Diarylureas: Repositioning from Antitumor to Antimicrobials or Multi-Target Agents against New Pandemics
Abstract
:1. Introduction
2. Diarylureas with Antimicrobial Activity
2.1. Diarylureas with Antiparasitic Activity
2.2. Diarylureas with Antibacterial and Antifungal Activity
3. Diarylureas with Antiviral Activity
4. Diarylureas as Antimalarial Agents
5. Diarylureas as Anti-Inflammatory Agents and Antiulcer Agents
6. Diarylureas as Integrine Antagonists
7. Diarylureas as Allosteric Modulators of Cannabinoid Receptor 1
8. Diarylureas as Antiplatelet Agents
9. Diarylureas Acting on Central Nervous System
10. Diarylureas for Neuroinflammation
11. Diarylureas as Inhibitors of AChE and BuChE
12. Summary
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ACE2 | angiotensin converting enzyme 2 |
AChE | acetylcholinesterase |
AD | Alzheimer’s disease |
ADP | adenosine-5′-diphosphate |
CB1 | cannabinoid receptor 1 |
CB2 | cannabinoid receptor 2 |
CL | clearance |
CNS | Central Nervous System |
COVID-19 | Coronavirus disease 2019 |
CXCR2 | CXC chemokine receptor 2 |
DENV | dengue virus |
ECAT | electrolytic-mediated carotid arterial thrombosis |
ENR | enoyl-acyl-carrier protein reductase |
FLIPR | fluorescent imaging plate reader |
FST | forced swim test |
HD | Huntington’s disease |
HFF | human foreskin fibroblast |
IGF-1R | insulin like growth factor I receptor |
IL-6 | interleukin-6 |
IP | interstitial pneumonia |
KB | binding affinity |
LPS | lipopolysaccharide |
MenG | demethylmenaquinone methyltranferase |
MERS | Swine flu |
Ebola | Middle East respiratory syndrome |
MES | maximal electroshock |
MIC | minimum inhibitory concentration |
MMV | Medicines for Malaria Venture |
MRSA | methicillin-resistant S. aureus |
MSSA | methicillin-sensitive S. aureus |
NTDs | neglected tropical diseases |
NTS | newly transformed schistosomula |
PGR | plant growth regulator |
PA | platelet aggregation |
PD | Parkinson’s disease |
PZQ | praziquantel |
SARS | severe acute respiratory syndrome |
SARS-CoV | respiratory syndrome coronavirus |
SARS-CoV-2 | respiratory syndrome coronavirus 2 |
scPTZ | subcutaneous pentylenetetrazole |
sEH | soluble epoxide hydrolase |
Sps | bacterial signal peptidase I enzyme |
TB | tuberculosis |
TCC | triclocarban |
TRPV1 | transient receptor potential vanilloid 1 |
TST | tail suspension test |
Vdss | volume of distribution |
VLA-4 | very late antigen-4 |
VRSA | vancomycin-resistant S. aureus |
WNV | West Nile virus |
YFV | Yellow fever virus |
ZIKV | Zika virus virus |
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Structure | Compd | Activity | Ref |
---|---|---|---|
Antiparasitic agents | |||
| MMV665852 | IC50 = 4.7 µM (S. mansoni NTS) IC50 = 0.8 µM (adult S. mansoni) IC50 = 4.4 µM (juvenile S. japonicum) IC50 = 2.2 µM (adult S. japonicum) | [47] [49] |
| Triclocarban (TCC) | IC50 = 0.07 µM (S. mansoni NTS) IC50 = 0.4 µM (adult S. mansoni) | [48] |
| 1 | IC50 = 1.3 µM (S. mansoni NTS) IC50 = 0.7 µM (adult S. mansoni) | [48] |
| 2 | IC50 = 0.2 µM (adult S. mansoni) | [48] |
| 3 | IC50 = 3.6 µM (adult S. mansoni) | [48] |
| 4 | IC50 = 7.0 µM (adult S. mansoni) | [48] |
| 5 | IC50 = 2.5 µM (juvenile S. japonicum) IC50 = 1.5 µM (adult S. japonicum) | [49] |
| 6 (Flucofuron) | IC50 = 2.8 µM (juvenile S. japonicum) IC50 = 1.5 µM (adult S. japonicum) | [49] |
| 7 | IC50 = 0.15 µM (S. mansoni NTS) IC50 = 0.19 µM (adult S. mansoni) | [19] |
| Sorafenib (BAY-43-9006) | IC50 = 4.1 µM (S. mansoni NTS) IC50 = 1.1 µM (adult S. mansoni) | [54] |
| Regorafenib (BAY-73-4506) | IC50 = 6.9 µM (S. mansoni NTS) IC50 = 1.0 µM (adult S. mansoni) | [54] |
Structure | Compd | Activity | Ref |
---|---|---|---|
Antibacterial activity | |||
| 8 | MIC50 = 0.05 µg/mL (S. aureus ATCC 12600 and MRSA) | [55] |
| PK150 | MIC = 0.3 µM (S. aureus NCTC 8325) | [56] |
| Sorafenib (BAY-43-9006) | MIC = 3 µM (S. aureus NCTC 8325) | [56] |
| Regorafenib (BAY-73-4506) | MIC = 3 µM (S. aureus NCTC 8325) | [56] |
| Triclocarban (TCC) | MIC50 = 0.5 µg/mL (S. aureus) | [55] |
| 6 (Flucofuron) | MIC = 0.25 mg/L (S. aureus NCTC 8325; ATCC 12598 and S. epidermidis ATCC 12228; 35984) | [58] |
| 9 | MIC = 0.5‒8.0 µg/mL (different gram-positive bacteria) | [59] |
| 10 | Inhibition zones = 14.0 mm Gram (+) B. subtilis NCTC-10400 and Gram (‒) P. aeruginosa ATCC 10145 and E. coli ATCC 23282 | [61] |
| PQ401 | MIC = 4 µg/mL (different S. aureus) MBC = 4 g/mL (S. aureus VRS1 strains) | [62] |
| 11 | Inhibition zone = 23 mm, at a concentration of 200 µg/mL (P. mirabilis ATCC 19181) | [63] |
| 12 | Inhibition zone = 24 mm, at a concentration of 200 µg/mL (P. mirabilis ATCC 19181) | [63] |
| 13 | MIC = 31.3 µg/mL (S. boydii ATCC 9905; E. faecalis ATCC 29212; B. cereus ATCC 10987; K. pneumoniae ATCC 10031) | [65] |
| 14 | MIC = 31.3 µg/mL (S. boydii ATCC 9905; E. faecalis ATCC 29212; B. cereus ATCC 10987; K. pneumoniae ATCC 10031) | [65] |
| 15 | MIC = 10 µg/mL (MRSA NRS123) | [67] |
| 16 | MIC = 8 µg/mL (MRSA NRS123) | [67] |
| 17 | MIC = 10 µg/mL (MRSA NRS123) | [67] |
| 18 | MIC = 2‒4 µg/mL (various MRSA) | [67,68] |
| 19 | MIC = 2‒4 µg/mL (various MRSA) | [68] |
| 20 | MIC = 6.25 µg/mL (M. tuberculosis H37Rv) | [69] |
| 21 | MIC = 3.125 µg/mL (M. tuberculosis H37Rv) | [69] |
| 22 | MIC = 6.0 µg/mL (M. tuberculosis pathogenic strain H37Rv) MIC = 2.0 µg/mL (M. tuberculosis nonpathogenic strain mc26030) | [70] |
| 23 | MIC = 5.2 µg/mL (M. tuberculosis pathogenic strain H37Rv) MIC = 1.0 µg/mL (M. tuberculosis nonpathogenic strain mc26030) | [70] |
Antifungal activity | |||
| 24 | Inhibition, at 30 μM, of the growth of P. obscurans by 80% and P. viticola and 100%, after 120 h exposure | [71] |
Structure | Compd | Ref | |
---|---|---|---|
Antiviral agents Inhibitors of Zika virus infection | |||
| ASN 07115851 | IC50 = 160.3 nM (by viral plaque assay and A549 human lung carcinoma cell line) | [73] |
| ASN 07115873 | IC50 = 189.2 pM (by viral plaque assay and A549 human lung carcinoma cell line) | [73] |
| ASN 07115881 | IC50 = 317.7 pM (by viral plaque assay and A549 human lung carcinoma cell line) | [73] |
| ASN 07115927 | IC50 = 26.9 nM (by viral plaque assay and A549 human lung carcinoma cell line) | [73] |
| 25 | IC50 = 85.1 pM (by viral plaque assay and A549 human lung carcinoma cell line) | [74] |
DENV | |||
| 26 | IC50 = 91 µM (DENV N7-MTase assay) IC50 = 51 µM (WNV 2′-O-MTase assay) | [75] |
| 27 | IC50 = 110 µM (DENV N7-MTase assay) IC50 = 71 µM (WNV 2′-O-MTase assay) | [75] |
Antimalarial agents | |||
| MMV665852 | EC50 = 1160 nM (P. falciparum) | [47] |
| WR268961 | IC50 = 0.03‒0.16 µg/mL (P. falciparum W2 and D6) | [76] |
| PQ401 | EC50 = 0.053 μM (P. falciparum 3D7 and K1) | [20] |
| 28 | EC50 = 0.32 μM (P. falciparum 3D7) | [20] |
| 29 | EC50 = 0.031 μM (P. falciparum 3D7) EC50 = 0.11 μM (P. falciparum K1) | [20] |
| 30 | EC50 = 0.016 μM) (P. falciparum 3D7) EC50 = 0.079 μM (P. falciparum K1) | [20] |
| 31 | EC50 = 0.037 µM (P. falciparum 3D7) EC50 = 0.055 µM (P. falciparum Dd2) | [77] |
Structure | Compd | Ref | |
---|---|---|---|
Anti-inflammatory and antiulcer agents | |||
| CP-214339 | IC50 = 0.13 µM (Δ5-desaturase inhibitor in rodents) | [78,79] |
| 32 | 85% inhibition TNF-α; 93% inhibition IL-6 | [80] |
| 33 | 58% inhibition TNF-α; 75% inhibition IL-6 | [80] |
| 34 | 61% inhibition TNF-α; 80% inhibition IL-6 | [80] |
| 35 | IC50 = 18.4 µg/mL (proton pump inhibition) | [81] |
| 36 | IC50 = 20.3 µg/mL (anti-inflammatory activity in human blood) | [81] |
Integrine antagonists | |||
| 37 | pKi = 7.2 (VLA-4 antagonist) | [85] |
| 38 | pKi = 9.1 (VLA-4 antagonist) | [85] |
| 39 | pKi = 8.7 (VLA-4 antagonist) | [86] |
| 40 | pKi = 9.3 (VLA-4 antagonist) | [86] |
Allosteric Modulators of CB1 | |||
| PSNCBAM-1 | CB1 agonist | [88] |
| 41 | CB1 agonist | [89] |
| 42 | CB1 agonist | [89] |
| LDK1317 | CB1 agonist | [90] |
| LDK1321 | CB1 agonist | [90] |
Antiplatelet agents | |||
| BPTU | Ki = 6 nM (P2Y1 receptor) IC50 = 0.28 µM (P2Y1 receptor) | [92] [95] |
| 43 | EC50 = 2 µM (ECAT) Ki = 17 nM (P2Y1 receptor) | [94] |
| 44 | Ki = 30 nM (P2Y1 receptor) | [94] |
| 45 | IC50 = 0.21 µM (P2Y1 receptor) | [95] |
| 46 | IC50 = 12.52 µM (P2Y1 receptor) | [95] |
| 47 | IC50 = 7.19 µM (P2Y1 receptor) | [95] |
| 48 | Ki = 4.3 nM (P2Y1 receptor); IC50 = 2,5 nM (P2Y1 FLIPR) | [96] |
| 49 | Ki = 7.9 nM (P2Y1 receptor); IC50 = 0.12 nM (P2Y1 FLIPR); IC50 = 0.13 µM (ADP-induced PA assay) | [97] |
| 50 | Ki = 4.0 nM (P2Y1 receptor); IC50 = 0.22 nM (P2Y1 FLIPR); IC50 = 0.17 µM (ADP-induced PA assay) | [98] |
| 51 | Ki = 12.9 nM (P2Y1 receptor); IC50 = 0.22 nM (P2Y1 FLIPR); IC50 = 0.41 µM (ADP-induced PA assay) | [98] |
Antiepileptic | |||
| 52 | ED50 = 28.5 mg/kg (MES induced seizures) | [99] |
Agents for neuroinflammation | |||
| 53 | Ki = 0.47 µM (TRPV1 capsaicin antagonism) | [101] |
| 54 | Ki = 0.49 µM (TRPV1 capsaicin antagonism); Ki = 1.39 μM (CB2) | [101] |
| 55 | Ki = 0.56 µM (TRPV1 capsaicin antagonism) | [101] |
| 56 | Binding prediction to CXCR2 (homology model) | [101] |
AChE and BuChE inhibitors | |||
| 57 | IC50 = 3.85 µM (AChE) IC50 = 9.25 µM (BuChE) | [102] |
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Catalano, A.; Iacopetta, D.; Pellegrino, M.; Aquaro, S.; Franchini, C.; Sinicropi, M.S. Diarylureas: Repositioning from Antitumor to Antimicrobials or Multi-Target Agents against New Pandemics. Antibiotics 2021, 10, 92. https://doi.org/10.3390/antibiotics10010092
Catalano A, Iacopetta D, Pellegrino M, Aquaro S, Franchini C, Sinicropi MS. Diarylureas: Repositioning from Antitumor to Antimicrobials or Multi-Target Agents against New Pandemics. Antibiotics. 2021; 10(1):92. https://doi.org/10.3390/antibiotics10010092
Chicago/Turabian StyleCatalano, Alessia, Domenico Iacopetta, Michele Pellegrino, Stefano Aquaro, Carlo Franchini, and Maria Stefania Sinicropi. 2021. "Diarylureas: Repositioning from Antitumor to Antimicrobials or Multi-Target Agents against New Pandemics" Antibiotics 10, no. 1: 92. https://doi.org/10.3390/antibiotics10010092