The Effect of Conjugation with Octaarginine, a Cell-Penetrating Peptide on Antifungal Activity of Imidazoacridinone Derivative

Abstract

Acridine cell-penetrating peptide conjugates are an extremely important family of compounds in antitumor chemotherapy. These conjugates are not so widely analysed in antimicrobial therapy, although bioactive peptides could be used as nanocarriers to smuggle antimicrobial compounds. An octaarginine conjugate of an imidazoacridinone derivative (Compound 1-R8) synthetized by us exhibited high antifungal activity against reference and fluconazole-resistant clinical strains (MICs ≤ 4 μg mL−1). Our results clearly demonstrate the qualitative difference in accumulation of the mother compound and Compound 1-R8 conjugate into fungal cells. Only the latter was transported and accumulated effectively. Microscopic and flow cytometry analysis provide some evidence that the killing activity of Compound 1-R8 may be associated with a change in the permeability of the fungal cell membrane. The conjugate exhibited low cytotoxicity against human embryonic kidney (HEK-293) and human liver (HEPG2) cancer cell lines. Nevertheless, the selectivity index value of the conjugate for human pathogenic strains remained favourable and no hemolytic activity was observed. The inhibitory effect of the analysed compound on yeast topoisomerase II activity suggested its molecular target. In summary, conjugation with R8 effectively increased imidazoacridinone derivative ability to enter the fungal cell and achieve a concentration inside the cell that resulted in a high antifungal effect.

Targeting yeast topoisomerase II by imidazo and triazoloacridinone derivatives resulting in their antifungal activity

“…For example, previous research showed that Candida TOPOII demonstrates less sensitivity for m-AMSA (Amsacrine; 4′-(9-Acridinylamino)methanesulfon-m-anisidide, acridine-compound) and etoposide than human enzyme while podophyllotoxins are inactive against mammalian enzyme but inhibit the activity of fungal TOPOII 13 . Also, our results obtained for antitumor imidazoacridinone C-1311 and triazoloacridinone C-1305 , whose molecular mechanism of action is related to hTOPOII poisoning 14 , 15 , indicated that the fungal enzyme is much less sensitive to both compounds than the human one 16 . Moreover, our preliminary studies showed that acridine/acridone derivatives may effectively inhibit yeast TOPOII (yTOPOII), which could be related to their antifungal activity 16 – 18 .…”

Searching for Conjugates as New Structures for Antifungal Therapies

“…Anticancer active conjugates of acridine can also be used as nanocarriers for antimicrobial compounds . Acridine and acridinone derivatives exhibit a wide spectrum of activity due to their effect on DNA damage, DNA repair and replication, inhibition of topoisomerase I and II, and induction of apoptosis. , Octaarginine imidazoacridinone derivative conjugate (5-((2-aminoethyl)­amino)-8-hydroxy-6H-imidazo­[4,5,1-de]­acridin-6-one) (Figure b, Table ) showed high antifungal activity against clinical reference and fluconazole-resistant strains ( C. albicans , C. glabrata , C. krusei , C. parapsiloris , S. cerevisiae MIC 90 0.25–4 μg/mL).…”

“…The tested conjugate changed the permeability of the fungal cell membrane and inhibited the activity of yeast topoisomerase II. No hemolytic activity was observed, and it showed low cytotoxicity against human embryonic renal cell carcinoma (HEK-293) and human liver (HEPG2) cell lines …”

“…58 Anticancer active conjugates of acridine can also be used as nanocarriers for antimicrobial compounds. 59 Acridine and acridinone derivatives exhibit a wide spectrum of activity due to their effect on DNA damage, DNA repair and replication, inhibition of topoisomerase I and II, and induction of apoptosis. 68,69 Octaarginine imidazoacridinone derivative conjugate ( 5 No hemolytic activity was observed, and it showed low cytotoxicity against human embryonic renal cell carcinoma (HEK-293) and human liver (HEPG2) cell lines.…”

“…68,69 Octaarginine imidazoacridinone derivative conjugate ( 5 No hemolytic activity was observed, and it showed low cytotoxicity against human embryonic renal cell carcinoma (HEK-293) and human liver (HEPG2) cell lines. 59 3.3.3. Conjugates of Antifungal Drugs with Other Polymers.…”