The synthesis of spiro[indole-3,1’-pyrrolo[3,4 -c]pyrrole]- 2,4’,6’-trione derivatives, the study of their antimicrobial activity and the molecular docking on staphylococcal dehydrosqualene synthase

R. G. Redkin, K. V. Hlebova

Abstract


Aim. To synthesize the series of new spiro[indole-3,1’-pyrrolo[3,4-c]pyrrole]-2,4’,6’-trione derivatives, study their physicochemical characteristics, antibacterial activity and precision of the molecular docking on the model of staphylococcal dehydrosqualene synthase.
Materials and methods. The methods of organic synthesis, instrumental methods for analysis of organic compounds, as well as the molecular docking method in silico and agar diffusion method in vitro were used.
Results and discussion. To synthesize new bis-derivatives of 3’a, 6’a-dihydro-3’H-spiro[indole-3,1’-pyrrolo[3,4-c]pyrrole]-2,4’,6’-triones the three-component reaction of 1,6-maleimidamidohexane with L-amino acids and isatin was studied. New bis-spiro derivatives were isolated with a double excess of the corresponding isatin and L-amino acids. With the equimolar ratio of three reagents 6-N-maleimidohexyl derivatives spiro[indole-3,1’-pyrrolo[3,4-c] pyrrole]-2,4’,6’-triones were isolated with the yields of 30-90 %. To prove their reactivity two symmetrical bis-spirooxindoles were counter-synthesized by condensation of two 6-N-maleimidohexyl spiro-2-oxindole derivatives with isatin, L-phenylalanine or sarcosine with the yields of 35 and 38 %. In the microbiological screening it was found that some compounds revealed the activity against S. aureus at the level of cefalexin and against C. albicans fungi relative to fluconazole. The docking in silico identified a high ability of the compounds studied to interact with at least six key amino acid residues – Arg45, Asp48, Asp52, Gln165, Asn168 and Asp172 of the active center of S. aureus dehydrosqualene synthase (CrtM).
Conclusions. It has been found that the one-pot three-component reaction of isatin, L-amino acids and 1,6-maleimidohexane as a function of the mole ratio of the reagents leads to both bis-derivatives of spiro[indole-3,1’-pyrrolo[3,4-c]pyrrole]-2,4’,6’-trione, and to the corresponding asymmetric 6-N-maleimidohexyl derivatives. The substances synthesized have predominantly shown the activity in relation to gram-positive bacteria and yeast-like fungi. For the first time it has been demonstrated by the molecular docking method that the compounds studied forming a complex with a high docking score are potential inhibitors of staphylococci CrtM.


Keywords


spiro-2-oxindoles; bis-spirocyclic systems; 1,3-cycloaddition; antimicrobial activity; dehydrosqualene synthase; molecular docking

Full Text:

PDF

References


Johnson, A. P. (2015). Surveillance of antibiotic resistance. Philosophical Transactions of the Royal Society of London. Series B, Biological

Sciences, 370 (1670), 20140080. doi: 10.1098/rstb.2014.0080

Clauditz, A., Resch, A., Wieland, K.–P., Peschel, A., Gotz, F. (2006). Staphyloxanthin Plays a Role in the Fitness of Staphylococcus

aureus and Its Ability To Cope with Oxidative Stress. Infection and Immunity, 74 (8), 4950–4953. doi: 10.1128/iai.00204–06

Liu, G. Y., Essex, A., Buchanan, J. T., Datta, V., Hoffman, H. M., Bastian, J. F., Nizet, V. (2005). Staphylococcus aureusgolden pigment

impairs neutrophil killing and promotes virulence through its antioxidant activity. The Journal of Experimental Medicine, 202 (2),

–215. doi: 10.1084/jem.20050846

Gao, P., Davies, J., Kao, R. Y. T. (2017). Dehydrosqualene Desaturase as a Novel Target for Anti–Virulence Therapy against Staphylococcus

aureus. mBio,8 (5), e01224–17. doi: 10.1128/mBio.01224–17

Liu, C.–I., Liu, G. Y., Song, Y., Yin, F., Hensler, M. E., Jeng, W.–Y., Oldfield, E. (2008). A Cholesterol Biosynthesis Inhibitor Blocks

Staphylococcus aureus Virulence. Science, 319 (5868), 1391–1394. doi: 10.1126/science.1153018

Lin, F.–Y., Liu, C.–I., Liu, Y.–L., Zhang, Y., Wang, K., Jeng, W.–Y., Oldfield, E. (2010). Mechanism of action and inhibition of dehydrosqualene

synthase. Proceedings of the National Academy of Sciences, 107 (50), 21337–21342. doi: 10.1073/pnas.1010907107

Redkin, R. G., Syumka, E. I, Shemchuk, L. A., Chernykh, V. P. (2017). Synthesis And Antimicrobial Activity of Bis–Derivatives of

a′,6a′–Dihydro2’H–Spiro[Indole–3,1’Pyrrolo[3,4–c]Pyrrole]–2,4’,6’(1H, 3’H, 5’H)–Trione. Journal of Applied Pharmaceutical Science,

(06), 069–078. doi: 10.7324/JAPS.2017.70610

Pavlovska, T. L., Redkin, R. G., Lipson, V. V., Atamanuk, D. V. (2015). Molecular diversity of spirooxindoles. Synthesis and biological

activity. Molecular Diversity, 20 (1), 299–344. doi: 10.1007/s11030–015–9629–8

Biot, C., Dessolin, J., Grellier, P., Davioud–Charvet, E. (2003). Double–drug development against antioxidant enzymes fromPlasmodium

falciparum. Redox Report, 8 (5), 280–283. doi: 10.1179/135100003225002916

Matsumoto, H., Hamawaki, T., Ota, H., Kimura, T., Goto, T., Sano, K., Kiso, Y. (2000). “Double–drugs”– A new class of prodrug form

of an HIV protease inhibitor conjugated with a reverse transcriptase inhibitor by a spontaneously cleavable linker. Bioorganic & Medicinal

Chemistry Letters, 10 (11), 1227–1231. doi: 10.1016/s0960–894x(00)00202–x

Suymka, Y. I., Red’kin, R. G., Shemchuk, L. A., Hlebova, K. V., Filimonova, N. I. (2017). Synthesis and the antimicrobial activity of

hexamethylene–Nmaleinimidospiroindole– 3,3’–pyrrolo[3,4–c]pyrrole derivatives. Žurnal Organìčnoï Ta Farmacevtičnoï Hìmìï, 15

(4(60)), 56–62. doi: 10.24959/ophcj.17.929

Blom, K. F., Glass, B., Sparks, R., Combs, A. P. (2004). Preparative LC−MS Purification: Improved Compound–Specific Method Optimization.

Journal of Combinatorial Chemistry, 6 (6), 874–883. doi: 10.1021/cc049890v

Volianskyi, Yu. L., Hrytsenko, I. S., Shyrobokov, V. P. et al. (2004). Vyvchennia spetsyfichnoi aktyvnosti protymikrobnykh likarskykh

zasobiv. Kyiv: DFTs Ukrainy, 38.

Trott, O., Olson, A. J. (2010). AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient

optimization and multithreading. Journal of Computational Chemistry, 31 (2), 455–461. doi: 10.1002/jcc.21334

Sanner, M. F. (1999). Python: a programming language for software integration and development. Journal of Molecular Graphics and

Modelling, 17 (2), 57–61. doi: 10.1016/S1093–3263(99)99999–0

Kahlon, A. K., Roy, S., Sharma, A. (2010). Molecular Docking Studies to Map the Binding Site of Squalene Synthase Inhibitors on Dehydrosqualene

Synthase ofStaphylococcus Aureus. Journal of Biomolecular Structure and Dynamics, 28 (2), 201–210. doi: 10.1080/07391102.2010.10507353


GOST Style Citations


1. Johnson, A. P. Surveillance of antibiotic resistance / A. P. Johnson // Phil. Trans. R. Soc. B. – 2015. – Vol. 370, Issue 1670. – 20140080 p.
doi: 10.1098/rstb.2014.0080

2. Staphyloxanthin plays a role in the fitness of Staphylococcus aureus and its ability to cope with oxidative stress / A. Clauditz, A. Resch,
K. P. Wieland et al. // Infect. Immun. – 2006. – Vol. 74, Issue 8. – P. 4950–4953. doi: 10.1128/IAI.00204–06

3. Staphylococcus aureus golden pigment impairs neutrophil killing and promotes virulence through its antioxidant activity / G. Y. Liu,
A. Essex, J. T. Buchanan et al. // J. Exp. Med. – 2005. – Vol. 202, Issue 2. – P. 209–215. doi: 10.1084/jem.20050846

4. Gao, P. Dehydrosqualene Desaturase as a Novel Target for Anti–Virulence Therapy against Staphylococcus aureus / P. Gao, J. Davies,
K. Ryt // MBio. – 2017. – Vol. 8, Issue 5. – P. 4–17. doi: 10.1128/mBio.01224–17

5. A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence / C. I. Liu, G. Y. Liu, Y. Song et al. // Sci. – 2008. –
Vol. 319, Issue 5868. – P. 1391–1394. doi: 10.1126/science.1153018

6. Mechanism of action and inhibition of dehydrosqualene synthase / F. Y. Lin, C. I. Liu, Y. L. Liu et al. // Proc. Natl. Acad. Sci. USA. –
2010. – Vol. 107, Issue 50. – P. 21337–21342. doi: 10.1073/pnas.1010907107

7. Synthesis and antimicrobial activity of Bis–Derivatives of 3a′,6a′–Dihydro–2’H–Spiro[Indole–3,1’–Pyrrolo[3,4–c]Pyrrole]–2,4’,6’(1H,3’H,5’H)–
Trione / R. G. Redkin, E. I. Syumka, L. A. Shemchuk, V. P. Chernykh // J. App. Pharm. Sci. – 2017. – Vol. 7, Issue 06. – P. 069–078.
doi: 10.7324/JAPS.2017.70610

8. Molecular diversity of spirooxindoles. Synthesis and biological activity / T. L. Pavlovska, R. Gr. Redkin, V. V. Lipson, D. V. Atamanuk //
Mol. Divers. – 2016. – Vol. 20, Issue 1. – P. 299–344. doi: 10.1007/s11030–015–9629–8

9. Double–drug development against antioxidant enzymes from Plasmodium falciparum / C. Biot, J. Dessolin, P. Grellier, E. Davioud–
Charvet // Redox Rep. – 2003. – Vol. 8, Issue 5. – P. 280–283. doi: 10.1179/135100003225002916

10. ‘’Double–Drugs’’ A New Class of Prodrug Form of an HIV Protease Inhibitor Conjugated with a Reverse Transcriptase Inhibitor by a
Spontaneously Cleavable Linker / H. Matsumoto, T. Hamawaki, H. Ota et al. // Bioorg. Med. Chem. Lett. – 2000. – Vol. 10, Issue 11. –
P. 1227–1231. doi: 10.1016/S0960–894X(00)00202–X

11. Synthesis and antimicrobial activity of hexamethylene–N–maleinimidospiroindole–3,3’–pyrrolo[3,4–с]pyrrole derivatives / Ye. I. Syumka,
R. G. Red’kin, L. A. Shemchuk et al. // ЖОФХ. – 2017. – Вип. 15, № 4 (60). – С. 56–62. doi: 10.24959/ophcj.17.929

12. Preparative LC–MS Purification : Improved Compound Specific Method Optimization / K. F. Blom, B. Glass, R. Sparks, A. P. Combs //
J. of Combinatorial Chem. – 2004. – Vol. 6, Issue 6. – P. 874–883. doi: 10.1021/cc049890v

13. Вивчення специфічної активності протимікробних лікарських засобів : метод. рек. МОЗ України / Ю. Л. Волянський, І. С. Гриценко, В. П. Широбоков та ін. – К. : ДФЦ МОЗ України, 2004. – 38 с.

14. Trott, O. AutoDock Vina : improving the speed and accuracy of dockin with a new scoring function, efficient optimization and multithreading
/ O. Trott, A. J. Olson // J. Comp. Chem. – 2010. – Vol. 31, Issue 2. – P. 455–461. doi: 10.1002/jcc.21334

15. Sanner, M. F. Python : a programming language for software integration and development / M. F. Sanner // J. Mol. Graph. Model. –
1999. – Vol. 17, Issue 2. – P. 57–61. doi: 10.1016/S1093–3263(99)99999–0

16. Kahlon, A. K. Molecular Docking Studies to Map the Binding Site of Squalene Synthase Inhibitors on Dehydrosqualene Synthase of
Staphylococcus Aureus / A. K. Kahlon, S. Roy, A. Sharma // J. Biomol. Struct. Dyn. – Vol. 28, Issue 2. – 2010. – P. 201–210.
doi: 10.1080/07391102.2010.10507353





DOI: https://doi.org/10.24959/nphj.18.2210

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

Abbreviated key title: Vìsn. farm.

ISSN 2415-8844 (Online), ISSN 1562-7241 (Print)