Synthesis and antibacterial and antimycobacterial evaluation of 4-hydroxyderricin and its analogs

Author(s)

Reinaldo dos Santos Theodoro

• Document type: Master's Dissertation
• Press: São José do Rio Preto. 2022-02-24.
• Institution: Universidade Estadual Paulista (Unesp). Instituto de Biociências Letras e Ciências Exatas. São José do Rio Preto
• Defense date: 2022-01-27
• Advisor: Luis Octavio Regasini; Miguel Divino da Rocha

Abstract

Microbial infections and antibiotic resistance have been the most significant challenges threatening the health of society today. 4-hydroxyderricin (4HD) is a naturally occurring prenylated chalcone that has been isolated from Angelica keiskei (Ashitaba) and demonstrates multiple pharmacological activities, mainly antibacterial. In this context, 4HD and three series of analogs were designed, synthesized, and investigated against clinically important bacteria, mycobacteria, and fungi. This work used 4-hydroxyderricin as a prototype for the planning of analogs, which were designed by the permutation of the p-hydroxyl subunit by electron donor and electro-attracting groups (Series I), changing the 2'-hydroxyl, 3'-prenyl and 4'-methoxyl subunits (Series II) and α,β-unsaturated ketone reductions (Series III). The synthesized 111 substances were described, including intermediates (68) and target substances (45), 26 of which were new and 8 were natural products. The target substances (1 – 45) were prepared through Regioselective Iodations, O-Methylations, Protections, Aldol Condensations between aldehydes and ketones on basic catalysis, Suzuki couplings, [1,3]-Sigmatropic Rearrangements, Deprotections, and reactions of Reduction. First, 4HD showed to be strongly active against bacteria and mycobacteria with MIC values of 1.56 – 400 µg.mL-1, mainly against gram-positive bacteria. 4HD showed potent inhibitory activity against S. aureus MSSA and MRSA biofilm with MICB50 values of 1.56 and 0.78 µg.mL-1, respectively. We also found that 4HD has a bactericidal action by damaging the cytoplasmatic membrane of B. subtilis, with low cytotoxicity against HaCaT cells. 4HD was shown to be a potent antifungal agent against T. rubrum, and T. mentagrophytes strains with MIC values of 0.9 – 31.2 µg.mL-1 and moderate activity against C. auris with MIC values of 31.2 µg.mL-1. 4HD acted synergistically and potentiated the activity of terbinafine 5- to 10-fold and itraconazole 2- to 4-fold. The cell membrane of dermatophyte fungi was the target of 4HD since exogenous ergosterol considerably decreased the antifungal activity (MIC>31.2 µg.mL-1). The antibacterial and antimycobacterial activities of the chalcones derivatives 2 – 38 ranged from 1.56 to 400 µg.mL-1. SAR studies have suggested that 3'-prenyl, 2'-hydroxyl, and 4-hydroxyl are fundamental pharmacophoric points of 4HD for antibacterial and antimycobacterial activity. Furthermore, exchanging the prenyl group in 4HD for a benzyl group did not significantly alter the antibacterial activity, providing a non-classical bioisosteric relationship between these two subunits. Reduced chalcones derivatives were the most active compounds classes in this work. The α,β-unsaturated ketone reduction strategy caused an increase in the antibacterial activity of some chalcones that were initially not active, such as 4'-O-methylbavachalcone (16). Furthermore, 4HD reduction formed dihydrochalcones 29 and 30 and 1,3-diarylpropane 35, which were more promising than their substrate, mainly against MSSA and MRSA. Therefore, reduction of α,β-unsaturated ketone from 4HD did not lead to loss of antibacterial activity. Compounds 13, 29, 30, and 37 showed potent activity in inhibiting the biofilm of MSSA and MRSA. Compound 29 (4-hydroxydihydroderricin) showed low cytotoxicity against HaCaT cells. Therefore, 4-hydroxyderricin and its analogs are promising antibacterial and antifungal agents and may be an alternative in treating and combating various infections caused by these bacteria, mycobacteria, and fungi. Thus, 4HD and 29 can be considered promising lead compounds to discover new drugs. (AU)

• FAPESP's process: 19/11979-4 - Synthesis and evaluation of 4-Hydroxyderricini (4-HD) and its analogs as potential agents against tuberculosis
• Grantee: Reinaldo dos Santos Theodoro
• Support Opportunities: Scholarships in Brazil - Master