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Abstract
Candida albicans, an opportunistic fungal pathogen, frequently colonizes immune-compromised patients and causes mild to severe systemic reactions. Only few antifungal drugs are currently in use for therapeutic treatment. However, evolution of a drug-resistant C. albicans fungal pathogen is of major concern in the treatment of patients, hence the clinical need for novel drug design and development. In this study, in vitro screening of novel putative pyrrolo[1,2-a]quinoline derivatives as the lead drug targets and in silico prediction of the binding potential of these lead molecules against C. albicans pathogenic proteins, such as secreted aspartic protease 3 (SAP3; 2H6T), surface protein β-glucanase (3N9K) and sterol 14-alpha demethylase (5TZ1), were carried out by molecular docking analyses. Further, biological activity-based QSAR and theoretical pharmacokinetic analysis were analyzed. Here, in vitro screening of novel analogue derivatives as drug targets against C. albicans showed inhibitory potential in the concentration of 0.4 µg for BQ-06, 07 and 08, 0.8 µg for BQ-01, 03, and 05, 1.6 µg for BQ-04 and 12.5 µg for BQ-02 in comparison to the standard antifungal drug fluconazole in the concentration of 30 µg. Further, in silico analysis of BQ-01, 03, 05 and 07 analogues docked on chimeric 2H6T, 3N9K and 5TZ1 revealed that these analogues show potential binding affinity, which is different from the therapeutic antifungal drug fluconazole. In addition, these molecules possess good drug-like properties based on the determination of conceptual Density Functional Theory (DFT)-based descriptors, QSAR and pharmacokinetics. Thus, the study offers significant insight into employing pyrrolo[1,2-a]quinoline analogues as novel antifungal agents against C. albicans that warrants further investigation.
Highlights
Candida albicans (C. albicans) is a genus of yeast that frequently causes nosocomial fungal infection in patients with a defined clinical condition—i.e., invasive candidiasis and candidemia [1,2]
The hydrogen bonds (H-bonds) forming amino acid residues identified by the interaction analyses were different from that of fluconazole, which indicates novel binding interaction of the ligand molecules to the macromolecular target. These results offers pyrrolo[1,2-a]quinoline analogues as putative novel targets against drug-resistant C. albicans fungal pathogens
Based on the chemical structure, BQ-01, 03, 05 and 07 consist of methyl ester groups at the second and third positions compared to that of only one methyl ester at the third position, which is the case for BQ-02, 04, 06 and 08
Summary
Candida albicans (C. albicans) is a genus of yeast that frequently causes nosocomial fungal infection in patients with a defined clinical condition—i.e., invasive candidiasis and candidemia [1,2]. Being an opportunistic fungal pathogen, C. albicans asymptomatically colonized mucosal surfaces of the skin, vagina, mouth, and intestine in patients suffering from invasive candidiasis as well as systemically colonizes the bloodstream in candidemia patients and poses a major therapeutic challenge in medically and immune-compromised patients, with a mortality rate of 30–40% [3,4,5,6]. The number of antifungal drugs in treatment are very limited [13] and new therapies for fungal infection are of public concern as drug-resistant C. albicans are increasing worldwide [9,14,15]
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