Major Research Project on Synthesis, Characterisation and Antimicrobial Activity Studies of Fluconazole Analogues

Major Research Project on Synthesis, Characterisation and Antimicrobial Activity Studies of Fluconazole Analogues

Dr Anitha Varghese

Associate Professor, Department of Chemistry

CHRIST (Deemed to be University), Bangalore

and

Dr Louis George

Professor, Department of Chemistry

CHRIST (Deemed to be University), Bangalore

 

Abstract:

 

The increasing incidence of fungal infection associated with unsatisfactory therapeutic treatment in immunocompromised patients and emergence of azole resistant antifungal strains have stimulated the search for new antifungal compounds which will have broader antifungal spectra and higher therapeutic indexes. Fluconazole, (2-(2, 4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol) is a triazole based drug that has established an exceptional therapeutic record for various fungal strains, but its extensive use has increased the number of Fluconazole resistant fungi due to mutations. Our research interest lies in the change of one of the triazole ring of fluconazole so to change the pharmacokinetic character to get a better drug than Fluconazole. In the present investigation we have synthesised novel Fluconazole analogues wherein one of the triazole moieties is replaced with amino heterocyclic moiety such as α-methyl benzyl, isoxazole and isothiazole derivatives by employing environmentally benign green protocols. All synthesised compounds were characterised by 1H NMR, 13C NMR, Mass and IR spectroscopy. In vitro evaluation was conducted against two clinically important fungi such as Candida albicans and Aspergillus fumigatus. The anti-fungal activities of the new analogues were compared with standard anti-fungal drug. In order to find the interaction of the synthesised novel analogues with the active site of CYP51, molecular docking studies were done for both synthesised compounds and standard Fluconazole drug.

 

Homology modelling of protein sterol 14 alpha demethyalse was carried for both the organisms C.albicans and A.fumigatus. The modelled proteins were refined by molecular dynamics and the average structure was obtained. The modelled proteins were then used for carrying out the docking studies of the novel compounds of Fluconazole analogues synthesized. The ligands were found to have lower docking score for A.fumigatus when compared to that the score with C.albicans. The docking score was found to be highest for the molecules with the naphthyl ring in both the series (6e and 7e). From the literature review we could conclude that the molecules with bulky or more hydrophobic group were found has a greater activity for A. Fumigatus. 6a molecule was found to be very active against C.albicans. Considerable variations in the bond distance as well as the bond angle were noticed for the 6 series compounds. The bond distance (π- π interaction between the triazole ring and HEM 500.e) as well as the bond angles as were found to be lowest in the case of the 6a, hence making the point that the ligand is in very much in close proximity with the HEM 500.e and so, can facilitate better activity than other compounds in the same series. When considering MIC values and docking score better activity against C.albicans was shown for 7d molecule. The better activity may be due to the presence of highly electro negative fluorine when compared to hydrogen. Literature survey reveals that not many of the reported fluconazole analogues are active against Aspergillus fumigatus and therefore noticeable point is that all our target compounds depicted very good antifungal activity against Aspergillus species. Comparing isothiazole and isoxazole compounds, isothiazole s derivative were found to be more active against C.albicans. Fluoro substituted isothiazole derivative was found to be the most potent compound. This can be attributed to the high electronegativity of fluorine.

 

Year of Publication: June 2014

ISBN:    978-93-82305-42-2

Major Research Project : Vol 4

Pages : xvi,   74  

Price: available on request

Funded by Centre for Research-Projects-CHRIST (Deemed to be University)

Published by Centre for Publications, CHRIST (Deemed to be University)