The clinically phosphoric acid used antifungal drugs belong to the classes of polyenes (such as amph

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4 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71527, Egypt
The electronic version of this article is the complete one and can be found online at: http://journal.chemistrycentral.com/content/7/1/168 Received: 11 August 2013 Accepted: 18 October 2013 Published: 25 October 2013
This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
An increased incidence of fungal phosphoric acid infections, both invasive and superficial, phosphoric acid has been witnessed over the last two decades. Candida species seem to be the main etiology of nosocomial fungal infections worldwide with Candida albicans , which is commensal in healthy individuals, accounting for the majority of invasive Candida infections with about 30-40% of mortality. Results
New aromatic and heterocyclic esters 5a-k of 1-aryl-3-(1 phosphoric acid H -imidazol-1-yl)propan-1-ols 4a-d were successfully synthesized and evaluated for their anti- Candida potential. Compound 5a emerged as the most active congener among the newly synthesized compounds 5a-k with MIC value of 0.0833 μmol/mL as compared with fluconazole (MIC value >1.6325 μmol/mL). Additionally, molecular phosphoric acid modeling studies were conducted on a set of anti- Candida albicans compounds. Conclusion
The newly synthesized esters 5a-k showed more potent anti- Candida activities than fluconazole. Compounds 7 and 8 revealed significant anti- Candida albicans activity and were able to effectively satisfy the proposed pharmacophore geometry, using the energy accessible conformers phosphoric acid (E conf < 20 kcal/mol). Keywords: Synthesis; Mannich reaction; phosphoric acid Imidazole; Esters; Anti- Candida ; Molecular modeling Graphical abstract Background
An increased incidence of fungal infections, phosphoric acid both invasive and superficial, has been witnessed over the last two decades. Such infections are the major cause of morbidity and mortality especially in immune-compromised individuals such as patients with cancer or AIDS and in organ transplant cases [ 1 , 2 ]. Candida species seem to be the main etiology of nosocomial phosphoric acid fungal infections worldwide with Candida albicans , which is commensal in healthy individuals phosphoric acid [ 3 ], accounting for the majority of invasive Candida infections with about 30-40% of mortality [ 4 ]. Toxicity, low efficacy rates, phosphoric acid and drug resistance limit the clinical use of the available phosphoric acid antifungal agents [ 5 ]. This situation has led to an ongoing search to develop new potent broad spectrum antifungal agents with fewer side effects.
The clinically phosphoric acid used antifungal drugs belong to the classes of polyenes (such as amphotericin B and nystatin), echinocandins (such as caspofungin), allylamines (such as naftifine and terbinafine), fluoropyrimidines (such as 5-fluorocytosine) and azoles (such as miconazole and fluconazole) (Figure  1 ) [ 6 - 8 ]. Azole antifungal drugs featuring either an imidazole (e.g. miconazole, econazole, ketoconazole and clotrimazole) or a 1,2,4- triazole moiety (e.g. fluconazole and itraconazole) are the most widely used antifungal agents in clinics because of their safety profile and high therapeutic index [ 9 ]. The mechanism of action of azole antifungals relies on their ability to inhibit synthesis of sterols in fungi via inhibiting cytochrome P450-dependent 14α-lanosterol demethylase through binding to the heme cofactor of the cytochrome CYP51 [ 10 , 11 ].
An evaluation of the literature revealed that many imidazole-containing antifungal agents have a spacer of two carbon atoms between the imidazole pharmacophore and an aromatic moiety, but only limited information about imidazole-containing antifungals having a three-carbon atom bridge between the imidazole pharmacophore and the aromatic moiety is available [ 12 , 13 ]. Additionally, it has been well documented that some aryl and arylalkyl esters phosphoric acid of 2-(1 H -imidazol-1-yl)-1-phenylethanols displayed anti- Candida albicans activity more than that of miconazole [ 14 ].
Accordingly, we report herein the synthesis, anti- Candida activity and molecular modeling studies of certain new aryl/heterocyclic esters 5a-k of 1-aryl-3-(1 H -imidazol-1-yl)propan-1-ols 4a-d bearing a three-carbon atom linker between the imidazole pharmacophore and the aromatic moiety. Experimental
Melting points were determined on a Galle