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Synthesis and biological evaluations of oleanolic acid indole derivatives as hyaluronidase inhibitors with enhanced skin permeability.

ABSTRACT: Oleanolic acid (OA) is a natural cosmeceutical compound with various skin beneficial activities including inhibitory effect on hyaluronidase but the anti-hyaluronidase activity and mechanisms of action of its synthetic analogues remain unclear. Herein, a series of OA derivatives were synthesised and evaluated for their inhibitory effects on hyaluronidase. Compared to OA, an induction of fluorinated (6c) and chlorinated (6g) indole moieties led to enhanced anti-hyaluronidase activity (IC₅₀ = 80.3 vs. 9.97 and 9.57 µg/mL, respectively). Furthermore, spectroscopic and computational studies revealed that 6c and 6g can bind to hyaluronidase protein and alter its secondary structure leading to reduced enzyme activity. In addition, OA indole derivatives showed feasible skin permeability in a slightly acidic environment (pH = 6.5) and 6c exerted skin protective effect by reducing cellular reactive oxygen species in human skin keratinocytes. Findings from the current study support that OA indole derivatives are potential cosmeceuticals with anti-hyaluronidase activity.

SUBMITTER: He H

PROVIDER: S-EPMC8317927 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:It is prudent that novel classes of antibiotics be urgently developed to manage the WHO prioritized multi-drug resistant (MDR) pathogens posing an unprecedented medical crisis. Simultaneously, multiple essential proteins have to be targeted to prevent easy resistance development. METHODS:An integration of structure-based virtual screening and ligand-based virtual screening was employed to explore the antimicrobial properties of indole derivatives from a compound database. RESULTS:Whole-genome sequences of the target pathogens were aligned exploiting DNA alignment potential of MAUVE to identify putative common lead target proteins. S-adenosyl methionine (SAM) biosynthesizing MetK was taken as the lead target and various literature searches revealed that SAM is a critical metabolite. Furthermore, SAM utilizing CobA involved in the B12 biosynthesis pathway, Dam in the regulation of replication and protein expression, and TrmD in methylation of tRNA were also taken as drug targets. The ligand library of 715 indole derivatives chosen based on kinase inhibition potential of indoles was created from which 102 were pursued based on ADME/T scores. Among these, 5 potential inhibitors of MetK in N. gonorrhoeae were further expanded to molecular docking studies in MetK proteins of all nine pathogens among which 3 derivatives exhibited inhibition potential. These 3 upon docking in other SAM utilizing enzymes, CobA, Dam, and TrmD gave 2 potential compounds with multiple targets. Further, docking with human MetK homolog also showed probable inhibitory effects however SAM requirements can be replenished from external sources since SAM transporters are present in humans. CONCLUSIONS:We believe these molecules 3-[(4-hydroxyphenyl)methyl]-6-(1H-indol-3-ylmethyl)piperazine-2,5-dione (ZINC04899565) and 1-[(3S)-3-[5-(1H-indol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyrrolidin-1-yl]ethanone (ZINC49171024) could be a starting point to help develop broad-spectrum antibiotics against infections caused by N. gonorrhoeae, A. baumannii, C. coli, K. pneumoniae, E. faecium, H. pylori, P. aeruginosa, S. aureus and S. typhi.

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Synthesis and biological evaluations of oleanolic acid indole derivatives as hyaluronidase inhibitors with enhanced skin permeability.

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