Structure-Based Design of Novel Tetrahydro-Beta-Carboline Derivatives with a Hydrophilic Side Chain as Potential Phosphodiesterase Inhibitors
نویسندگان
چکیده
Tadalafil is a clinically approved phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction and pulmonary arterial hypertension. It contains two chiral carbons, and the marketed isomer is the 6R, 12aR isomer with a methyl substituent on the terminal nitrogen of the piperazinedione ring. In this report, tadalafil analogues with an extended hydrophilic side chain on the piperazine nitrogen were designed to interact with particular hydrophilic residues in the binding pocket. This leads to analogues with moderate inhibitory activity on phosphodiesterase-5, even for isomers in which chiral carbons are of the S configuration.
منابع مشابه
Synthesis, Molecular Modeling, and Biological Evaluation of Novel Tetrahydro-β-Carboline Hydantoin and Tetrahydro-β-Carboline Thiohydantoin Derivatives as Phosphodiesterase 5 Inhibitors
Two series of fused tetrahydro-β-carboline hydantoin and tetrahydro-β-carboline thiohydantoin derivatives with a pendant 2,4-dimethoxyphenyl at position 5 were synthesized, and chiral carbons at positions 5 and 11a swing from R,R to R,S, S,R, and S,S. The prepared analogues were evaluated for their capacity to inhibit phosphodiesterase 5 (PDE5) isozyme. The R absolute configuration of C-5 in th...
متن کاملDetermination of Structural Requirements of N-Substituted Tetrahydro-β-Carboline Imidazolium Salt Derivatives Using in Silico Approaches for Designing MEK-1 Inhibitors.
Novel N-substituted tetrahydro-β-carboline imidazolium salt derivatives proved to have potent antitumor activity in past research. The Topomer CoMFA and CoMSIA function in Sybyl-X 2.0 software was applied for the identification of important features of N-substituted tetrahydro-β-carboline-imidazolium salt derivative moieties. In the case of Topomer CoMFA, all the compounds were split into two f...
متن کاملTraceless synthesis of hydantoin fused tetrahydro-beta-carboline on ionic liquid support in green media.
A novel ionic liquid (IL) supported, green synthetic protocol has been developed toward the synthesis of oxo and thio hydantoin analogues tethered with tetrahydro-beta-carboline by the use of focused microwave irradiation. IL-bound tryptophan underwent a Pictet-Spengler reaction with various carbonyl compounds to generate the IL-immobilized tetrahydro-beta-carbolines in aqueous isopropanol medi...
متن کاملDesigning and Synthesis of Novel Celecoxib Derivatives with Aminosulfonylmethyl and Azidomethyl Substituents as Selective Cyclooxygenase-2 Inhibitors
Introduction: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are used in treating pathologic conditions such as fever, pain and inflammation by inhibiting cyclooxygenase and consequently prostaglandin production. Recently , the discovery of different isoforms of this enzyme, Cyclooxygenase-1 (COX-1) and Cyclooxygense-2 (COX-2), has led to the synthesis and introduction of novel drugs with selec...
متن کاملDesigning and Synthesis of Novel Celecoxib Derivatives with Aminosulfonylmethyl and Azidomethyl Substituents as Selective Cyclooxygenase-2 Inhibitors
Introduction: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are used in treating pathologic conditions such as fever, pain and inflammation by inhibiting cyclooxygenase and consequently prostaglandin production. Recently , the discovery of different isoforms of this enzyme, Cyclooxygenase-1 (COX-1) andCyclooxygense-2 (COX-2), has led to the synthesis and introduction of novel drugs with select...
متن کامل