Discovery of Marinoquinolines as Potent and Fast-Acting Plasmodium falciparum Inhibitors with in Vivo Activity

Abstract

We report the discovery of marinoquinoline (3 H-pyrrolo[2,3- c]quinoline) derivatives as new chemotypes with antiplasmodial activity. We evaluated their inhibitory activities against P. falciparum and conducted a structure-activity relationship study, focusing on improving their potency and maintaining low cytotoxicity. Next, we devised quantitative structure-activity relationship (QSAR) models, which we prospectively validated, to discover new analogues with enhanced potency. The most potent compound, 50 (IC = 39 nM; IC = 41 nM), is a fast-acting inhibitor with dual-stage (blood and liver) activity. The compound showed considerable selectivity (SI > 6410), an additive effect when administered in combination with artesunate, excellent tolerability in mice (all mice survived after an oral treatment with a 1000 mg/kg dose), and oral efficacy at 50 mg/kg in a mouse model of P. berghei malaria (62% reduction in parasitemia on day 5 postinfection); thus, compound 50 was considered a lead compound for the discovery of new antimalarial agents.

<p>Fullerene Derivatives as Lung Cancer Cell Inhibitors: Investigation of Potential Descriptors Using QSAR Approaches</p>

“…The QSAR can provide predictive models based on mathematical and statistical relations that can be used to optimize the design of known types of chemical drugs to achieve an improved activity. 21,22 However, there are still very few studies focused on the design of nanomedicines with the assistance of QSAR or other CADD techniques. 23 Here, we explored the potential of developing predictive computer models for a series of water-soluble fullerene derivatives acting as inhibitors of NSCLC cancer cells.…”

Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum

“…The pyrrolo[2,3‐c]quinoline 103 with IC 50 of 39 and 41 nM against CQS 3D7 and multidrug‐resistant K1 strains respectively was intoxic toward HepG2 cells (EC 50 : >250 μM), and SI was more than 6400 . IC 50 values of compound 103 (28‐50 nM) against asynchronous, rings, trophozoites, and schizont were equivalent to the values for the ring stages, suggesting that this compound was a potent inhibitor of all erythrocytic forms of P falciparum .…”

“…All mice survived after oral treatment with a 1000 mg/kg dose, demonstrating its excellent safety profile. On the basis of the above research results, compound 103 could be acted as a lead compound for the discovery of new antimalarial agents …”

The Chemistry and Biological Applications of 3H‐Pyrrolo[2,3‐c]quinolines and Marinoquinolines

“…Aiming at further exploring the potential of marinoquinolines as antimalarial compounds, in 2018, Correia, Guido and co‐workers reported the discovery of unnatural analogues as new leading candidates for antimalarial drug development [46] . Several MQ analogues were synthesized in a very flexible strategy and they were then tested for their inhibitory activity against P. falciparum involving SAR and QSAR analysis as well as in vitro and in vivo studies.…”

“…The complementary CoMFA analysis also showed that bulky and electropositive substituents at the 4‐phenyl position of the marinoquinoline core increases the potency. Using the insights provided by the QSAR studies, the new derivatives 118 – 120 (Table 4, entries 4–6) were synthetized and evaluated for their biological activity [46] …”