Cinnamic Acid/Chloroquinoline Conjugates as Potent Agents against Chloroquine‐Resistant Plasmodium falciparum

In vitro efficiency of 9-(N-cinnamoylbutyl)aminoacridines against blood- and liver-stage malaria parasites

“…The antiplasmodial activity was significantly improved by introducing a substituent on the cinnamoyl moiety: the unsubstituted derivative, 6a, showed an IC 50 of 892 nM while the substituted compound, 6e, is approximately 3-fold more active (IC 50 345 nM). The most active compound of the series, 6c, bears an isopropyl group in the para-position, similar to what was previously observed by our group for 4-or 8-(N-cinnamoylalkyl)aminoquinolines, 5,6 suggesting that a bulky lipophilic cinnamic substituent is preferred to enhance antiparasitic activity. However, in our previous work we observed the best homogeneity in activity amongst cinnamic derivatives belonging to the same series, meaning that substituent R had only a slight effect on activity.…”

“…1) or CQ, led to substantially enhanced antimalarial activity as compared to those classical drugs. [4][5][6] In view of this, we have investigated whether a similar effect would be obtained by coupling a butylcinnamoyl moiety to the amino group of 9-aminoacridine, the unsubstituted heterocyclic scaffold of quinacrine. In this context, we report the synthesis and in vitro evaluation of novel 9-(N-butylcinnamoyl)aminoacridines, 6, which were found to have greater activity than the acridine analogue of CQ, 3 (Fig.…”

“…Methods employed were as previously reported by us. 4,5,8 CQ and its acridine analogue 3 were chosen as reference drugs for blood-stage assays, whereas PQ was the reference compound for liver-stage studies.…”

“…However, in our previous work we observed the best homogeneity in activity amongst cinnamic derivatives belonging to the same series, meaning that substituent R had only a slight effect on activity. 4,5 In contrast, the influence of cinnamoyl substituent R on the antiplasmodial activity of compounds 6 is apparent, but the SAR is unclear: the best three compounds, 6c, 6d and 6g (IC 50 values of 126, 138 and 142 nM, respectively), exhibit quite different substituents regarding their lipophilicity and electron-donating/-withdrawing properties. Yet, comparison of compounds 6e (R = m-F; IC 50 = 345 nM) and 6f (R = p-F; IC 50 = 145 nM) demonstrates a clear preference for substituents in the para-over the meta-position.…”

“…11 Given that both QA and compounds 6 share the acridine moiety as a central scaffold, it was conceivable that they operated via a similar mechanism. Thus, compounds 6 were evaluated in vitro as inhibitors of heme biocrystallization, by methods previously reported by us, [4][5][6] but none of them was found to be capable of inhibiting this process (data not shown). Still, compounds 6 are active against Plasmodium, and this may be due to one of the other mechanisms earlier proposed for acridines with antimalarial activity, such as inhibition of mitochondrial bc1 complex or DNA Topoisomerase II, and interaction with DNA.…”