Favorable Preclinical Pharmacological Profile of a Novel Antimalarial Pyrrolizidinylmethyl Derivative of 4-amino-7-chloroquinoline with Potent In Vitro and In Vivo Activities
Articolo
Data di Pubblicazione:
2023
Citazione:
Favorable Preclinical Pharmacological Profile of a Novel Antimalarial Pyrrolizidinylmethyl Derivative of 4-amino-7-chloroquinoline with Potent In Vitro and In Vivo Activities / N. Basilico, S. Parapini, S. D’Alessandro, P. Misiano, S. Romeo, G. Dondio, V. Yardley, L. Vivas, S. Nasser, L. Rénia, B.M. Russell, R. Suwanarusk, F. Nosten, A. Sparatore, D. Taramelli. - In: BIOMOLECULES. - ISSN 2218-273X. - 13:5(2023 May 14), pp. 836.1-836.23. [10.3390/biom13050836]
Abstract:
The 4-aminoquinoline drugs, such as chloroquine (CQ), amodiaquine or piperaquine, are
still commonly used for malaria treatment, either alone (CQ) or in combination with artemisinin
derivatives. We previously described the excellent in vitro activity of a novel pyrrolizidinylmethyl
derivative of 4-amino-7-chloroquinoline, named MG3, against P. falciparum drug-resistant parasites.
Here, we report the optimized and safer synthesis of MG3, now suitable for a scale-up, and its additional
in vitro and in vivo characterization. MG3 is active against a panel of P. vivax and P. falciparum
field isolates, either alone or in combination with artemisinin derivatives. In vivo MG3 is orally active
in the P. berghei, P. chabaudi, and P. yoelii models of rodent malaria with efficacy comparable, or better,
than that of CQ and of other quinolines under development. The in vivo and in vitro ADME-Tox
studies indicate that MG3 possesses a very good pre-clinical developability profile associated with
an excellent oral bioavailability, and low toxicity in non-formal preclinical studies on rats, dogs, and
non-human primates (NHP). In conclusion, the pharmacological profile of MG3 is in line with those
obtained with CQ or the other quinolines in use and seems to possess all the requirements for a
developmental candidate.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
kidney transplant; immunosuppression; virus-related malignancy; trend; Italy; cohort study;
Elenco autori:
N. Basilico, S. Parapini, S. D’Alessandro, P. Misiano, S. Romeo, G. Dondio, V. Yardley, L. Vivas, S. Nasser, L. Rénia, B.M. Russell, R. Suwanarusk, F. Nosten, A. Sparatore, D. Taramelli
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