Novel Macrocyclic Inhibitors of Hepatitis C NS3/4A Protease Featuring a 2-Amino-1,3-thiazole as a P4 Carbamate Replacement

Francesco, Maria Emilia Di; Dessole, Gabriella; Nizi, Emanuela; Pace, Paola; Koch, Uwe; Fiore, F.; Pesci, Silvia; Muzio, Jillian Di; Monteagudo, Edith; Rowley, Michael; Summa, Vincenzo

doi:10.1021/jm900524b

Cited by 18 publications

(7 citation statements)

References 51 publications

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“…These early studies paved the way for the subsequent extensive research into macrocyclic inhibitors of HCV NS3 protease. As the HCV protease inhibitor field matured, both the initial and later alternative macrocyclization schemes were employed with peptide-based molecules by many pharmaceutical industry discovery groups, − eventually leading to the discovery of several FDA-approved drugs. Efforts at Janssen (initiated at Tibotec, in collaboration with Medivir) in this area led to the discovery of simeprevir, the first macrocyclic NS3 inhibitor to be approved by the FDA for HCV therapy (Figure ).…”

Section: Structure-based Design Of Small-molecule Macrocyclesmentioning

confidence: 99%

Structure-Based Macrocycle Design in Small-Molecule Drug Discovery and Simple Metrics To Identify Opportunities for Macrocyclization of Small-Molecule Ligands

Cummings

Sekharan²

2019

J. Med. Chem.

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Interest is growing in the use of macrocycles in pharmaceutical discovery. Macrocylization may provide a gateway to an expanded chemical space for small-molecule drug discovery, and this could be beneficial in prosecuting difficult targets, e.g., protein–protein interactions. Most, but not all, macrocycle drugs are derived from natural products. Studies on synthetic drug-like small-molecule macrocycles are limited, and our current understanding of macrocycle drugs is similarly limited. Following some background discussion, we review several examples of the structure-based design of synthetic macrocycles. Our opinion is that in conformationally suitable systems macrocycles are an analog class worthy of consideration. We then summarize an approach for the initial evaluation of molecules as candidates for macrocyclization.

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Section: Structure-based Design Of Small-molecule Macrocyclesmentioning

confidence: 99%

Structure-Based Macrocycle Design in Small-Molecule Drug Discovery and Simple Metrics To Identify Opportunities for Macrocyclization of Small-Molecule Ligands

Cummings

Sekharan²

2019

J. Med. Chem.

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“…Di Francesco et al 95 synthesized 1,3,4-oxadiazole derivative (compound 50) which showed excellent cellular anti-HCV activity.…”

Section: Oxadiazole-containing Compounds As Antiviral Agentsmentioning

confidence: 99%

Antiviral activity of thiadiazoles, oxadiazoles, triazoles and thiazoles

Tawfik¹,

Liu²,

Farahat³

2020

Arkivoc

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Drugs containing the heterocyclic five-membered thiadiazoles and isosteres possess a wide range of biological activities, including but not limited to, antiviral, antifungal, antihistamine, anticancer. In this study, we list the agents containing thiadiazoles and isosteres which are reported to have antiviral activity. We believe that this compilation will be a useful resource for researchers working in the field of antiviral agents.

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“…al. [93] reported a unique type of inhibitor, which designates the identification of a structurally various series of compounds including a 2-amino-1,3-thiazole as substitution of the carbamate in P4. Optimization studies motivated on structural variations in the P3, P2, and P1 regions of the macrocycle as well as on the linked chain caused the discovery of numerous analogs characterized by outstanding levels of enzyme and cellular activity.…”

Section: Sheme 32 Sch32mentioning

confidence: 99%

Scope of Selective Heterocycles from Organic and Pharmaceutical Perspective

Varala¹

2016

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Ravi Varala received his PhD from the Indian Institute of Chemical Technology (CSIR), India, and was awarded the degree in 2006. Later on, he moved for postdoctoral research in the FCT University of New Lisbon, Portugal, during 2007Portugal, during -2009. He worked as scientist for a year (2010) in pharmaceutical industry, before joining the present organization -Rajiv Gandhi University of Knowledge Technologies (RGUKT), Basar campus, Telangana. He has been working as faculty member there since 2011 onward. Dr. Varala has served as the head of department of chemistry and R&D Cell for more than 3 years. He also got experience as a visiting scientist in the University of Sao Paulo, Brazil, for a period of 1 year (March 2015-2016) and then resumedhis work in RGUKT. His research interests include catalysis, green chemistry, and organic synthesis. Currently he is guiding two students for doctoral degree. He has collaborations in several state and central universities.

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Novel Macrocyclic Inhibitors of Hepatitis C NS3/4A Protease Featuring a 2-Amino-1,3-thiazole as a P4 Carbamate Replacement

Cited by 18 publications

References 51 publications

Structure-Based Macrocycle Design in Small-Molecule Drug Discovery and Simple Metrics To Identify Opportunities for Macrocyclization of Small-Molecule Ligands

Structure-Based Macrocycle Design in Small-Molecule Drug Discovery and Simple Metrics To Identify Opportunities for Macrocyclization of Small-Molecule Ligands

Antiviral activity of thiadiazoles, oxadiazoles, triazoles and thiazoles

Scope of Selective Heterocycles from Organic and Pharmaceutical Perspective

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