THERAPEUTIC INDICES OF SOME ANTIFUNGAL ORGANIC COMPOUNDS
Objective: The objective of the study was to evaluate the therapeutic indices (TIs) some antifungal organic compounds and to compare their safety.
Methods: TIs of 55 organic compounds were evaluated by dividing their mammalian toxicity values given as median lethal doses ([mg/kg] rat, oral) collected from literature by experimentally determined fungitoxicity values evaluated as median effective concentration (EC50 [mg/L]) for the mycelial growth inhibition of Colletotrichum gloeosporioides on potato dextrose agar medium.
Results: Large variations in TIs are observed in different classes of compounds, namely, alcohols, carboxylic acids, phenols, esters, and aldehydes. The relationship between carbon chain length of saturated monohydric alcohols and mammalian toxicity shows that toxicity increases from chain length 1 to 5, declines from 5 to 6, increases from 6 to 7, and steadily declines from 7 to 10. Thus, the relationship is by and large parabolic. The relationship between carbon chain length and molar antifungal activity is also parabolic. In spite of this, large differences are found in TIs making 1-decanol (TI=42.1) a very safe antifungal compound and 1-pentanol (TI=0.17) a hazardous antifungal compound. This is because mammalian toxicity reaches a maximum around carbon chain length of 5, while in the case of antifungal activity, it reaches a maximum around carbon chain length of 10.
Conclusions: Among the 55 compounds, whose TIs were evaluated, some compounds with high TIs (>10) which can be considered safe as antifungal compounds are citronellol, geraniol, 1-decanol, 1-octanol, phenyl acetaldehyde, methyl anthranilate, 1-naphthol, 2-naphthol, and propionic acid. Some compounds with low TIs (<0.50) which can be considered hazardous as antifungal compounds are resorcinol, hydroquinone, oxalic acid, and acetyl acetone.
2. Khan FAK, Sangshetti JN. Design, synthesis and molecular docking study of hybrid quinolone-4-yl-oxadiazoles/oxathiadiazoles as potent antifungal agents. Int J Pharm Pharm Sci 2015;7:223-9.
3. Kumar A, Kumar S, Sharma V. A review article: Antifungal activity of eucalyptus genus. Int J Pharmacol Clin Sci 2019;3:122-32.
4. Soni A, Dahiya P. Screening of phytochemicals and antimicrobial potential of extracts of Vetiver zizanoides and Phragmites karka against clinical isolates. Int J App Pharm 2017;9:83-90.
5. Nidiry ES. Structure-fungitoxicity relationships of the monoterpenoids of the essential oils of peppermint (Mentha piperita) and scented geranium (Pelargonium graveolens). J Essent Oil Res 1998;10:628-31.
6. Nidiry ES. Structure-fungitoxicity relationships of some volatile flavour constituents of the edible mushrooms Agaricus bisporus and Pleurotus florida. Flavour Frag J 2001;16:245-8.
7. Nidiry ES. Quantitative structure-fungitoxicity relationships of some monohydric alcohols. J Agric Food Chem 2003;51:5337-43.
8. Nidiry ES. Structure-antifungal activity relationships of some organic compounds with varying number of hydroxyl groups for their inhibition of Colletotrichum gloeosporioides. Internet Electron J Mol Des 2005;4:803-12.
9. Nidiry ES, Babu CS. Antifungal activity of tuberose absolute and some of its constituents. Phytother Res 2005;19:447-9.
10. Muller PY, Milton MN. The determination and interpretation of therapeutic index in drug development. Nat Rev Drug Discov 2012;11:751-61.
11. Trevor A, Katzung B, Masters S, Knuidering-Hall M. Pharmacodynamics. In: Pharmacology Examination and Board Review. 10th ed., Ch. 2. New York: McGraw-Hill Medical; 2013. p. 17.
12. Aniszewski T. Alkaloids-secrets of Life. Amsterdam, Netherlands: Elsevier; 2007. p. 208.
13. Albert A. The basis of selective toxicity. Ann N Y Acad Sci 1965;123:5-18.
14. Nene YL, Thapliyal PN. Fungicides in Plant Disease Control. New Delhi: Oxford and IBH Publishing Co. Pvt. Ltd.; 2002. p. 531.
15. Finney DJ. Probit Analysis. Cambridge: Cambridge University Press; 1981. p. 283-7.
16. Available from: http://www.hmdb.ca.
17. Hansch C, Lien EJ. Structure-activity relationships of some antifungal agents, a survey. J Med Chem 1971;14:653-70.
18. Available from: http://www.en.wikipedia.org.
19. Available from: http://www.safetymanagementlikely.com.
20. Available from: http://www.fscimage.fishersci.com.
21. Available from: htttp://www.pubchem.ncbi.nlm.nih.gov.
22. Available from: http://www.fishersci.com.
23. Available from: http://www.goodscentscompany.com.
24. Available from: http://www.fishersci.ca.
25. Available from: http://www.merckmillipore.com.
26. Available from: http://www.datasheets.scbt.com.
27. Available from: http://www.msdonline.com.
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