Dual-Targeting, Hybrid Antifungal Agents Targeting Candida albicans-An Overview

Due to environmental degradation, substance abuse, and immunological loss, fungal diseases are rising. Candida sp. can inflame tissues and organs. In addition, fungi enter deep tissues to generate invasive fungal infections (IFIs), a long-term worldwide health risk, especially for HIV/chemotherapy patients with compromised immune systems. The present treatment uses single-target antifungals like azoles, allylamines, and pyrimidines. But drug-resistant fungi and widespread adverse effects have limited their therapeutic efficacy. Thus, innovative, safe, and effective antifungals are needed. Through the 20th century, the pharmaceutical industry adopted the "one molecule, one target, one disease" mentality which led to various effective selective drugs that will dominate disease treatment. But, unfortunately, even with the best research, targeting one target may not work in complicated illnesses. Thus, drugs that activate several targets simultaneously, to improve efficacy and safety, are gaining interest. Multitarget medicines involve monotherapies, medication cocktails, and combination drugs. The second method, multitarget-directed ligands (MTDLs), uses one active component that treats multifactorial diseases. In MTDL, new chemical entities (NCEs) are created which may solve various issues related to combination therapies, including: (1) establishing balanced and multi-selective potency across targets, (2) matching PK/PD properties for components, (3) better patient compliance, (4) straightforward approval from regulatory authorities, (5) higher cost of medication etc. To optimize developability, effectiveness, and safety, multitarget drug design should be more methodical and thorough in target combinations, ligand selection, and desired activity equilibrium. In this review, the hybrid, dual-targeting antifungal agents are classified into four major categories, based on the combination of their mechanisms, namely-(1) Antifungal + antifungal (involves dual mode of DNA damage + membrane polarization), (2) Antifungal + Resistance reversal (includes proteasome inhibition, Coumarin + CYP51 inhibitors, CYP51 + Hsp90 inhibitors), (3) Antifungal + Host immunity modulators (includes CYP51 + HDAC inhibitors, NLRP3 inflammasome + AHAS inhibitors, COX + CYP51 inhibitors, PD-L1 + CYP51 inhibition etc.), (4) Azole sensitisers (JAK2 + HDAC inhibition, BRD4 + HDAC inhibition etc.), (5) Multifunctional, miscellaneous antifungal agents (DNA intercalation + intracellular ROS production) etc. Thus, it covers significant achievements and the associated challenges of antifungal multitarget drug design, which might be helpful to the researchers who are interested in delving into the development of fungicidal agents as a drug to address the burning question of drug-resistant Candida albicans and invasive fungal infections (IFIs).