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.
Highlights
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
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 %
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
Summary
In order to synthesize a new series of the target 1R1-3’-R2-5’-(6-{3’-R2-1-R1-2,4’,6’-trioxo-3’a,6’-dihydro3’H-spiro[indole-3,1’-pyrrolo[3,4-c]pyrrole]-5’-yl} hexyl)-3’a,6’a-dihydro-3’H-spiro[indole-3,1’-pyrrolo[3,4-c]pyrrole]-2,4’,6’-triones 4.1-4.15 the three-component condensation of isatines 1.1-1.4, amino acids 2.1-2.11 and 1,6-bis-maleimidohexane 3 were studied. The compounds with a free maleimidine residue exhibited greater activity, in particular substances 5.1, 5.2 and 5.5 among a number of 1-R1-3’-R2- 5’-(6-N-maleimidogexyl)-3’a,6’adihydro-3’H-spiro [indole-3,1’-pyrrolo [3,4c]pyrrole]2,4’,6’-triones 5.1-5.10 exhibited the bactericidal action (MBC = 12.5 mcg/mL) relative to S. aureus (Fig. 1). The validation of binding of the control structure of BPH-65 to the amino acid residues of the active CrtM center after the results of the docking obtained by us in silico on the 3D CrtM model (Fig. 6) is close to the parameters of formation of the ligand-target complex obtained by the X-ray method for the co-crystal of the BPH-65 compound with the CrtM enzyme in the literature [5]. In our experiment the ability of molecules to form hydrogen bonds with at least six key amino acid residues – Arg, Asp, Asp, Gln165, Asn168 and Asp172 has been found in silico
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