Synthesis of Isosteric Triterpenoid Derivatives and Antifungal Activity

Abstract

Dermatomycoses are among the most widespread and common superficial and cutaneous fungal infections in humans. There is an urgent need to develop efficient and non-toxic antimycotic agents with a specific spectrum of activity. Triterpenes have been demonstrated to exhibit a wide range of biological activities, including antifungal activities. In this study, through hemisynthesis, we aimed to obtain triterpene-isosteric molecules from betulinic and ursolic acids to improve the antifungal activity and spectrum of action of these compounds. Six compounds were resynthesized and tested against eleven mucocutaneous and cutaneous mycotic agents. The results of the susceptibility assays were expressed as the minimal inhibitory concentration (MIC). The MIC values of the piperazinyl derivatives of ursolic and betulinic acids that were active against pathogenic yeasts were in the range of 16-32 μg/mL and 4-16 μg/mL, respectively, whereas fungicidal effects were observed at concentrations ranging from 16 to 128 μg/mL and 8 to 128 μg/mL, respectively. The piperazinyl derivative of betulinic acid exhibited an antifungal profile similar to that of terbinafine and was the most effective derivative against dermatophytes. This strategy led to a promising candidate for the development of a new antifungal agent.

New Pharmacological Opportunities for Betulinic Acid

“…The most potent compound was the amide of 3-acetyl-betulinic acid with N,N-bis-2-aminoethylpiperazine. It should be noted that this compound was also the most potent against different species of fungi belonging to Candida, Tricophyton, Epidermophyton, Microsporum, and Scytalidium [76].…”

C-28 Esters of Triterpenoid Acids Bearing Tris(hydroxymethyl)aminomethane: Synthesis and Anticancer/Antimicrobial Activity

“…The minimum inhibitory concentrations (MICs) of ursolic and oleanolic acids against various Staphylococcus aureus strains, including the methicillin-resistant (MRSA) strain, were in the range from 8 to 64 μg/mL, while betulinic acid was less active against these strains [20]. Some semisynthetic analogues of betulinic, ursolic, and oleanolic acids were synthesized and studied in vitro as potential antimicrobial agents [21][22][23]. We have studied the antibacterial activities of dihydrobetulinic, ursolic, and oleanolic acids and their conjugates 2, 3, 5, 6, 8, and 9 using four bacterial strains, including Gram-negative Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa and Gram-positive methicillin-resistant Staphylococcus aureus (MRSA).…”

Ursolic acid derivatives as potential antidiabetic agents: In vitro, in vivo, and in silico studies

“…Natural products represent a great source for to study and develop new drugs candidates for the treatment of diabetes (Liu, Chen, Hu, Guo, & Shen, ). Ursolic acid (UA) is a triterpene that has shown metabolic (Sheng & Sun, ), cardiovascular (Aguirre‐Crespo et al, ; Rios et al, ; Somova, Nadar, Rammanan, and Shode, ; Somova, Shode, Ramnanan, & Nadar, ), antibacterial (Nascimento et al, ), antifungal (Innocente et al, ), cytotoxic (Li et al, ), antidepressant (Colla et al, ; Machado et al, ), antioxidant and antiatherogenic effects (Allouche, Beltrán, Gaforio, Uceda, & Mesa, ), among others, which makes it an important scaffold in medicinal chemistry. Currently, is known that the ursolic acid antidiabetic effect is mediated by its interaction with different targets: UA acts as insulinomimetic (Jung et al, ), increasing the autophosphorylation and activation of insulin receptor, and also proceeds as insulin sensitizer since it is able to inhibit the PTP‐1B enzyme (Ramírez‐Espinosa et al, ; Zhang et al, ).…”