A Conformational Mimetic Approach for the Synthesis of Carbocyclic Nucleosides as Anti‐HCV Leads

Kasula, Mohan; Balaraju, Tuniki; Toyama, Massaki; Thiyagarajan, Anandarajan; Bal, Chandralata; Baba, Masanori; Sharon, Ashoke

doi:10.1002/cmdc.201300277

Cited by 13 publications

(4 citation statements)

References 56 publications

(27 reference statements)

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“…Overall, drug-resistance, drug–drug interactions, and side effects are major concerns, which demand effective PegIFN/RBV free regimen. In addition to recent success in protease inhibitors, , parallel research efforts are in progress to discover nucleoside inhibitors (NIs) to find novel DAAs to target HCV RdRp. , Similarly, several non-nucleoside allosteric inhibitors are in development phase, which may provide a choice of combination with other DAAs to discover PegIFN/RBV free regimen in future . Recently several non-nucleosides (Figure ) had shown promising results and opened a scope for the development of new anti-HCV drug candidates …”

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confidence: 99%

Synthesis and Anti-HCV Activity of 4-Hydroxyamino α-Pyranone Carboxamide Analogues

Konreddy

Toyama

Ito

et al. 2013

ACS Med. Chem. Lett.

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High genetic variability in hepatitis C virus (HCV), emergence of drug resistant viruses and side effects demand the requirement for development of new scaffolds to show an alternate mechanism. Herein, we report discovery of new scaffold I based on 4-hydroxyamino α-pyranone carboxamide as promising anti-HCV agents. A comprehensive structure−activity relationship (SAR) was explored with several newly synthesized compounds. In all promising compounds (17−19, 21−22, 24− 25, and 49) with EC 50 ranging 0.15 to 0.40 μM, the aryl group at C-6 position of α-pyranone were unsubstituted. In particular, 25 demonstrated potential anti-HCV activity with EC 50 of 0.18 μM in cell based HCV replicon system with lower cytotoxicity (CC 50 > 20 μM) and provided a new scaffold for anti-HCV drug development. Further investigations, including biochemical characterization, are yet to be performed to elucidate its possible mode of action. KEYWORDS: Hepatitis C virus, non-nucleoside inhibitor, α-pyranone carboxamide H epatitis C virus (HCV) is a single stranded 9.6 kb RNA virus of the Flaviviridae family predominantly infecting hepatocytes. HCV infection is silent and in long-term may lead to serious liver disease, including fibrosis and cirrhosis followed by hepatocellular carcinoma. 1,2 The prophylactic treatment has been of very limited success, 3 and so far no vaccine is available. 4 A serious health threat has been realized, and a series of investigations are underway to discover direct acting antivirals (DAAs) as promising anti-HCV agents. 5 The potential molecules 1−4 (Figure 1) belonging to DAAs target mainly three viral enzymes: (i) protease NS3/4A, (ii) replicase factor NS5A, and (iii) HCV RNA-dependent RNA polymerase (HCV RdRp) NS5B. 6 The medicinal chemistry approaches with breakthrough exploration in HCV biology 7 were translated recently into first generation DAAs, boceprevir 8 and telaprevir 9 (protease inhibitors) approved by US FDA. Several new generation protease inhibitors are under serious investigations to combat the challenges associated with anti-HCV therapy. 10,11 The current standard of care (SoC) for HCV treatment includes one of the approved protease inhibitors combined with pegylated interferon-α (PegIFN) and ribavirin (RBV).The new regimen improves sustained viral response (SVR) rates to ∼75%; 8,9 however, it also adds side effect burden to patients. The use of PegIFN/RBV is associated with severe side effects followed by treatment discontinuation and contraindication. 12 Overall, drug-resistance, drug−drug interactions, and side effects are major concerns, 13 which demand effective PegIFN/RBV free regimen. In addition to recent success in protease inhibitors, 10,11 parallel research efforts are in progress to discover nucleoside inhibitors (NIs) to find novel DAAs to target HCV RdRp. 14,15 Similarly, several non-nucleoside allosteric inhibitors are in development phase, which may provide a choice of combination with other DAAs to discover

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confidence: 99%

Synthesis and Anti-HCV Activity of 4-Hydroxyamino α-Pyranone Carboxamide Analogues

Konreddy

Toyama

Ito

et al. 2013

ACS Med. Chem. Lett.

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“…Sharon et al [15] have explored the conformational mimetic approach between this heterocycle condensed to a cyclopentene ring compared with the conventional neplanocin ( Figure 8). …”

Section: Synthesis Of the Carbocyclic Neplanocinsmentioning

confidence: 98%

Recent Progress for the Synthesis of Selected Carbocyclic Nucleosides

et al. 2015

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Nucleoside analogs are extremely useful for the development of therapeutic agents to control viral diseases and cancer. Among the numerous modifications on the nucleoside skeleton, replacement of the oxygen of the furanose ring by a CH2 group resulted in increased flexibility and higher resistance to phosphorylases and led to carbocyclic nucleoside analogs (or carbanucleosides). The broad spectrum of biological activities of carbocyclic nucleosides led to tremendous research interest in their syntheses. The article documents recent strategies for the synthesis of active carbocyclic nucleosides by presenting individual case studies, such as the neplanocins, entecavir and selected fluorinated carbocyclic nucleosides. Furthermore, it provides new insights into new directions for more potent and active carbocyclic nucleoside analogs.

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“…Co-crystal acarbose was redocked into the active site of 3WY1 and the best predicted bound conformation having lowest docking energy was selected. Glide uses an explicit water model for modelling salvation effects [30,31]. The demonstrated research output and results are the structural model exploration and involved methodology is very effective, which was analyzed in few of research papers also [21,25,32].…”

Section: Receptor Grid Generation and Dockingmentioning

confidence: 99%

“…We designed, few more novel quinazoline based derivatives by exploring the central moieties at C-7 position The first biochemical screening yielded a considerable activity against α-glucosidase function inhibition i.e. IC50 ≤ 1.8 uM, after that we selected a specific molecular frame of quinazoline core b Blood glucose levels of all the groups (n = 6) compared with that of negative control group using one way ANOVA followed by Dunnett's test [30]. moiety and we prepared an SAR which finally resulted in significant activity of the synthesized molecules.…”

Section: Molecular Modelling and Drug Designingmentioning

confidence: 99%

Quinazolin derivatives as emerging alpha-glucosidase inhibitors

et al. 2018

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A series of C-7 substituted-2-morpholino-N-(pyridin-2-ylmethyl)quinazolin-4-amine have been synthesized and biochemical assay was examined against α-glucosidase function inhibition activity. A structure activity and structure property relationship study was experimented to surface the new hit compound. This study led to the identification of C-7substituted quinazolines with minimum inhibitory concentrations (MICs) in the preffered micromolar range in addition with interesting physicochemical properties. Biological evaluation yielded eight analogs which rose with significant α-glucosidase inhibition potency (IC50 values < 2 μM, where reference compound (Acarbose) potency value is IC50 = 0.586 uM) and could be promising candidates for further lead optimization.

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A Conformational Mimetic Approach for the Synthesis of Carbocyclic Nucleosides as Anti‐HCV Leads

Cited by 13 publications

References 56 publications

Synthesis and Anti-HCV Activity of 4-Hydroxyamino α-Pyranone Carboxamide Analogues

Synthesis and Anti-HCV Activity of 4-Hydroxyamino α-Pyranone Carboxamide Analogues

Recent Progress for the Synthesis of Selected Carbocyclic Nucleosides

Quinazolin derivatives as emerging alpha-glucosidase inhibitors

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