Pyridin‐2(1<i>H</i>)‐ones: A Promising Class of HIV‐1 Non‐nucleoside Reverse Transcriptase Inhibitors

Medina‐Franco, José L.; Martínez‐Mayorga, Karina; Juarez‐Gordiano, Cecilia; Castillo, Rafael

doi:10.1002/cmdc.200700054

Cited by 38 publications

(30 citation statements)

References 36 publications

(78 reference statements)

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“…An unstablep recursor mightb eh ydrolytically released fromC lbJ to form 10 after two intramolecularc ondensations and an oxidation.I ti sn oteworthy that 10 is the first 1H-pyrrolo[3,4-c]pyridine-3,6(2H,5H)-dione-and thiazole-containingc ompound to be discovered in the colibactin pathway. Becauset he thiazole ring is an essential functional element in causing DNA damage duet oi ts ability to interact withD NA and alter its electronic distribution, [23,24] and the pyridin-2-one structuralu nit is present in various molecules exhibiting diverseb iological activities( Figure S27), [25][26][27] the structure of 10 provides informationregarding the functionalactivity of (pre)colibactin.We predicted the structure of 12 based on its MS n fragmentation, which demonstrated the potential of another thiazole (Figures S25-S26). This proposed structure could facilitate our understanding of the function of ClbK because the fragmentation result was consistentw ith bioinformatics analysiso fC lbK.…”

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confidence: 99%

Critical Intermediates Reveal New Biosynthetic Events in the Enigmatic Colibactin Pathway

Lai

et al. 2015

ChemBioChem

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Colibactin is a potent genotoxin that induces DNA double-strand breaks; it is produced by Escherichia coli strains harboring a pks+ island. However, the structure of this compound remains elusive. Here, using transformation-associated recombination (TAR) cloning to perform heterologous expression, we took advantage of the significantly increased yield of colibactin pathway-related compounds to determine and isolate a series of vital (pre)colibactin intermediates. The chemical structures of compounds 8, 10 and 11 were identified by NMR and MS(n) analyses. The new 1H-pyrrolo[3,4-c]pyridine-3,6(2H,5H)-dione- and thiazole-containing compound 10 provides new insights regarding the biosynthetic pathway to (pre)colibactin and establishes foundations for future investigation of the intriguing (pre)colibactin structures and its modes of action.

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confidence: 99%

Critical Intermediates Reveal New Biosynthetic Events in the Enigmatic Colibactin Pathway

Lai

et al. 2015

ChemBioChem

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“…Based on the scheme of structures analyzed in our previous publication [1] we propose 320 chemical structures that are synthetically accessible. The goal is to maintain the main structural characteristics of the hybrid pyridinone-UC781 molecule [4] but using the quinolone scaffold according to the matrix of substituent in Figure 2. In general, the design was constituted by a polar group at C-3…”

Section: Methodsmentioning

confidence: 99%

“…This kind of compounds belongs to a family of non-nucleoside reverse transcriptase inhibitors (NNRTI) [3]. In our last publica-teract with conserved aminoacids in RT to inhibit the activity of the enzyme [4] [5]. Also, the substituents in the pyridinone derivates could interact with Mg ++ ions located in a small space between DNA and IN in the nucleus of the cell.…”

Section: Introductionmentioning

confidence: 99%

Molecular Modeling of Quinoline-Based Compounds as Potential Dual Inhibitors of Reverse Transcriptase and Integrase of HIV

Cabrera¹,

Huerta²,

Chávez³

et al. 2018

CMB

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As follow-up of our past publication [1], we propose that quinolones (as part of the pyridinone family) are capable to increase the number of interactions with HIV reverse transcriptase (RT) or integrase (IN) by adding a halogen in position C-8 of aromatic portion of the quinolones. This addition could help with the activity of dual inhibitors of RT and IN. In this work, we add a chlorine atom with the rationale to identify in the docking simulations a halogen interaction with the oxygen in the near aminoacids in the binding pockets of RT and IN enzymes. Our docking studies started with RT and 320 structures. Later, we took 73 structures with good results in docking with RT. The structures that we choose contain ester or acids groups in C-3 due the structural similarity with groups in charge to interact with the Mg ++ ions in Elvitegravir.In conclusion, we obtained 14 structures that could occupy the allosteric pocket of RT and could inhibit the catalytic activity of IN, for this reason could be dual inhibitors. A major perspective of this work is the synthesis and testing of the potential dual inhibitors designed.

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“…Biologically, women are more vulnerable than men to HIV infection during a single sexual encounter, and microbicides would provide a convenient and readily available method of self‐protection against HIV. The class of non‐nucleoside reverse transcriptase inhibitors featuring potent and selective anti‐HIV‐1 activity have recently emerged . Some of these showed potential as microbicides to prevent sexual HIV‐1 transmission/acquisition .…”

Section: Introductionmentioning

confidence: 99%

Asymmetric Synthesis of Potential Precursors of the HIV Drug MC1220 and Its Analogues by Hydrogenation of (1‐Arylvinyl)pyrimidines

Loksha

Pedersen

2018

Journal of Heterocyclic Chem

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Because MC1220 is a promising microbicide with anti‐HIV‐1 activity, the possibility for asymmetric synthesis of its potential precursors is explored. Here, we investigate asymmetric reduction of the vinyl double bond of 6‐(1‐arylvinyl)pyrimidine derivatives to their corresponding ethylidene analogues. Catalysts with ligands bearing trivalent phosphorus ligating the soft metals rhodium(I), ruthenium(II), or iridium(I) are used for asymmetric reduction of the vinyl derivatives 5a–e. The enantioselective reduction reaches 92% ee and about 71% conversion for reduction of the 6‐(1‐(3,5‐dimethylphenyl)vinyl)pyrimidine derivative 5b using the asymmetric catalyst catASium M(R)Rh (7m). However, for the more sterically hindered double bond in the corresponding 2,6‐difluorophenyl derivative 5e, the enantioselective reduction dropped to 30% ee and 14% conversion.

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Pyridin‐2(1H)‐ones: A Promising Class of HIV‐1 Non‐nucleoside Reverse Transcriptase Inhibitors

Cited by 38 publications

References 36 publications

Critical Intermediates Reveal New Biosynthetic Events in the Enigmatic Colibactin Pathway

Critical Intermediates Reveal New Biosynthetic Events in the Enigmatic Colibactin Pathway

Molecular Modeling of Quinoline-Based Compounds as Potential Dual Inhibitors of Reverse Transcriptase and Integrase of HIV

Asymmetric Synthesis of Potential Precursors of the HIV Drug MC1220 and Its Analogues by Hydrogenation of (1‐Arylvinyl)pyrimidines

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