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Acta Poloniae Pharmaceutica Drug Research, Vol. 65 No. 6 pp. 795798, 2008 ISSN 0001-6837Polish Pharmaceutical Society

The incidence of fungal infections has

increased significantly in the past two decades (1,2). The first generation of azoles antifungalinhibitors of CYP51, have revolutionized treatmentof some serious fungal infections. Triazoles hasbeen the leading agents for the control of fungaldiseases of humans and animals for over 20 years(3-5). According to this, azole derivatives are cur-rently the most widely studied class of antifungalagents. The triazole alcohols such as 2-(2,4-difluo-rophenyl)-1,3-di(1H-1,2,4-triazol-1-yl)propan-2-oli.e. fluconazole and (2R,3R)-2-(2,4-difluo-rophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-

triazol-1-yl)butan-2-ol i.e. voriconazole are therepresentatives of the second generation of triazoleantifungal drug. The newest compound 7-chloro-3-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)quinazolin-4(3H)-one, labeled as UR-9825, exhibits twoimportant types of activity against certain fungalpathogens i.e. activity against yeasts and filamen-tous fungi (6). Up to date the name of compoundUR-9825 is albaconazole and it is undergoing thePhase II clinical trials, but its future is uncertain (7,8). Our recent docking experiments for flucona-

zole, voriconazole and UR-9825 into the catalyticsite of MT-CYP51 (pdb code: 1ea1) as template (9)showed that the molecules bind to the catalytic siteadopting the similar bioactive conformation asobserved in the crystallized complex of flucona-zole with the enzyme (10). The aim of this study isa comparison of pharmacophore features of activeconformation obtained via docking of the drug in

Mycobacterium tuberculosis CYP51, with the phar-macophore model proposed for the antifungaldrugs (11). In order to define more precisely the

structure-activity relationship within the investi-

gated compounds a molecular modeling study wasundertaken.

EXPERIMENTAL

Molecular modeling and docking were carriedout with the commercially available CACheWorkSystem Pro (version 7.5.0.85) software pack-age. All computations were performed on a HP-6200wx workstation. The crystallographic structure of theenzyme CYP51 were obtained from the BrookhavenProtein Databank, accession number 1EA1. Missing

atoms in the crystal structure were added and thestructure was optimized. Structures of all drugs wereconstructed using 3D-sketcher module available inthe software. All the molecule geometries were opti-mized using the molecular mechanics methods MM3until the root mean square (RMS) gradient valuebecomes smaller than 0.1 kcal/mol. Force field cal-culations were used to ascertain whether the resultingstructures corresponded to energy minima. Dockingexperiments were preformed using a knowledge-based strategy (11, 12). The optimized drug structurewas docked into the active site of MT-CYP51 auto-

matically by placing the nitrogen atom in position 4of the triazole ring at the 2.37 from the heme ironatom on the center orthogonal of the heme plane inMT-CYP51. The above value is the average distanceof Fe-N coordination bonds observed in the crystal-lized complexes of MT-CYP51 with fluconazole and4-phenylimidazole. First, the validation of the dock-ing method was carried out by redocking fluconazoleinto its crystal structure in 1EA1.pdb. After success-ful validation, voriconazole and albaconazole weredocked into MT-CYP51. The active structures

TRIAZOLE DERIVATIVES WITH ANTIFUNGAL ACTIVITY:A PHARMACOPHORE MODEL STUDY

ALICJA NOWACZYK* and BOENA MODZELEWSKA-BANACHIEWICZ

Department of Organic Chemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, NicolausCopernicus University, Skodowskiej-Curie 9, 85-094 Bydgoszcz, Poland

Keywords: antifungal activity, pharmacophore model of triazole alcohols, UR-9825

795

* Corresponding author: e-mail: alicja@cm.umk.pl

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Triazole derivatives with antifungal activity... 797

extra methyl group attached to the C3 atom ofvoriconazole molecule (15). In the literature, thepharmacophore model was proposed for azole anti-

fungals (11, 15).According to the literature we have to definepharmacophore points such as: A coordination sitein heme, B hydrogen bond acceptor atom, C hydrophobic interaction groups [i.e. the center ofdiphenylphenyl ring and methyl group or prochiralhydrogen atom (17)]. The intermolecular distancesand angles in the proposed pharmacophore modelare as follows: a1 the distance between the hetero-cyclic N4(3) nitrogen atom of triazole moiety andthe hydrogen bond acceptor a2 the distancebetween N4(3) atom and the center of hydrophobicinteraction; b

1

the distance between OH groupattached to C2 and the center of diphenylphenylring; b2 the distance between CH3 group or prochi-ral hydrogen atom attached to C3 atom and the cen-ter of diphenylphenyl ring; c the distance betweenthe N4(3) and the center of diphenylphenyl ring. Theinvestigated active structures were compared bymeans of the distances listed above. In Figure 1pharmacophore feature scheme is presented for theinvestigated compounds. The obtained values forthe compounds and references modeling data formthe literature are shown in Table 2.

It was found that the distances between the

pharmacophore features, estimated for the selectedligands, are within the following range: a1 = 4.253

4.528; b1 = 3.545 3.642; a2 = 6.233 6.596;b2 = 3.638 4.059 ; c = 4.888 5.193 . Theresults obtained show that the distance values are in

the range of references data. Based on this we cantreat the geometries of drugs obtained in this studyas the active conformation for the investigated tria-zole alcohols.

To obtain additional information concerningthe shape of the investigated drug, the active confor-mations were chosen for superimposition. Theatoms (except hydrogen atoms) common to thesemolecules were selected for the fitting procedure.Their similarity was calculated as RMS fit. TheRMS routine provided estimates of how closelymolecules fit to each other. The lower the RMSvalue, the better similarity.

The RMS deviations for each group are as fol-lows: 0,399 (fluconazole albaconazole); : 0,497 (fluconazole voriconazole); 0,610 (voricona-zole albaconazole). A comparison of the geome-tries of compounds shown above indicates high sim-ilarity in the orientation of the all pharmacophorepoints. These results confirm that the chosen groupis an important structural unit for antifungal activity.The pair voriconazole albaconcazole the highestRMS value in the set is due to the terminal aromaticfragments (5-fluoropyrimidin-4-yl and 7-chloro-quinazolin-4(3H)-one, respectively) that have dif-

ferent orientation, this does not influence the phar-macophore features of the molecule though.

Figure 1. The pharmacophore model of triazole antifungal alcohols.

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798 ALICJA NOWACZYK and BOENA MODZELEWSKA-BANACHIEWICZ

CONCLUSION

According to obtained results concerning the

pharmacophore features of antifungal drugs, it isseen that active conformations of analyzed drugspreserve the conditions imposed by existing phar-macophore model derived for antifungal drugs.According to this one can state that application inthe docking studies Mycobacterium tuberculosisCYP51 is reasonable approach in case of absence ofgenuine fungal CYP51.

The analysis of similarity of obtained activestructures shows that all three compounds adoptvery similar conformation in the target site of theenzyme. The only significant deviation of the struc-

ture concern fragment apart of the pharmacophorespoints. The presence of hydroxyl group in the sec-ond position and the methyl group in the third posi-tion of the propyl chain in the triazole alcohol is acrucial structure feature determining the affinity ofcompounds to target site. More extensive structure-activity relationship studies are in progress and willbe reported in due course.

Acknowledgment

This study was supported by the research grantfrom the UMK no. 13/2008.

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Erratum:The names of authors of the paper GADOLINIUM Gd(III) COMPLEXES WITH DERIVATIVESOF NITRILOACETIC ACID: SYNTHESIS AND BIOLOGICAL PROPERTIES from Acta Pol.Pharm. Drug Res. 65, issue 5, 535 (2008) are: Bolesaw Karwowski, Magorzata Witczak, Elbieta

Mikiciuk-Olasik, and Micha Studniarek.

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