Letters in Drug Design & Discovery

ISSN: 1570-1808

Letters in Drug Design & Discovery
Volume 3, Number 1, February 2006

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Preliminary Investigation of Structure-Activity Relationship of Cytotoxic Physalins Pp. 9-13

H.I.F. Magalhães, M.L. Veras, O.D.L. Pessoa, E.R. Silveira, M.O. Moraes, C. Pessoa & L.V. Costa-Lotufo

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C5,C6-Disubstituted 1H-Indole-2-Carboxamides: Synthesis and Cytotoxic Activity in the Human Non-Small Lung Cancer Cell Line NSCLC-N16-L16 Pp. 14-16

Andrew Tsotinis, Maria Gerasimopoulou, Margarita Vlachou, Dimitri Moreau & Christos Roussakis A series of disubstituted 1H-indole-2-carboxamides was synthesized and evaluated in the NSCLC-N16-L16 tumor tumor cell line in vitro. One of these analogs, 6-benzyloxy-N-[2-(1-pyrrolidinyl)ethyl]-5-methoxy-1H-indole-2-carboxamide, showed satisfactory activity (IC50 = 13.9 µM), which merits further investigation.

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Computer-Assisted Analysis of the Interactions of Macrocyclic Inhibitors with wild Type and Mutant D168A Hepatitis C Virus NS3 Serine Protease Pp. 17-28

Elaine F.F. da Cunha, Teodorico C. Ramalho, Carlton A.Taft & Ricardo B. de Alencastro Molecular-mechanics-based methods have been carried out to understand the forms of interaction of BILN 2061 macrocyclic analogs, with wild-type and D168A enzymes of HCV NS3 serine protease. Significant differences between the wild type enzyme and mutant active sites were observed such as in the case of BILN 2061-D168A NS3 complex, the methoxy group and nitrogen atom of the quinoline unit does not make electrostatic contact with any residue. But, in the case of BILN 2061-wild type NS3 complex, the methoxy group and nitrogen atom of the quinoline unit make significant electrostatic contact with Arg123 and Asp168 residues. This results in enhanced binding affinity of BILN 2061 towards the wild type NS3 serine protease. In general, the ligand-D168A complexes were less favorable binding free energy (ΔG) than the ligand-wild type complexes. Based on the binding conformations from molecular docking, highly predictive CoMFA model were developed. These models match well the 3D topology of the binding site of the wild type NS3 serine protease.

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Synthesis and Evaluation of Anthelmintic and Cytotoxic Properties of bis-1,3-Azole Analogs of Natural Products Pp. 35-43

D. Sellanes, L. Scarone, G. Mahler, E. Manta, A. Baz, S. Dematteis, J. Saldaña, L. Domínguez, P. Wipf & G. Serra Tandem cyclizations to [2,5’] bis-1,3-azoles provided simplified and stable models of biological active marine natural products. The cytotoxic activity in HCT-15 cells and the effect on the L4 larvae of Nippostrongylus brasiliensis of the heterocycles were evaluated.

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Initial Design and Synthesis of Conformationally Restricted and Pharmacophore-Based Scaffold Hopping Analogs of a Ras Pathway Modulator and Evaluation of Their MAPK Inhibitory Activities Pp. 44-48

Sukumar Sakamuri, Quin-Zene Chen, Yingchun Lu, Yen-Fang Keng, Vladimir Khazak, Katrin Illgen, Silke Schabbert, Lutz Weber & Sanjay R. Menon Initial conformationally restricted and ligand pharmacophore-based scaffold hopping analogs of a Ras/Raf protein interaction inhibitor were designed and synthesized in an effort to identify alternate chemical scaffolds inhibiting the MAPK pathway.

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Novel 5-HT7 Ligands as Antidepressants: Automated Synthesis of N-Substituted-N-[1-Methyl-3-(4-Methylpiperidin-1-yl)propyl]-Arylsulfonamides Pp. 49-54

Eric Lattmann, Isidro Merino, Simon Dunn, Bushra Parveen, Pornthip Lattmann, David C. Billington, Yodchai Bunprakob & Jintana Sattayasai Using an automated solution phase synthesis, a combinatorial library of 384 Nsubstituted N-arylsulfonamides was prepared with 24 chemically diverse amines 1-24 and 16 sulfonyl chlorides A-P. Sulfonamide J20, B23, D23, G23, G23, J23, I24 and O24 displayed a binding affinity between 100 nM and 10 nM. The crystalline amide J20 (IC50=39 nM) and O24 (IC50=83 nM) have shown an antidepressant activity in mice in the despair swimming test and the tail suspension assay.

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Evaluation of 2,3,4,8,13a Hexahydro-1H-Benzo[5,6]Cyclohepta-6,7 Dihydroxy[1,2,3-ef][3]Benzazepine Derivatives as Dopamine Receptor Ligands Pp. 55-60

P. Sozio, F. Pinnen, A. Cocco, I. Cacciatore, G. Giorgioni, B. Costa, M. Montali, G. Spoto, F. Santoleri & Antonio Di Stefano This paper reports the synthesis of 2,3,4,8,13a-hexahydro-1H benzo[5,6]cyclohepta-[1,2,3-ef][3]benzazepine derivatives. 2d showed weak D1-like agonistic activity using cGMP content assay in rat neostriatal membranes.

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Pyrrolo[3,4-c]Quinoline-1,3-Diones as Potent Caspase-3 Inhibitors: Synthesis and SAR of 8-Sulfamoyl-1,3-Dioxo-2,3-Dihydro-1H-Pyrrolo[3,4-c]Quinolines Pp. 61-70

Dmitri V. Kravchenko, Julia A. Kuzovkova, Volodymyr M. Kysil, Sergey E. Tkachenko, Sergey Malarchuk, Ilya M. Okun & Alexandre V. Ivachtchenko Synthesis, biological evaluation and structure-activity relationships for a series of 8-sulfamide derivatives of 2,3-dihydro-1H-pyrrolo[ 3,4-c]quinolines are described. These compounds represent a new chemotype of nonpeptide small molecule inhibitors of caspase-3. Among the studied compounds, several nanomolar inhibitors have been identified.

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