Primary amoebic meningoencephalitis (PAM) is a fatal disease with 97% fatal rate outcome caused by free-living ameboflagellate Naegleria fowleri present in soil and warm fresh water. Upon accidental introduction into the nose, the ameba invades the central nervous system which leads the death of the infected patients within a week. Despite been stated as a rare disease with only 381 global cases, these cases could be the tip of an iceberg considering the dramatic loss of patience and complexity of its diagnosis. Additionally, there is no standard treatment and patients are reported to be treated with Amphotericin B either alone or in combination with other drugs. However, its toxicity and side effects such as acute infusion-related reactions and dose-related nephrbotoxicity makes it difficult for its clinical use. Overall, these facts indicate PAM as an unmet medical need. Moreover, sterol 14-demethylase (CYP51) has been reported as an essential drug target in literature and there are studies indicating the use of CYP51 inhibitors such as antifungal conazole drugs accompanied with Amphotericin B despite their low blood-brain barrier (BBB) penetrance in PAM cases. Within this work, we would like to highlight the potential use of miconazole-like compounds for PAM treatment. By testing 124 compounds in silico against N. fowleri trophozoites, we have obtained 9 hits having EC50 ≤ 10 µM, which was further identified via cross - co-crystallization with the NfCYP51 target, leading to identification of the best drug-target for miconazole-like scaffolds. Accordingly, a set of analogs was synthesized and biochemically evaluated. These results showed excelled superiority of having S- over R-configuration and the advantage of ether over ester linkage at the scaffolds. Moreover, the two most promising structures, having improved EC50 and KD were further tested for their brain penetrance. The result of brain-to-plasma distribution coefficient highlights a potential for further optimization of the compound as a drug candidate.
New blood-brain-barrier permeable compounds as Naegleria Fowleri CYP51 inhibitors / Arpacioglu, M.; Madia, V. N.; Ialongo, D.; Patacchini, E.; Messore, A.; Tudino, V.; Sharma, V.; Nguyen, J.; Debnath, A.; Podust, L.; Palenca, I.; Basili Franzin, S.; Seguella, L.; Esposito, G.; Petrucci, R.; Di Matteo, P.; Bortolami, M.; Scipione, L.; Costi, R.; Di Santo, R.. - (2023). (Intervento presentato al convegno XXVIII edition of the National Meeting on Medicinal Chemistry tenutosi a Chieti; Italy).
New blood-brain-barrier permeable compounds as Naegleria Fowleri CYP51 inhibitors.
Arpacioglu, M.;Madia, V. N.;Ialongo, D.;Patacchini, E.;Messore, A.;Tudino, V.;Palenca, I.;Basili Franzin, S.;Seguella, L.;Esposito, G.;Petrucci, R.;Di Matteo, P.;Bortolami, M.;Scipione, L.;Costi, R.;Di Santo, R.
2023
Abstract
Primary amoebic meningoencephalitis (PAM) is a fatal disease with 97% fatal rate outcome caused by free-living ameboflagellate Naegleria fowleri present in soil and warm fresh water. Upon accidental introduction into the nose, the ameba invades the central nervous system which leads the death of the infected patients within a week. Despite been stated as a rare disease with only 381 global cases, these cases could be the tip of an iceberg considering the dramatic loss of patience and complexity of its diagnosis. Additionally, there is no standard treatment and patients are reported to be treated with Amphotericin B either alone or in combination with other drugs. However, its toxicity and side effects such as acute infusion-related reactions and dose-related nephrbotoxicity makes it difficult for its clinical use. Overall, these facts indicate PAM as an unmet medical need. Moreover, sterol 14-demethylase (CYP51) has been reported as an essential drug target in literature and there are studies indicating the use of CYP51 inhibitors such as antifungal conazole drugs accompanied with Amphotericin B despite their low blood-brain barrier (BBB) penetrance in PAM cases. Within this work, we would like to highlight the potential use of miconazole-like compounds for PAM treatment. By testing 124 compounds in silico against N. fowleri trophozoites, we have obtained 9 hits having EC50 ≤ 10 µM, which was further identified via cross - co-crystallization with the NfCYP51 target, leading to identification of the best drug-target for miconazole-like scaffolds. Accordingly, a set of analogs was synthesized and biochemically evaluated. These results showed excelled superiority of having S- over R-configuration and the advantage of ether over ester linkage at the scaffolds. Moreover, the two most promising structures, having improved EC50 and KD were further tested for their brain penetrance. The result of brain-to-plasma distribution coefficient highlights a potential for further optimization of the compound as a drug candidate.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
