Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists

Sasmal, Pradip K.; Krishna, C. Vamsee; Adabala, S. Sudheerkumar; Roshaiah, M.; Rawoof, Khaji Abdul; Thadi, Emima; Sukumar, K. Pavan; Cheera, Srisailam; Abbineni, Chandrasekhar; Rao, K. Venkat; Prasanthi, A.; Nijhawan, Kamal; Jaleel, Mahaboobi; Iyer, L.R.; Chaitanya, T. Krishna; Tiwari, Nirbhay Kumar; Krishna, Nareen; Potluri, Vijay; Khanna, Ish; Frimurer, Thomas M.; Lückmann, Michael; Rist, Øystein; Elster, Lisbeth; Högberg, Thomas

doi:10.1016/j.bmcl.2014.12.064

Cited by 8 publications

(5 citation statements)

References 38 publications

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“…Lu AF33241 (1) is a dual inhibitor of phosphodiesterase (PDE) 2A and PDE10A [10]. Compound (2) is a kappa opioid receptor (KOR) agonist [11]. Compound (3) is a 5-HT4 partial agonist [12].…”

Section: Recently Reported Cases Of Brain-penetrant Compoundsmentioning

confidence: 99%

Intelligent Design of Brain-penetrant Compounds Based on Transporter- Conscious Drug Design

Tashima¹

2016

Int J Clin Pharmacol Pharmacother

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“…Lu AF33241 (1) is a dual inhibitor of phosphodiesterase (PDE) 2A and PDE10A [10]. Compound (2) is a kappa opioid receptor (KOR) agonist [11]. Compound (3) is a 5-HT4 partial agonist [12].…”

Section: Recently Reported Cases Of Brain-penetrant Compoundsmentioning

confidence: 99%

Intelligent Design of Brain-penetrant Compounds Based on Transporter- Conscious Drug Design

Tashima¹

2016

Int J Clin Pharmacol Pharmacother

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“…The literature analysis for the last 15 years shows that a variation of amide and alkyl(aryl) substituents in fluoroaromatic ring of salicylic acid is favorable approach to bioactive molecules synthesis. A number of biologically active compounds was obtained based on this strategy, e. g., potent non‐nucleoside HBV inhibitors, myxochelin‐inspired 5‐lipoxygenase inhibitors, antimicrobial and antibacterial agents,, potent inhibitors of RANKL‐induced osteoclastogenesis and bone resorption, anti‐EV71 agents via cyclophilin A inhibition, selective kappa opioid receptor agonists, antituberculous agents, inhibitors of toxoplasma gondii, anti‐hepatitis B virus, and anti‐HIV‐1 agents, inhibitors of the molecular chaperone heat shock protein 90 (Hsp90), CCR3 antagonists, inhibitors of type III secretion in Yersinia, inhibitors of aldose reductase for treatment of chronic diabetic complications, inhibitors of the menin‐MLL interaction, CD73 inhibitors, pyruvate dehydrogenase kinase inhibitors, anticancer agents,, KCNQ2/3 modulators, anticoagulants, anti‐inflammatory agents and analgesics,, antidiabetic agents,, RORc modulators, PGD2 receptor antagonists…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Activity of 4‐Cycloaminopolyfluorosalicylic Acids

et al. 2019

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A series of novel 4-cycloamino-substituted polyfluorosalicylic acids, their esters and amides have been synthesized by the reactions of alkyl polyfluorosalicylates with morpholine, Nmethylpiperazine, pyrrolidine and proline. It was observed that esters of polyfluorosalicylic acids under prolonged heating with amines could undergo one pot nucleophilic substitution of fluorine and intramolecular acidic hydrolysis owing to catalysis by the neighboring hydroxyl group. According to ADME calculations, the synthesized compounds are suitable for drug-design. 4-(N-Methylpiperazinyl)-substituted polylfluorosalicylic acids were found to have good analgesic activity while 4morphonyl-containing analogs revealed moderate anti-inflammatory action. In addition, the presence of amine fragment in polyfluorosalicylates reduced acute toxicity comparing to nonsubstituted polyfluorosalicylic acids. The molecular docking of the most active compounds was carried out into the tyrosine site of cyclooxygenase-1.

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“…4 As a continuation of our previous work, we now focus on the synthesis of 2amidobenzo [d]imidazole because benzo [d]imidazole is a wellknown biologically active structure in medicinal chemistry. 5 Figure 1 shows that 2-amidobenzo [d]imidazoles in particular exhibit interesting biological activities, such as opioid-type drugs, 6 inhibitor of epidermal growth factor receptor (EGFR), 7 interleukin-1 receptor-associated kinase-4, 8 inducible T-cell kinase (ITK), 9 and histone demethylase JMJD2A. 10 For this reason, the benzo [d]imidazole core skeleton has been targeted for synthesis by many organic and medicinal chemists.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Figure shows that 2-amidobenzo[ d ]imidazoles in particular exhibit interesting biological activities, such as opioid-type drugs, inhibitor of epidermal growth factor receptor (EGFR), interleukin-1 receptor-associated kinase-4, inducible T-cell kinase (ITK), and histone demethylase JMJD2A . For this reason, the benzo[ d ]imidazole core skeleton has been targeted for synthesis by many organic and medicinal chemists .…”

Section: Introductionmentioning

confidence: 99%

Construction of Druglike 2-Amido Benzo[d]imidazole Analogues via Desulfurative Cyclization of Thiourea Intermediate Resin on Solid-Phase

et al. 2018

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A 2-amido benzo[ d]imidazole library has been constructed by solid-phase synthesis. The key step of this solid-phase synthesis involves the preparation of polymer-bound 2-amino benzo[ d]imidazole resin through desulfurative cyclization of thiourea resin using 2-chloro-1,3-dimethylimidazolinium chloride and N, N-diisopropylethylamine in dichloromethane (DCM), and the resin is then functionalized by acylation at the 2-amine position to afford 2-amidobenzo[ d]imidazole resin. In the case of 2-amidobenzo[ d]imidazole resin having a p-I or m-NO, the resin was further functionalized by Suzuki/Sonogashira-coupling ( p-I) and reduction to the primary amine ( m-NO) followed by acylation. Finally, the functionalized 2-amido-benzo[ d]imidazole resin was cleaved from the polymer support by treatment with a cocktail of trifluoroacetic acid and DCM. As a result, we obtained 2-amidobenzo[ d]imidazole analogues in high yield and good purities.

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Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists

Cited by 8 publications

References 38 publications

Intelligent Design of Brain-penetrant Compounds Based on Transporter- Conscious Drug Design

Intelligent Design of Brain-penetrant Compounds Based on Transporter- Conscious Drug Design

Synthesis and Biological Activity of 4‐Cycloaminopolyfluorosalicylic Acids

Construction of Druglike 2-Amido Benzo[d]imidazole Analogues via Desulfurative Cyclization of Thiourea Intermediate Resin on Solid-Phase

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