Optimization of piperazine-derived ureas privileged structures for effective antiadenovirus agents

Marrugal-Lorenzo, José Antonio; Vega-Holm, Margarita; Serna-Gallego, Ana; Álvarez-Vidal, Jaime; Berastegui‐Cabrera, Judith; Palacio, José Pérez del; Díaz, Caridad; Aiello, Francesca; Pachón, Jerónimo; Iglesias‐Guerra, Fernando; Vega‐Pérez, José M.; Sánchez‐Céspedes, Javier

doi:10.1016/j.ejmech.2019.111840

Cited by 17 publications

(16 citation statements)

References 48 publications

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“…In general, species B, C, and E lead to respiratory illness, whereas species D and F cause eye and gastrointestinal infections, respectively. − The infections are usually self-limiting with mild clinical symptoms in healthy individuals, resulting in lifelong immunity to this infected type. However, HAdV infections can cause serious and often life-threatening disease in immunocompromised patients, such as solid-organ transplant (SOT) and allogenic hematopoietic stem cell transplant (allo-HSCT) recipients receiving immunosuppressive therapy. , Pediatric allo-HSCT recipients are the most severely affected group, where HAdV infections occur in frequencies from 5–6 to 42–47% and mortality rates are up to 80% with disseminated disease. ,, In recent years, along with the progress in molecular techniques of diagnosis, HAdV was also identified as an important etiologic agent of both occasional cases and outbreaks of community-acquired pneumonia (CAP) in healthy individuals. − Despite the great clinical significance, there are still no specific antiviral drugs approved for the treatment of HAdV infections. − At present, the off-label use of intravenous cidofovir is the major therapeutic option to treat HAdV diseases in many transplant clinics. Cidofovir is an acyclic nucleotide phosphonate cytosine analogue which was approved to treat cytomegalovirus (CMV) retinitis in acquired immune deficiency syndrome (AIDS) patients, acting as a chain terminator during DNA replication .…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Substituted N-(4-Amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide Analogues as Potent Human Adenovirus Inhibitors

Berastegui‐Cabrera

et al. 2020

J. Med. Chem.

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An effective therapy for human adenovirus (HAdV) infections in immunocompromised patients and healthy individuals with community-acquired pneumonia remains an unmet medical need. We herein reported a series of novel substituted N-(4-amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide analogues as potent HAdV inhibitors. Compounds 6, 15, 29, 40, 43, 46, 47, and 54 exhibited increased selectivity indexes (SI > 100) compared to the lead compound niclosamide, while maintaining sub-micromolar to low micromolar potency against HAdV. The preliminary mechanistic studies indicated that compounds 6 and 43 possibly target the HAdV DNA replication process, while compounds 46 and 47 suppress later steps of HAdV life cycle. Notably, among these derivatives, compound 15 showed improved anti-HAdV activity (IC50 = 0.27 μM), significantly decreased cytotoxicity (CC50 = 156.8 μM), and low in vivo toxicity (maximum tolerated dose = 150 mg/kg in hamster) as compared with niclosamide, supporting its further in vivo efficacy studies for the treatment of HAdV infections.

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Section: Introductionmentioning

confidence: 99%

Discovery of Novel Substituted N-(4-Amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide Analogues as Potent Human Adenovirus Inhibitors

Berastegui‐Cabrera

et al. 2020

J. Med. Chem.

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“…Despite the consequences of acquiring disseminated HAdV infection, there are no antiviral drugs specifically approved for the treatment of HAdV infections [14][15][16][17][18][19][20][21]. Currently, intravenous cidofovir ( Figure 1) is used off-label to treat HAdV-associated diseases in many transplant clinics.…”

Section: Introductionmentioning

confidence: 99%

“…Inhibition of HAdV in plaque assay, cytotoxicity, and selectivity index for compounds[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. Percentage of control HAdV5-GFP inhibition at 10 μM and inhibitory concentration 50% (IC50) at low MOI in a plaque assay using the 293β5 cell line.…”

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confidence: 99%

Discovery of a Small Molecule Inhibitor of Human Adenovirus Capable of Preventing Escape from the Endosome

Berastegui‐Cabrera

Carretero-Ledesma

et al. 2021

IJMS

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Human adenoviruses (HAdVs) display a wide range of tissue tropism and can cause an array of symptoms from mild respiratory illnesses to disseminated and life-threatening infections in immunocompromised individuals. However, no antiviral drug has been approved specifically for the treatment of HAdV infections. Herein, we report our continued efforts to optimize salicylamide derivatives and discover compound 16 (JMX0493) as a potent inhibitor of HAdV infection. Compound 16 displays submicromolar IC50 values, a higher selectivity index (SI > 100) and 2.5-fold virus yield reduction compared to our hit compound niclosamide. Moreover, unlike niclosamide, our mechanistic studies suggest that the antiviral activity of compound 16 against HAdV is achieved through the inhibition of viral particle escape from the endosome, which bars subsequent uncoating and the presentation of lytic protein VI.

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“…In particular, they showed different biological properties, becoming innovative tools for the development of new therapeutic entities [2]. In this field, several aromatic and aliphatic nitrogen heterocycles have been reported as antibacterials [3], antivirals [4], anticancer [5,6], anti-inflammatory [7,8], and antihypertensive [9], among others [10]. Pyrrole is a fivemembered aromatic ring, widely present in a variety of biological contexts, as a xenobiotic or cofactor.…”

Section: Introductionmentioning

confidence: 99%

Green Synthesis of New Pyrrolo [1,2-a] quinoxalines as Antiproliferative Agents in GPER-expressing Breast Cancer Cells

Carullo

Giordano

Aiello

2021

Journal of Chemistry

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4,5-Dihydropyrrolo [1,2-a]quinoxalines are interesting druggable scaffolds, with multifaceted biological properties, including anticancer properties targeting the G protein-coupled estrogen receptor 1 (GPER). In this work, the synthesis and preliminary antiproliferative activity of a small set of new 4,5-dihydropyrrolo[1,2-a]quinoxalines (18-20) and pyrrolo[1,2-a]quinoxalines (21, 22) has been reported, inspired by known antiproliferative agents (G-1, G-15, and G-36). The synthesis of the pyrroloquinoxalinic core was employed following the Pictet–Spengler reaction, using the surfactant p-dodecylbenzene sulphonic acid (p-DBSA), as catalyst. It demonstrated efficiency in the catalysis of the 4-phenylpyrrole [1,2-a] quinoxaline type compound formation in mild solvents such as water, ethanol, and hydroalcoholic solutions. In addition, the reactions proceeded in a short time (between 15 and 120 minutes) at room temperature and with high yields. The in vitro MTT assays showed that the presence of isopropyl groups furnished promising antiproliferative compounds. Although, the acetyl group provided also antiproliferative effects, breaking down its responsibility in the GPER transactivation. Nevertheless, it is possible to conclude that the 4,5-dihydropyrrolo[1,2-a]quinoxalines remain a feasible scaffold to develop anticancer agents against GPER-expressing cells.

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Optimization of piperazine-derived ureas privileged structures for effective antiadenovirus agents

Cited by 17 publications

References 48 publications

Discovery of Novel Substituted N-(4-Amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide Analogues as Potent Human Adenovirus Inhibitors

Discovery of Novel Substituted N-(4-Amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide Analogues as Potent Human Adenovirus Inhibitors

Discovery of a Small Molecule Inhibitor of Human Adenovirus Capable of Preventing Escape from the Endosome

Green Synthesis of New Pyrrolo [1,2-a] quinoxalines as Antiproliferative Agents in GPER-expressing Breast Cancer Cells

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