type: 杂志文章


    authors: Song J,Lan J,Chen C,Hu S,Song J,Liu W,Zeng X,Lou H,Ben-David Y,Pan W

    更新日期:2018-05-04 00:00:00

  • Microwave-enhanced Friedländer synthesis for the rapid assembly of halogenated quinolines with antibacterial and biofilm eradication activities against drug resistant and tolerant bacteria.

    abstract::Herein, we disclose the development of a catalyst- and protecting-group-free microwave-enhanced Friedländer synthesis which permits the single-step, convergent assembly of diverse 8-hydroxyquinolines with greatly improved reaction yields over traditional oil bath heating (increased from 34% to 72%). This rapid synthes...


    pub_type: 杂志文章


    authors: Garrison AT,Abouelhassan Y,Yang H,Yousaf HH,Nguyen TJ,Huigens Iii RW

    更新日期:2016-07-27 00:00:00

  • Importance of lipophilicity for potent anti-herpes simplex virus-1 activity of α-hydroxytropolones.

    abstract::We previously reported that troponoid compounds profoundly inhibit replication of herpes simplex virus (HSV)-1 and HSV-2 in cell culture, including acyclovir-resistant mutants. Synthesis of 26 alpha-hydroxylated tropolones (αHTs) led to a preliminary structure-activity relationship highlighting the potency of bi-pheny...


    pub_type: 杂志文章


    authors: Berkowitz AJ,Franson AD,Gazquez Cassals A,Donald KA,Yu AJ,Garimallaprabhakaran AK,Morrison LA,Murelli RP

    更新日期:2019-05-30 00:00:00

  • Synthesis and in vitro evaluation of substituted 3-cinnamoyl-4-hydroxy-pyran-2-one (CHP) in pursuit of new potential antituberculosis agents.

    abstract::Tuberculosis is an ever-evolving infectious disease that urgently needs new drugs. In the search for new antituberculosis agents, a library of 3-cinnamoyl-4-hydroxy-6-methyl-2H-pyran-2-ones (CHPs) (2a-2y) was synthesized and evaluated against a standard virulent laboratory strain of Mycobacterium tuberculosis H37Rv. O...


    pub_type: 杂志文章


    authors: Bhat ZS,Ul Lah H,Rather MA,Maqbool M,Ara T,Ahmad Z,Yousuf SK

    更新日期:2017-12-06 00:00:00

  • Synthesis and biological activity evaluation of novel peroxo-bridged derivatives as potential anti-hepatitis B virus agents.

    abstract::Previous studies have demonstrated that natural steroid compounds containing a peroxide bridge exhibited potential anti-hepatitis B virus activity. To continue our research, a simple and regioselective methodology, using Eosin Y as a clean photosensitized oxidation catalyst, was developed for the synthesis of a peroxi...


    pub_type: 杂志文章


    authors: Jia M,Zhao R,Xu B,Yan W,Chu F,Gu H,Xie T,Xiang H,Ren J,Chen D,Wang P,Lei H

    更新日期:2016-10-19 00:00:00

  • The use of 111Ag as a tool for studying biological distribution of silver-based antimicrobials.

    abstract::Recently, there has been an emergence of significant interest in silver-based antimicrobials. Our goal was to develop a radioactive tracer for investigating the biological fate of such compounds. Purified 111Ag was incorporated into the methylated caffeine analogue, IC1 to yield the silver carbene complex designated a...


    pub_type: 杂志文章


    authors: Aweda TA,Ikotun O,Mastren T,Cannon CL,Wright B,Youngs WJ,Cutler C,Guthrie J,Lapi SE

    更新日期:2013-06-01 00:00:00

  • Facilitating the presentation of antigen peptides on dendritic cells for cancer immunotherapy using a polymer-based synthetic receptor.

    abstract::The introduction of proteins into dendritic cells (DCs) ex vivo is a critical step for the DC-based immunotherapy of cancer. Here, we developed a biotin-modified polymer with multiple hydrophobic membrane anchors for cells that functions as a synthetic receptor for an antigen protein, ovalbumin (OVA), to introduce it ...


    pub_type: 杂志文章


    authors: Li C,Takeo M,Matsuda M,Nagai H,Xizheng S,Hatanaka W,Kishimura A,Inoue H,Tani K,Mori T,Katayama Y

    更新日期:2017-05-12 00:00:00

  • Synthetic glycopeptides as a designated standard in focused glycoproteomics to discover serum cancer biomarkers.

    abstract::Previous studies on the large-scale glycomics of more than 3500 human serum samples revealed that the serum glycoproteins of cancer patients often have more dominant and specific glycoforms, namely, branched tri- and tetra-antennary N-glycans, most cancer patient groups than normal control groups. We herein establishe...


    pub_type: 杂志文章


    authors: Yogesh KV,Kamiyama T,Ohyama C,Yoneyama T,Nouso K,Kimura S,Hinou H,Nishimura SI

    更新日期:2018-06-29 00:00:00

  • Antifungal amphiphilic kanamycins: new life for an old drug.

    abstract::Classical aminoglycoside antibiotics are obsolete or hampered by the emergence of drug resistant bacteria. Recent discoveries of antifungal amphiphilic kanamycins offer new strategies for reviving and repurposing these old drugs. A simple structural modification turns the clinically obsolete antibacterial kanamycin in...


    pub_type: 杂志文章,评审


    authors: Subedi YP,AlFindee MN,Takemoto JY,Chang CT

    更新日期:2018-04-17 00:00:00

  • Synthesis, structure-activity relationship and binding mode analysis of 4-thiazolidinone derivatives as novel inhibitors of human dihydroorotate dehydrogenase.

    abstract::A series of 4-thiazolidinone derivatives were synthesized and evaluated as novel human dihydroorotate dehydrogenase (hDHODH) inhibitors. Compounds 26 and 31 displayed IC50 values of 1.75 and 1.12 μM, respectively. The structure-activity relationship was summarized. Further binding mode analysis revealed that compound ...


    pub_type: 杂志文章


    authors: Zeng F,Qi T,Li C,Li T,Li H,Li S,Zhu L,Xu X

    更新日期:2017-04-26 00:00:00

  • Exploiting the co-reliance of tumours upon transport of amino acids and lactate: Gln and Tyr conjugates of MCT1 inhibitors.

    abstract::Glutamine and tyrosine-based amino acid conjugates of monocarboxylate transporter types 1 and 2 inhibitors (MCT1/2) were designed, synthesized and evaluated for their potency in blocking the proliferation of a human B lymphoma cell line that expresses the transporters Asct2, LAT1 and MCT1. Appropriate placement of an ...


    pub_type: 杂志文章


    authors: Nair RN,Mishra JK,Li F,Tortosa M,Yang C,Doherty JR,Cameron M,Cleveland JL,Roush WR,Bannister TD

    更新日期:2016-05-01 00:00:00