Modern antifungal therapy have to deal with number of issues associated with broad but inadequate arsenal of drugs. The most commonly used agents have serious drawbacks as toxicity and resistance. On the other hand new drugs and drug candidates under clinical trials do not guarantee better overall performance. This is not the only reason of strong need for new antifungals. The other is – observed during last four decades – steadily growth of the fungal infections. Especially in patients with compromised immune system [1]. Morbidity and mortality of some endemic and opportunistic mycoses is still very high[2]. Thus we strongly need new drugs acting through new mechanisms on new targets.

Lack of expected success form established methodology like combinatorial chemistry and high throughput screening we turn on fragment based design and search for privileged structures. Quinoline moiety by its abundant presence in various natural and bioactive compounds may be considered as such structure [3-6]. We wish to introduce here the fragment based approach to quinolines mimicking known antifungal allylamines. 

This approach lead to well known for their biological activity styrylquinolines as naftifine analogues. Styrylquinolines were broadly studied for their anticancer and antiviral activity and FZ-41 is an example of HIV integrase inhibitor under clinical trials. We explored the styrylquinolines finding some highly active antifungals. Further modification of the quinoline scaffold led us to even more active compounds. Namely we used dicholroquinoline as this moiety has established position between antimicrobial agents. Chloroxine is used for long time as antibiotic for shampoos or topical ointments. Combine chloroxine scaffold and styryl moiety afforded us with compounds active against fungi and bacteria. The most active compounds were up to ten times more active than bacitracin against bacteria including metilicin resistant strains of Staphylococcus aureus.

Literature

[1]   J. Bastert, M. Schaller, H.C. Korting, and E.G. Evans, “Current and future approaches to antimycotic treatment in the era of resistant fungi and immunocompromised hosts.,” International journal of antimicrobial agents, vol. 17, Feb. 2001, pp. 81-91.

[2]   M.M. McNeil, S.L. Nash, R.A. Hajjeh, M.A. Phelan, L.A. Conn, B.D. Plikaytis, and D.W. Warnock, “Trends in mortality due to invasive mycotic diseases in the United States, 1980-1997.,” Clinical infectious diseases, vol. 33, Sep. 2001, pp. 641-7.

[3]   R. Musiol, M. Serda, S. Hensel-Bielowka, and J. Polanski, “Quinoline-based antifungals.,” Current medicinal chemistry, vol. 17, Jan. 2010, pp. 1960-73.

[4]   J.P. Michael, “Quinoline, quinazoline and acridone alkaloids.,” Natural product reports, vol. 25, 2008, pp. 166-87.

[5]   R. Solomon and H. Lee, “Quinoline as a Privileged Scaffold in Cancer Drug Discovery,” Current Medicinal Chemistry, vol. 18, 2011, pp. 1488-1508.

[6]   P. Hall-Smith, “Quinoline Derivatives in Dermatology,” British Medical Journal, vol. 1, 1964, p. 1510.

• Legal notice:
  

  Copyright (c) Pielaszek Research, all rights reserved.
  The above materials, including auxiliary resources, are subject to Publisher's copyright and the Author(s) intellectual rights. Without limiting Author(s) rights under respective Copyright Transfer Agreement, no part of the above documents may be reproduced without the express written permission of Pielaszek Research, the Publisher. Express permission from the Author(s) is required to use the above materials for academic purposes, such as lectures or scientific presentations.
  In every case, proper references including Author(s) name(s) and URL of this webpage: https://science24.com/paper/28035 must be provided.

1. Glutathione depletion and reactive oxygen species generation by thiosemicarbazones in cancer therapy.
2. Iron chelators in photodynamic therapy
3. Synthesis and potential spectrum of biological activities of glycoconjugates derivatives of hydroxy-2-methylquinoline carboxylic acids
4. Studies on anticancer iron chelators
5. Iron chelators- the novel perspective in cancer treatment
6. The biological activity of sugar derivatives based on quinoline scaffold
7. Structure-Lipophilicity Relationships in Series of Quinoline Derivatives