Ribocil

Ribocil
Names
	IUPAC name 2-[1-[[2-(methylamino)pyrimidin-5-yl]methyl]piperidin-3-yl]-4-thiophen-2-yl-1H-pyrimidin-6-one
Identifiers
CAS Number	1381289-58-2;
3D model (JSmol)	Interactive image;
ChEMBL	ChEMBL5266420;
ChemSpider	29906465;
PubChem CID	136881500;
	InChI InChI=1S/C19H22N6OS/c1-20-19-21-9-13(10-22-19)11-25-6-2-4-14(12-25)18-23-15(8-17(26)24-18)16-5-3-7-27-16/h3,5,7-10,14H,2,4,6,11-12H2,1H3,(H,20,21,22)(H,23,24,26) Key: ZSXCVAIJFUEGJR-UHFFFAOYSA-N;
	SMILES CNC1=NC=C(C=N1)CN2CCCC(C2)C3=NC(=CC(=O)N3)C4=CC=CS4;
Properties
Chemical formula	C19H22N6OS
Molar mass	382.49 g·mol−1
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Ribocil is chemical compound which is found to be a potent inhibitor of the FMN riboswitch, meaning it could serve as a promising lead compound for developing a new antibiotic class. The compound was discovered by Merck & Co. through a phenotypic screen of the Gram-positive bacteria Staphylococcus aureus.^[1] The binding mode of this small molecule to its binding site has been confirmed through the use of X-Ray crystallography.^[2]

Binding mode

X-Ray crystallography of the FMN riboswitch bound to FMN (upper, PDB code: 2yie) and ribocil (lower, PDB code: 5c45) and juxtaposed (middle). Residues which form interactions with the binders are highlighted with text.

The structure of ribocil versus previously discovered binders to the FMN riboswitch makes it unique, as it is not a structural analogue to the natural ligand, flavin mononucleotide (FMN). The binding mode of this compound has some similarities with ribocil, where the same π-π stacking interaction and two hydrogen bond is also conserved. Ribocil also makes two new contacts with the binding site which notably differs from FMN: a π-π interaction between the aminopyrimidine of ribocil and residue G62 and an edge-face π-interaction.^[2]

Challenges and derivatives

One major obstacle of using ribocil as a bona fide antibiotic is that although it kills bacteria in culture, Gram-positive organisms can scavenge riboflavin from their environment.^[3] While ribocil in itself has no activity towards Gram-negative bacteria, derivatives of ribocil which enhance the accumulative properties of these compounds have been synthesized to show whole-cell activity against wild-type strains of these bacteria.^[1]^[3]^[4]

References

^ ^a ^b Howe, John A.; Wang, Hao; Fischmann, Thierry O.; Balibar, Carl J.; Xiao, Li; Galgoci, Andrew M.; Malinverni, Juliana C.; Mayhood, Todd; Villafania, Artjohn; Nahvi, Ali; Murgolo, Nicholas; Barbieri, Christopher M.; Mann, Paul A.; Carr, Donna; Xia, Ellen; Zuck, Paul; Riley, Dan; Painter, Ronald E.; Walker, Scott S.; Sherborne, Brad; de Jesus, Reynalda; Pan, Weidong; Plotkin, Michael A.; Wu, Jin; Rindgen, Diane; Cummings, John; Garlisi, Charles G.; Zhang, Rumin; Sheth, Payal R.; Gill, Charles J.; Tang, Haifeng; Roemer, Terry (2015-10-29). "Selective small-molecule inhibition of an RNA structural element". Nature. 526 (7575): 672–677. Bibcode:2015Natur.526..672H. doi:10.1038/nature15542. ISSN 0028-0836. PMID 26416753. Retrieved 2017-02-02.
^ ^a ^b Howe, John A.; Xiao, Li; Fischmann, Thierry O.; Wang, Hao; Tang, Haifeng; Villafania, Artjohn; Zhang, Rumin; Barbieri, Christopher M.; Roemer, Terry (2016-10-02). "Atomic resolution mechanistic studies of ribocil: A highly selective unnatural ligand mimic of the E. coli FMN riboswitch". RNA Biology. 13 (10): 946–954. doi:10.1080/15476286.2016.1216304. ISSN 1547-6286. PMC 5056776. PMID 27485612. Retrieved 2020-09-08.
^ ^a ^b Wang, Hao; Mann, Paul A.; Xiao, Li; Gill, Charles; Galgoci, Andrew M.; Howe, John A.; Villafania, Artjohn; Barbieri, Christopher M.; Malinverni, Juliana C.; Sher, Xinwei; Mayhood, Todd; McCurry, Megan D.; Murgolo, Nicholas; Flattery, Amy; Mack, Matthias (2017-05-18). "Dual-Targeting Small-Molecule Inhibitors of the Staphylococcus aureus FMN Riboswitch Disrupt Riboflavin Homeostasis in an Infectious Setting". Cell Chemical Biology. 24 (5): 576–588.e6. doi:10.1016/j.chembiol.2017.03.014. ISSN 2451-9456. PMID 28434876.
^ Motika, Stephen E.; Ulrich, Rebecca J.; Geddes, Emily J.; Lee, Hyang Yeon; Lau, Gee W.; Hergenrother, Paul J. (2020-06-17). "Gram-Negative Antibiotic Active Through Inhibition of an Essential Riboswitch". Journal of the American Chemical Society. 142 (24): 10856–10862. Bibcode:2020JAChS.14210856M. doi:10.1021/jacs.0c04427. ISSN 0002-7863. PMC 7405991. PMID 32432858.

[:0-1] Howe, John A.; Wang, Hao; Fischmann, Thierry O.; Balibar, Carl J.; Xiao, Li; Galgoci, Andrew M.; Malinverni, Juliana C.; Mayhood, Todd; Villafania, Artjohn; Nahvi, Ali; Murgolo, Nicholas; Barbieri, Christopher M.; Mann, Paul A.; Carr, Donna; Xia, Ellen; Zuck, Paul; Riley, Dan; Painter, Ronald E.; Walker, Scott S.; Sherborne, Brad; de Jesus, Reynalda; Pan, Weidong; Plotkin, Michael A.; Wu, Jin; Rindgen, Diane; Cummings, John; Garlisi, Charles G.; Zhang, Rumin; Sheth, Payal R.; Gill, Charles J.; Tang, Haifeng; Roemer, Terry (2015-10-29). "Selective small-molecule inhibition of an RNA structural element". Nature. 526 (7575): 672–677. Bibcode:2015Natur.526..672H. doi:10.1038/nature15542. ISSN 0028-0836. PMID 26416753. Retrieved 2017-02-02.

[:1-2] Howe, John A.; Xiao, Li; Fischmann, Thierry O.; Wang, Hao; Tang, Haifeng; Villafania, Artjohn; Zhang, Rumin; Barbieri, Christopher M.; Roemer, Terry (2016-10-02). "Atomic resolution mechanistic studies of ribocil: A highly selective unnatural ligand mimic of the E. coli FMN riboswitch". RNA Biology. 13 (10): 946–954. doi:10.1080/15476286.2016.1216304. ISSN 1547-6286. PMC 5056776. PMID 27485612. Retrieved 2020-09-08.

[:2-3] Wang, Hao; Mann, Paul A.; Xiao, Li; Gill, Charles; Galgoci, Andrew M.; Howe, John A.; Villafania, Artjohn; Barbieri, Christopher M.; Malinverni, Juliana C.; Sher, Xinwei; Mayhood, Todd; McCurry, Megan D.; Murgolo, Nicholas; Flattery, Amy; Mack, Matthias (2017-05-18). "Dual-Targeting Small-Molecule Inhibitors of the Staphylococcus aureus FMN Riboswitch Disrupt Riboflavin Homeostasis in an Infectious Setting". Cell Chemical Biology. 24 (5): 576–588.e6. doi:10.1016/j.chembiol.2017.03.014. ISSN 2451-9456. PMID 28434876.

[4] Motika, Stephen E.; Ulrich, Rebecca J.; Geddes, Emily J.; Lee, Hyang Yeon; Lau, Gee W.; Hergenrother, Paul J. (2020-06-17). "Gram-Negative Antibiotic Active Through Inhibition of an Essential Riboswitch". Journal of the American Chemical Society. 142 (24): 10856–10862. Bibcode:2020JAChS.14210856M. doi:10.1021/jacs.0c04427. ISSN 0002-7863. PMC 7405991. PMID 32432858.

[1]

[2]

[3]

[4]