Diaryl Urea: A Privileged Structure in Anticancer Agents

Garuti, L.; Roberti, Marinella; Bottegoni, Giovanni; Ferraro, Mariarosaria

doi:10.2174/0929867323666160411142532

Cited by 52 publications

(37 citation statements)

References 83 publications

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“…Diarylureas are known to be important pharmacophores in drug discovery (22). Indeed, diarylurea derivatives have been developed as antimalarial (23), antischistosomal (24), antimicrobial (25,26), and anticancer (22,27) agents. We identified the diarylurea compound PQ401 as a hit in the C. elegans screen (described above) that not only blocks the ability of MRSA to kill C. elegans but also induces rapid MRSA membrane permeabilization.…”

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confidence: 99%

The Neutrally Charged Diarylurea Compound PQ401 Kills Antibiotic-Resistant and Antibiotic-Tolerant Staphylococcus aureus

Kim

Zou

Pan

et al. 2020

mBio

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Resistance or tolerance to traditional antibiotics is a challenging issue in antimicrobial chemotherapy. Moreover, traditional bactericidal antibiotics kill only actively growing bacterial cells, whereas nongrowing metabolically inactive cells are tolerant to and therefore “persist” in the presence of legacy antibiotics. Here, we report that the diarylurea derivative PQ401, previously characterized as an inhibitor of the insulin-like growth factor I receptor, kills both antibiotic-resistant and nongrowing antibiotic-tolerant methicillin-resistant Staphylococcus aureus (MRSA) by lipid bilayer disruption. PQ401 showed several beneficial properties as an antimicrobial lead compound, including rapid killing kinetics, low probability for resistance development, high selectivity to bacterial membranes compared to mammalian membranes, and synergism with gentamicin. In contrast to well-studied membrane-disrupting cationic antimicrobial low-molecular-weight compounds and peptides, molecular dynamic simulations supported by efficacy data demonstrate that the neutral form of PQ401 penetrates and subsequently embeds into bacterial lipid bilayers more effectively than the cationic form. Lastly, PQ401 showed efficacy in both the Caenorhabditis elegans and Galleria mellonella models of MRSA infection. These data suggest that PQ401 may be a lead candidate for repurposing as a membrane-active antimicrobial and has potential for further development as a human antibacterial therapeutic for difficult-to-treat infections caused by both drug-resistant and -tolerant S. aureus. IMPORTANCE Membrane-damaging antimicrobial agents have great potential to treat multidrug-resistant or multidrug-tolerant bacteria against which conventional antibiotics are not effective. However, their therapeutic applications are often hampered due to their low selectivity to bacterial over mammalian membranes or their potential for cross-resistance to a broad spectrum of cationic membrane-active antimicrobial agents. We discovered that the diarylurea derivative compound PQ401 has antimicrobial potency against multidrug-resistant and multidrug-tolerant Staphylococcus aureus. PQ401 selectively disrupts bacterial membrane lipid bilayers in comparison to mammalian membranes. Unlike cationic membrane-active antimicrobials, the neutral form of PQ401 rather than its cationic form exhibits maximum membrane activity. Overall, our results demonstrate that PQ401 could be a promising lead compound that overcomes the current limitations of membrane selectivity and cross-resistance. Also, this work provides deeper insight into the design and development of new noncharged membrane-targeting therapeutics to combat hard-to-cure bacterial infections.

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confidence: 99%

The Neutrally Charged Diarylurea Compound PQ401 Kills Antibiotic-Resistant and Antibiotic-Tolerant Staphylococcus aureus

Kim

Zou

Pan

et al. 2020

mBio

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“…Diaryl urea derivatives have been of great interest in medicinal chemistry and the small molecules containing a diaryl urea scaffold have exhibited a broad spectrum of biological activities including anti-inflammatory, antithrombotic and antimicrobial effects 2 . Additionally, diaryl urea derivatives such as sorafenib and regorafenib are used clinically for cancer treatment 3 .…”

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confidence: 99%

Development of Potent Forchlorfenuron Analogs and Their Cytotoxic Effect in Cancer Cell Lines

Kim

Singh

Khazan

et al. 2020

Sci Rep

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forchlorfenuron (fcf) is a synthetic plant cytokinin widely used in agriculture to promote fruit size, that paradoxically inhibits proliferation, migration, and invasion in human cancer cell lines. fcf has also been shown to affect HIF-1α and HER2, which are both known to play a crucial role in cancer cell survival. In this study, we have developed potent FCF analogs through structural modification of FCF, coined UR214-1, UR214-7, and UR214-9. Compared to parental FCF, these analogs are more effective in decreasing viability and proliferation in both ovarian and endometrial cancer cell lines. these fcf analogs also suppress HER2 expression at a concentration lower than that of FCF. In addition, we found that treatment with either fcf or its analogs decreases the expression of human epididymis protein 4 (HE4), which is commonly upregulated in ovarian and endometrial cancers. Given the association between cancer behavior and HE4 production in gynecologic cancers, our findings may provide insight useful in the development of new treatment strategies for gynecologic cancers.

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“…When a urea function was inserted on the pyrazole nucleus in position 3, 4, or 5, different biologically active compounds with a broad spectrum of pharmacological properties were obtained, from antibacterial or antiparasitic to anti-inflammatory and, above all, anticancer ones [8].…”

Section: Introductionmentioning

confidence: 99%

Pyrazolyl-Ureas as Interesting Scaffold in Medicinal Chemistry

2020

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The pyrazole nucleus has long been known as a privileged scaffold in the synthesis of biologically active compounds. Within the numerous pyrazole derivatives developed as potential drugs, this review is focused on molecules characterized by a urea function directly linked to the pyrazole nucleus in a different position. In the last 20 years, the interest of numerous researchers has been especially attracted by pyrazolyl-ureas showing a wide spectrum of biological activities, ranging from the antipathogenic activities (bacteria, plasmodium, toxoplasma, and others) to the anticarcinogenic activities. In particular, in the anticancer field, pyrazolyl-ureas have been shown to interact at the intracellular level on many pathways, in particular on different kinases such as Src, p38-MAPK, TrKa, and others. In addition, some of them evidenced an antiangiogenic potential that deserves to be explored. This review therefore summarizes all these biological data (from 2000 to date), including patented compounds.

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Diaryl Urea: A Privileged Structure in Anticancer Agents

Cited by 52 publications

References 83 publications

The Neutrally Charged Diarylurea Compound PQ401 Kills Antibiotic-Resistant and Antibiotic-Tolerant Staphylococcus aureus

The Neutrally Charged Diarylurea Compound PQ401 Kills Antibiotic-Resistant and Antibiotic-Tolerant Staphylococcus aureus

Development of Potent Forchlorfenuron Analogs and Their Cytotoxic Effect in Cancer Cell Lines

Pyrazolyl-Ureas as Interesting Scaffold in Medicinal Chemistry

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