Effect of quinoline based 1,2,3-triazole and its structural analogues on growth and virulence attributes of Candida albicans

Abstract

Candida albicans, along with some other non-albicans Candida species, is a group of yeast, which causes serious infections in humans that can be both systemic and superficial. Despite the fact that extensive efforts have been put into the discovery of novel antifungal agents, the frequency of these fungal infections has increased drastically worldwide. In our quest for the discovery of novel antifungal compounds, we had previously synthesized and screened quinoline containing 1,2,3-triazole (3a) as a potent Candida spp inhibitor. In the present study, two structural analogues of 3a (3b and 3c) have been synthesized to determine the role of quinoline and their anti-Candida activities have been evaluated. Preliminary results helped us to determine 3a and 3b as lead inhibitors. The IC50 values of compound 3a for C. albicans ATCC 90028 (standard) and C. albicans (fluconazole resistant) strains were 0.044 and 2.3 μg/ml, respectively while compound 3b gave 25.4 and 32.8 μg/ml values for the same strains. Disk diffusion, growth and time kill curve assays showed significant inhibition of C. albicans in the presence of compounds 3a and 3b. Moreover, 3a showed fungicidal nature while 3b was fungistatic. Both the test compounds significantly lower the secretion of proteinases and phospholipases. While, 3a inhibited proteinase secretion in C. albicans (resistant strain) by 45%, 3b reduced phospholipase secretion by 68% in C. albicans ATCC90028 at their respective MIC values. Proton extrusion and intracellular pH measurement studies suggested that both compounds potentially inhibit the activity of H+ ATPase, a membrane protein that is crucial for various cell functions. Similarly, 95–97% reduction in ergosterol content was measured in the presence of the test compounds at MIC and MIC/2. The study led to identification of two quinoline based potent inhibitors of C. albicans for further structural optimization and pharmacological investigation.

Promising Antifungal Targets Against Candida albicans Based on Ion Homeostasis

“…Activated lansoprazole is a novel benzimidazole proton pump inhibitor, which assists in the inhibition of hyphal growth (Monk et al, 1995 ; Perlin et al, 1997 ; Biswas et al, 2001 ). Furthermore, NC1175 and 1,2,3-triazole 3a are synthetic compounds that exhibit inhibitory activity against C. albicans by restraining the acidification of external medium with an minimum inhibitory concentration (MIC) of 25 μg/mL (Manavathu et al, 1999 ; Irfan et al, 2017 ). Additionally, concanamycin A, the most commonly used V-ATPase inhibitor, displays antifungal properties especially against C. albicans , and the MIC of concanamycin A is 25 μg/mL (Okoli et al, 2009 ).…”

Discovery of a Novel Dibromoquinoline Compound Exhibiting Potent Antifungal and Antivirulence Activity That Targets Metal Ion Homeostasis

“…A survey of literature pertaining to quinoline or quinolone antifungal agents revealed that some compounds exhibit fungistatic activity while other compounds exhibit fungicidal activity against C. albicans 23 . To investigate this matter further, compound 4b and the control antifungal drug 5-Fluorocytsine were examined against C. albicans in a time-kill assay (Figure 2).…”

1,2,3-Triazole–quinazolin-4(3H)-one conjugates: evolution of ergosterol inhibitor as anticandidal agent

“…20 To support this argument in case of azole drugs, we also determined the ergosterol content in the presence of our lead inhibitor 5n by sterol quantitation method in C. albicans ATCC 90028. 22,23 UV spectrophotometric sterol prole of C. albicans showed a dose-dependent sharp decrease in sterol content as shown in Fig. 6.…”

“…The total intracellular sterols were extracted as reported earlier with slight modications. 22,23 50 mL of SD broth medium prepared in four conical asks, sterilized and inoculated with freshly cultured cells of C. albicans ATCC 90028. All conical asks were incubated at 30 C and 160 rpm for 3 hours.…”