Current Topics in Medicinal Chemistry - Volume 19, Issue 28, 2019

Fungal infections are a veritable public health problem worldwide. The increasing number of patient populations at risk (e.g. transplanted individuals, cancer patients, and HIV-infected people), as well as the use of antifungal agents for prophylaxis in medicine, have favored the emergence of previously rare or newly identified fungal species. Indeed, novel antifungal resistance patterns have been observed, including environmental sources and the emergence of simultaneous resistance to different antifungal classes, especially in Candida spp., which are known for the multidrug-resistance (MDR) profile. In order to circumvent this alarming scenario, the international researchers’ community is engaged in discovering new, potent, and promising compounds to be used in a near future to treat resistant fungal infections in hospital settings on a global scale. In this context, many compounds with antifungal action from both natural and synthetic sources are currently under clinical development, including those that target either ergosterol or β(1,3)-D-glucan, presenting clear evidence of pharmacologic/pharmacokinetic advantages over currently available drugs against these two well-known fungal target structures. Among these are the tetrazoles VT-1129, VT-1161, and VT-1598, the echinocandin CD101, and the glucan synthase inhibitor SCY-078. In this review, we compiled the most recent antifungal compounds that are currently in clinical trials of development and described the potential outcomes against emerging and rare Candida species, with a focus on C. auris, C. dubliniensis, C. glabrata, C. guilliermondii, C. haemulonii, and C. rugosa. In addition to possibly overcoming the limitations of currently available antifungals, new investigational chemical agents that can enhance the classic antifungal activity, thereby reversing previously resistant phenotypes, were also highlighted. While novel and increasingly MDR non-albicans Candida species continue to emerge worldwide, novel strategies for rapid identification and treatment are needed to combat these life-threatening opportunistic fungal infections.

Background: Candida species are in various parts of the human body as commensals. However, they can cause local mucosal infections and, sometimes, systemic infections in which Candida species can spread to all major organs and colonize them. Objective: For the effective treatment of the mucosal infections and systemic life-threatening fungal diseases, a considerably large number of antifungal drugs have been developed and used for clinical purposes that comprise agents from four main drug classes: the polyenes, azoles, echinocandins, and antimetabolites. Methods: The synthesis of some of these drugs is available, allowing synthetic modification of the molecules to improve the biological activity against Candida species. The synthetic methodology for each compound is reviewed. Results: The use of these compounds has caused a high-level resistance against these drugs, and therefore, new antifungal substances have been described in the last years. The organic synthesis of the known and new compounds is reported. Conclusion: This article summarizes the chemistry of the existing agents, both the old drugs and new drugs, in the treatment of infections due to C. albicans, including the synthesis of the existing drugs.

Background: Biofilm is a critical virulence factor associated with the strains of Candida spp. pathogens as it confers significant resistance to the pathogen against antifungal drugs. Methods: A systematic review of the literature was undertaken by focusing on natural products, which have been reported to inhibit biofilms produced by Candida spp. The databases explored were from PubMed and Google Scholar. The abstracts and full text of the manuscripts from the literature were analyzed and included if found significant. Results: Medicinal plants from the order Lamiales, Apiales, Asterales, Myrtales, Sapindales, Acorales, Poales and Laurales were reported to inhibit the biofilms formed by Candida spp. From the microbiological sources, lactobacilli, Streptomyces chrestomyceticus and Streptococcus thermophilus B had shown the strong biofilm inhibition potential. Further, the diverse nature of the compounds from classes like terpenoids, phenylpropanoid, alkaloids, flavonoids, polyphenol, naphthoquinone and saponin was found to be significant in inhibiting the biofilm of Candida spp. Conclusion: Natural products from both plant and microbial origins have proven themselves as a goldmine for isolating the potential biofilm inhibitors with a specific or multi-locus mechanism of action. Structural and functional characterization of the bioactive molecules from active extracts should be the next line of approach along with the thorough exploration of the mechanism of action for the already identified bioactive molecules.

Background: Human infections associated with skin and mucosal surfaces, mainly in tropical and sub-tropical parts of the world. During the last decade, there have been an increasing numbers of cases of fungal infections in immunocompromised patients, coupled with an increase in the number of incidences of drug resistance and toxicity to anti fungal agents. Hence, there is a dire need for safe, potent and affordable new antifungal drugs for the efficient management of candidal infections with minimum or no side effects. Introduction: Candidiasis represents a critical problem to human health and a serious concern worldwide. Due to the development of drug resistance, there is a need for new antifungal agents. Therefore, we reviewed the different medicinal plants as sources of novel anticandidal drugs. Methods: The comprehensive and detailed literature on medicinal plants was carried out using different databases, such as Google Scholar, PubMed, and Science Direct and all the relevant information from the articles were analyzed and included. Results: Relevant Publications up to the end of November 2018, reporting anticandidal activity of medicinal plants has been included in the present review. In the present study, we have reviewed in the light of SAR and mechanisms of action of those plants whose extracts or phytomolecules are active against candida strains. Conclusion: This article reviewed natural anticandidal drugs of plant origin and also summarized the potent antifungal bioactivity against fungal strains. Besides, mechanism of action of these potent active plant molecules was also explored for a comparative study. We concluded that the studied active plant molecules exhibit potential antifungal activity against resistant fungal strains.

Background: Candida species are the important etiologic agents for candidiasis, the most prevalent cause of opportunistic fungal infections. Candida invasion results in mucosal to systemic infections through immune dysfunction and helps in further invasion and proliferation at several sites in the host. The host defence system utilizes a wide array of the cells, proteins and chemical signals that are distributed in blood and tissues which further constitute the innate and adaptive immune system. The lack of antifungal agents and their limited therapeutic effects have led to high mortality and morbidity related to such infections. Methods: The necessary information collated on this review has been gathered from various literature published from 1995 to 2019. Results: This article sheds light on novel drug delivery approaches to target the immunological axis for several Candida species (C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, C. rugose, C. hemulonii, etc.). Conclusion: It is clear that the novel drug delivery approaches include vaccines, adoptive transfer of primed immune cells, recombinant cytokines, therapeutic antibodies, and nanoparticles, which have immunomodulatory effects. Such advancements in targeting various underpinning mechanisms using the concept of novel drug delivery will provide a new dimension to the fungal infection clinic particularly due to Candida species with improved patient compliance and lesser side effects. This advancement in knowledge can also be extended to target various other similar microbial species and infections.

Background: The considerable increase in the incidence of Candida infection in recent times has prompted the use of numerous antifungal agents, which has resulted in the development of resistance towards various antifungal agents. With rising Candida infections, the need for design and development of novel antifungal agents is in great demand. However, new therapeutic approaches are very essential in preventing the mortality rate and improving the patient outcome in those suffering from Candida infections. Objective: The present review objective is to describe the burden, types of Candidiasis, mechanism of action of antifungal agents and its resistance and the current novel approaches used to combat candidiasis. Methods: We have collected and analyzed 135 different peer-reviewed literature studies pertinent to candidiasis. In this review, we have compiled the major findings from these studies. Results and Conclusion: The review describes the concerns related to candidiasis, its current treatment strategy, resistance mechanisms and imminent ways to tackle the problem. The review explored that natural plant extracts and essential oils could act as sources of newer therapeutic agents, however, the focus was on novel strategies, such as combinational therapy, new antibodies, utilization of photodynamic therapy and adaptive transfer primed immune cells with emphasis on the development of effective vaccination.

Background: In the last few decades, mycoses caused by opportunistic fungi namely Candida species has gained significant attention. Such infections are very common and present high mortality rates, especially in immunocompromised patients. Currently, a limited number of antifungal drugs are available for the treatment of these infections and are also often related to severe adverse side effects. Therefore, new drugs and innovative technologies for the treatment of this infection are necessary. Objective: The aim of this study was to evaluate the development of new drugs, formulations, as well as patents for the treatment of infections caused by Candida spp. Methods: The present patent review was carried out through a specialized search database Espacenet. The patent selection was based on the following inclusion criteria: Recent patents published in English or Spanish containing candidiasis as the keyword in the title, abstract or full text. This survey was conducted in October and November 2018. Results: As a result of that, 22 patents were selected to the final selection, the most common routes of application were oral (n = 6), vaginal (n = 6), topical (n = 5) and others (n = 5). This fact is related to the clinical manifestations of candidiasis. Conclusion: Through this review, it was possible to identify significant improvements and advances in the area of antifungal therapeutic innovation research. In addition, we demonstrated the growing interest of academic and industrial groups in pharmaceutical development and novel formulations for the treatment of candidiasis. New therapeutic options can contribute to improve the quality of patient’s life, prevent infections and promote the search for an innovative and effective treatment of Candida infections.