Synthesis of Ursolic Acid-based Hybrids: In Vitro Antibacterial, Cytotoxicity Studies, In Silico Physicochemical and Pharmacokinetic Properties.

BACKGROUND: There is a critical need for the discovery of novel and effective antibacterial or anticancer molecules. OBJECTIVES: Amine-linked ursolic acid-based hybrid compounds were prepared in good yields in the range of 60-68%. METHODS: Their molecular structures were successfully confirmed using different spectroscopic methods including 1H/13C NMR, UHPLC-HRMS and FTIR spectroscopy. The in vitro cytotoxicity of some of these hybrid molecules against three human tumour cells, such as MDA-MB23, MCF7, and HeLa was evaluated using the MTT colorimetric method. RESULT: Their antibacterial efficacy was evaluated against eleven bacterial pathogens using a serial dilution assay. Majority of the bacterial strains were inhibited significantly by compounds 17 and 24, with the lowest MIC values in the range of 15.3-31.25 µg/mL. Compound 16 exhibited higher cytotoxicity against HeLa cells than ursolic acid, with an IC50 value of 43.64 g/mL. CONCLUSION: The in vitro antibacterial activity and cytotoxicity of these hybrid compounds demonstrated that ursolic acid-based hybrid molecules are promising compounds. Further research into ursolic acid-based hybrid compounds is required.

Computational Target-Based Screening of Anti-MRSA Natural Products Reveals Potential Multitarget Mechanisms of Action through Peptidoglycan Synthesis Proteins.

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the leading causes of bacterial infections in both healthcare and community settings. MRSA can acquire resistance to any current antibiotic, which has major implications for its current and future treatment options. As such, it is globally a major focus for infection control efforts. The mechanical rigidity provided by peptidoglycans in the bacteria cell walls makes it a promising target for broad-spectrum antibacterial drug discovery. The development of drugs that can target different stages of the synthesis of peptidoglycan in MRSA may compromise the integrity of its cell wall and consequently result in the rapid decline of diseases associated with this drug-resistant bacteria. The present study is aimed at screening natural products with known in vitro activities against MRSA to identify their potential to inhibit the proteins involved in the biosynthesis of the peptidoglycan cell wall. A total of 262 compounds were obtained when a literature survey was conducted on anti-MRSA natural products (AMNPs). Virtual screening of the AMNPs was performed against various proteins (targets) that are involved in the biosynthesis of the peptidoglycan (PPC) cell wall using Schrödinger software (release 2020-3) to determine their binding affinities. Nine AMNPs were identified as potential multitarget inhibitors against peptidoglycan biosynthesis proteins. Among these compounds, DB211 showed the strongest binding affinity and interactions with six protein targets, representing three stages of peptidoglycan biosynthesis, and thus was selected as the most promising compound. The MD simulation results for DB211 and its proteins indicated that the protein-ligand complexes were relatively stable over the simulation period of 100 ns. In conclusion, DB211 showed the potential to inhibit six proteins involved in the biosynthesis of the peptidoglycan cell wall in MRSA, thus reducing the chance of MRSA developing resistance to this compound. Therefore, DB211 provided a starting point for the design of new compounds that can inhibit multiple targets in the biosynthesis of the peptidoglycan layer in MRSA.

Cheminformatic Characterization of Natural Antimicrobial Products for the Development of New Lead Compounds.

The growing antimicrobial resistance (AMR) of pathogenic organisms to currently prescribed drugs has resulted in the failure to treat various infections caused by these superbugs. Therefore, to keep pace with the increasing drug resistance, there is a pressing need for novel antimicrobial agents, especially from non-conventional sources. Several natural products (NPs) have been shown to display promising in vitro activities against multidrug-resistant pathogens. Still, only a few of these compounds have been studied as prospective drug candidates. This may be due to the expensive and time-consuming process of conducting important studies on these compounds. The present review focuses on applying cheminformatics strategies to characterize, prioritize, and optimize NPs to develop new lead compounds against antimicrobial resistance pathogens. Moreover, case studies where these strategies have been used to identify potential drug candidates, including a few selected open-access tools commonly used for these studies, are briefly outlined.