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


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.


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

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