US-12616755-B1 - Antifungal quercetin conjugates, methods of preparation and uses thereof

Abstract

An antifungal compound/conjugate is derived from quercetin, a naturally occurring flavonoid, through a strategic conjugation approach. The resulting quercetin conjugate exhibits enhanced antifungal activity and improved pharmacological properties compared to its parent molecule. The conjugate demonstrates potent efficacy against a range of drug-resistant fungal pathogens, including Candida auris , a critical threat in clinical settings due to its multidrug resistance. The invention also encompasses methods for synthesizing the conjugate, formulating the conjugate in a pharmaceutical preparation, and methods of use for treatment and prevention of superficial and systemic fungal infections.

Inventors

• Mohmmad Younus Wani
• Waleed Ahmed El-Said
• Abdullah S. Al-Bogami
• Ziya Ahmad Khan
• Aijaz Ahmad

Assignees

• University of Jeddah

Dates

Publication Date

20260505

Application Date

20251008

Claims (5)

1. 1 . A quercetin conjugate antifungal entity, comprising: quercetin; guar gum; and a cystamine linker joining the quercetin to the guar gum, wherein the cystamine linker comprise a redox-responsive disulfide bond enabling intracellular cleavage and controlled release of quercetin and wherein the conjugate mediated reactive oxygen species (ROS), induced oxidative stress-associated genes, induced mitochondrial membrane potential, and apoptosis of Candida auris.
2. 2 . The antifungal entity of claim 1 wherein the quercetin is covalently coupled to the cystamine linker and the cystamine linker is covalently coupled to the guar gum.
3. 3 . The antifungal entity of claim 1 , wherein the antifungal entity has the general structure wherein A is quercetin; B is a cystamine linker; and C is guar gum, where n is an integer representing a number of repeating saccharide units of the guar gum.
4. 4 . A pharmaceutical composition, comprising: an antifungal entity of claim 1 ; and a pharmaceutically acceptable carrier, excipient, or diluent.
5. 5 . The pharmaceutical composition of claim 4 , wherein the pharmaceutical composition is formulated for administration via a route selected from the group consisting of oral, topical, intravenous, or inhalation.

Description

SEQUENCE LISTING This application includes as the Sequence Listing the complete contents of the accompanying text file “Sequence.txt”, created Oct. 3, 2025, containing 2200 bytes, hereby incorporated by reference. FIELD OF THE INVENTION The invention generally relates to antifungal agents and methods for use thereof, and in particular to an antifungal agent derived from quercetin. The invention further relates to methods for the treatment of drug-resistant fungal infections, including those caused by Candida auris. BACKGROUND Antimicrobial resistance is a growing global health threat, with resistance observed across nearly all classes of antimicrobial agents. In response, the World Health Organization (WHO) has introduced the AWaRe classification, listing over 200 antibiotic molecules and formulations to promote their responsible use and preserve their clinical efficacy. Among the most concerning challenges is the rise in drug-resistant fungal infections. Fungal pathogens affect over a billion people globally, leading to an estimated 11.5 million serious infections and more than 1.5 million deaths each year. Invasive fungal infections in particular are associated with alarmingly high mortality rates-often exceeding 50%-despite the availability of antifungal therapies. This underscores the urgent need for the development of new and effective antifungal agents capable of combating resistant fungal strains. Quercetin is a naturally occurring flavonoid widely recognized for its antioxidant, anti-inflammatory, and antimicrobial properties. However, its clinical potential, particularly as an antifungal agent, is limited due to poor water solubility, rapid metabolism, and low bioavailability. Some articles describing the use of quercetin to treat fungal infections include Journal of Obstetrics, Gynecology and Cancer Research 2025, 10 (2): 127-144; Phytomedicine 114 (2023) 154800; Molecules 27 (2022) 2494; International Immunopharmacology 93 (2021) 107435; Fungal Biology 124 (2020) 83-90; Journal de Mycologie Médicale 30 (2020) 101014; Biofouling, 35 (3), 320-328; Cellular Physiology and Biochemistry 40 (2016) 727-742 and Medicinal Chemistry Research 21 (2012) 2217-2222. Several patents discuss the use of quercetin in different compositions for enhancing physical or mental performance or treating various diseases or disorders. For example, U.S. Pat. No. 8,440,704B2 to Thomas Christian Lines, describes a preparation method of genipin-crosslinked quercetin-zein/pectin/chitosan nanoparticles, and Jia Chengsheng et al. in CN114098076B as similar technology. A quercetin drug-loading system based on copper sulfide-metal organic framework material is described in Luan Yuxia et al. in CN108524935B. The World Health Organization (WHO) notes that fungal pathogens are a major threat to public health as they are becoming “increasingly common and resistant to treatment with only four classes of antifungal medicines currently available”, and few candidates are in the clinical pipeline. Up to 95% of all invasive Candida infections in the United States are caused by non-albicans Candida species. Although C. albicans is still the leading cause of candidemia, increasing proportions of cases in recent years have been attributed to non-albicans species, that are resistant to antifungal drugs. C. auris is an emerging multidrug-resistant fungal pathogen that is associated with nosocomial infections and presents a serious global health threat. Centers for Disease Control (CDC) is concerned about this pathogen because it is often multi-drug resistant, is difficult to identify using standard laboratory methods, and has caused outbreaks in healthcare settings. In the United States, about 90% of C. auris isolates have been resistant to fluconazole, about 30% have been resistant to amphotericin B, and around 5% have been resistant to echinocandins. Therefore, urgent and serious steps need to be taken to prevent outbreaks that could prove devastating. Additionally, systemic candidiasis is linked with a high rate of mortality in immunocompromised individuals. In the past few years, the escalating use of drugs for the treatment of Candida infections ranging from superficial to invasive has resulted in the emergence of drug-resistant strains of Candida. Therefore, the development of a potential anti-Candida agent with lesser toxicities has become a high priority in the field. Moreover, individuals suffering from conditions such as HIV/AIDS, organ transplantation, and chemotherapy are expected to rise over the next ten years and these patients are susceptible to Candida infections with serious side effects. Thus, the requirement for a novel anti-Candida agent with targeted action is increasing. The emergence of multi-drug-resistant Candida strains has been widely reported in the past few years, and it is well demonstrated that these resistant phenotypes can emerge over the period of infection and even in response to the treatment process, which po