Synthesis and Antibacterial Evaluation of Novel 3-Substituted Ocotillol-Type Derivatives as Leads

Abstract

Due to the rapidly growing bacterial antibiotic-resistance and the scarcity of novel agents in development, bacterial infection is still a global problem. Therefore, new types of antibacterial agents, which are effective both alone and in combination with traditional antibiotics, are urgently needed. In this paper, a series of antibacterial ocotillol-type C-24 epimers modified from natural 20(S)-protopanaxadiol were synthesized and evaluated for their antibacterial activity. According to the screening results of Gram-positive bacteria (B. subtilis 168 and MRSA USA300) and Gram-negative bacteria (P. aer PAO1 and A. baum ATCC19606) in vitro, the derivatives exhibited good antibacterial activity, particularly against Gram-positive bacteria with an minimum inhibitory concentrations (MIC) value of 2–16 µg/mL. The subsequent synergistic antibacterial assay showed that derivatives 5c and 6c enhanced the susceptibility of B. subtilis 168 and MRSA USA300 to chloramphenicol (CHL) and kanamycin (KAN) (FICI < 0.5). Our data showed that ocotillol-type derivatives with long-chain amino acid substituents at C-3 were good leads against antibiotic-resistant pathogens MRSA USA300, which could improve the ability of KAN and CHL to exhibit antibacterial activity at much lower concentrations with reduced toxicity.

Design, Synthesis and Antibacterial Evaluation of 3-Substituted Ocotillol-Type Derivatives

“…Fourteen ocotillol-type derivatives that we had synthesised were selected with good activity against B. sub , including the compounds that at the C-3 position had free amino and carboxy group. All the structures are attached in Appendix Table A1 [16,17,18,23]. The final pharmacophore models were achieved with follow operations, including a population size value of 20, a maximum generation value of 100 and the value of molecular required hitting was 8.…”

“…Ocotillol-type saponins are one kind of tetracyclic triterpenoids, bearing a tetrahydrofurane ring in the side chain [17,18]. Natural ocotillol-type saponins have been isolated from Panax quinquefolius , Panax japonicus L., Hana mina and Vietnamese ginseng [19].…”

“…In our recent research, we designed C-3 with free aliphatic amino derivatives which exhibited good antibacterial activity against Gram-positive bacteria; compound I was one of these derivatives with a minimum inhibitory concentrations (MIC) value of 4 µg/mL against MRSA USA300. Besides, when combined with kanamycin and chloramphenicol, compound I also showed good synergistic inhibitory effects against Gram-positive bacteria [17]. Furthermore, through design and synthesis of compound II , we found that the ocotillol-type triterpenoid core may play a role in the bacterial membrane [22].…”

Synthesis and Bioactivity Evaluation of N-Arylsulfonylindole Analogs Bearing a Rhodanine Moiety as Antibacterial Agents

“…Bacterial drug resistance has emerged and become increasingly serious on a global scale, both in developed and developing countries [ 1 ]. Drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), multi-drug resistant Escherichia coli , and multi-drug resistant Pseudomonas aeruginosa , cause lethal diseases and cause great difficulties in the treatment of nosocomial infections [ 2 , 3 , 4 , 5 ], which severely threaten global public health while resulting in very large economic costs [ 6 ]. Currently the development of new antimicrobial drugs cannot keep pace with the development of bacterial drug resistance, and the number of new antibiotics approved for marketing per year is declining continuously.…”

Special Issue: Frontiers in Antimicrobial Drug Discovery and Design

“…A number of 3-substituted ocotillol-type C-24 epimers, modified from natural 20( S )-protopanaxadiol, were synthesized and evaluated for their antibacterial activity by Bi et al [ 1 ]. They were effective both alone and in combination with traditional antibiotics, exhibiting a particularly interesting activity against Gram-positive bacteria and enhancing the susceptibility of B. subtilis 168 and Methicillin-Resistant Staphylococcus aureus USA300 to chloramphenicol and kanamycin, making these latter drugs active at much lower concentrations with reduced toxicity.…”