Discovery of biphenyl imidazole derivatives as potent antifungal agents: Design, synthesis, and structure-activity relationship studies
Introduction
Fungal infections have been increasing dramatically and present a serious threat to human health, especially in immunocompromised patients. The occurrence of these infections have increased since the early 1980s and have resulted from many factors, such as patients undergoing organ transplants or anticancer chemotherapy and patients with AIDS as well as patients given potent pharmacologic immunomodulators or broad-spectrum antibiotics.1, 2, 3, 4 Clinically, the three major pathogens Candida spp., Cryptococcus neoformans and Aspergillus spp. account for most fungal infections. Currently, the conventional antifungal agents to treat fungal infections can be divided into four categories based on their mode of action, including the polyenes (e.g., amphotericin B and nystatin),5 echinocandins (e.g., caspofungin and micafungin),6 azoles (e.g., fluconazole, voriconazole and itraconazole),7 and antimetabolites (e.g., 5-fluorocytosine).8 Among these agents, azoles are most widely used in front-line antifungal therapy.9
Azole antifungal agents inhibit the activity of lanosterol 14-demethylase (CYP51), a member of the CYP51 class of cytochrome P450 enzymes.5 The inhibition of CYP51 enzymes reduces endogenous concentrations of ergosterol, a significant cellular membrane component, and causes the accumulation of 14α-methylsterols (e.g., lanosterol and 14α-methyl-3-6-diol).5, 10, 11, 12 The active site of CYP51 contains a heme cofactor that can coordinate to an imidazole ring or the triazole ring of azole drugs.13 Not only are these drugs essential for the clinical treatment of systemic fungal infections, but they are also a major focus in the search for new antifungals.14, 15, 16 Several azole antifungal agents, such as itraconazole, voriconazole and bifonazole have been approved (Fig. 1).17 However, these antifungal agents exist many problems, such as drug resistance, narrow antifungal spectrum and low bioavailability, which negatively affect their clinical efficacy.12, 18 Therefore, it is necessary to develop novel antifungal compounds with potent activity, broad spectrum and low resistance.
Based on results obtained from structure-activity relationships of azole antifungal agents and computational docking experiments, we performed a cell-based antifungal screening of an in-house library19, 20, 21 using standard NCCLS (National Committee for Clinical Laboratory Standards) protocols. Compound 5, which features biphenyl and imidazole scaffolds, showed modest antifungal activities, with an MIC value of 2 μg/mL against Candida albicans. The common pharmacophore of classic azole antifungal drugs include a N-(phenethyl) azole skeleton and a tertiary alcohol group, both of which contribute to their antifungal activities.22 Compound 5 contains an imidazole group but no tertiary alcohol group or N-(phenethyl) azole skeleton, rendering the chemical scaffold of compound 5 a novel structure compared to the classic azole antifungal agents and necessitating the investigation of its structure-activity relationships (SARs) to design a novel antifungal lead compound.
Section snippets
Chemistry
The synthetic routes of the key intermediates 8a–m are illustrated in Scheme 1. Commercially available 4-bromobenzoic acid 6 and the substituted phenylboronic acids 7a–m were subjected to a Suzuki coupling in the presence of Pd(PPh3)4 to afford the key intermediates 8a–m.
The target compounds 12a–v were synthesized according to our previously reported procedure (Scheme 2).13, 21 l-Serine 9 was treated with an alcohol (methanol, ethanol, propanol, isopropyl alcohol, or isobutyl alcohol) in the
Conclusion
In summary, we discovered a novel class of compounds with excellent antifungal activities. Further examination of their antifungal activity and structure-activity relationship (SAR) led to a series of novel biphenyl imidazole derivatives that were designed, synthesized and evaluated for in vitro antifungal activity. Most compounds displayed moderate or strong antifungal activities with MIC values in the range of 0.03125 μg/mL to 2 μg/mL against Candida albicans and Cryptococcus neoformans.
General procedure for the synthesis of compounds
Unless otherwise noted, all reagents and solvents were obtained from commercially available sources and were used without purification. TLC analysis was performed on GF254 silica gel plates (Jiangyou, Yantai). Column chromatography was performed with silica gel (200–300 mesh) from Qingdao Haiyang Chemicals (Qingdao, Shandong, China). Mass spectrometry was performed using ESI mode on an Agilent 1200 LC-MS (Agilent, Palo Alto, CA, USA). High-resolution accurate mass determinations (HRMS) were
Acknowledgements
The authors thank Prof. Yongbing Cao from School of Pharmacy, the Second Military Medical University, for providing the fluconazole-resistant strains of Candida albicans (strain 100 and strain 103). This work was supported by Program for Innovative Research Team of the Ministry of Education and Program for Liaoning Innovative Research Team in University.
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