Antimalarial Activity of Cryptolepine and Some Other Anhydronium Bases

Abstract

Eight naturally occurring anhydronium bases and the synthetic quaternary compound Nb‐methylharmalane were tested against Plasmodium falciparum (strain K1) in vitro. Cryptolepine was found to have similar activity to that of chloroquine but alstonine, 5,6‐dihydroflavopereirine, matadine, Nb‐methylharmalane, melinonine F, normelinonine F, strychnoxanthine and serpentine were found to have little activity. Cryptolepine, given orally to mice infected with Plasmodium berghei berghei was found to have moderate antimalarial activity; parasitaemia was suppressed by 80% at 50 mg/kg/day.

Structure–activity relationship of antiparasitic and cytotoxic indoloquinoline alkaloids, and their tricyclic and bicyclic analogues

“…26 For normelinonine F an IC 50 of 13.6 ± 9.9 lM was reported, which is an order of magnitude less active than in our case. Nostocarboline (41) is a chloro-substituted quaternary bcarbolinium alkaloid isolated from the cyanobacterium Nostoc 78-12A.…”

Structure–activity relationship of antiparasitic and cytotoxic indoloquinoline alkaloids, and their tricyclic and bicyclic analogues

“…26 For normelinonine F an IC 50 of 13.6 ± 9.9 lM was reported, which is an order of magnitude less active than in our case. Nostocarboline (41) is a chloro-substituted quaternary bcarbolinium alkaloid isolated from the cyanobacterium Nostoc 78-12A.…”

Synthesis and Evaluation of Cryptolepine Analogues for Their Potential as New Antimalarial Agents

“…Toxicity appears to be related to the route of administration as no deaths were reported in previous studies in which subcutaneous (at 113 mg -1 kg -1 day) 11 or oral (50 mg kg -1 day -1 ) 2 routes were used. In the former study, no effect on parasitemia was observed, but oral administration of 1 at 50 mg kg -1 day -1 for 4 days suppressed parasitemia by 80.5% 2 .…”

Antiplasmodial Activity and Pharmacokinetic Profiling of Cryptolepine and 2,7‐Dibromocryptolepine With a View to Informing the Design of Novel Antimalarial Cryptolepine Analogues

“…Overall, this study has shown that 2 is superior to 1 with respect to antiplasmodial properties but its higher lipophilicity and potential hERG inhibitory activity are of concern and indicate that the development of cryptolepine analogues substituted with 1 halogen and an alkylamino group in place of the second halogen may be worthwhile, as it has been shown that a number of 11‐aminoalkyl‐cryptolepine analogues have enhanced antiplasmodial activities with improved selectivity in comparison to 1 (Lavrado et al 2011 ). In another study by Mudududdla et al ( 2018 ), a series of indolo[3,2‐ b ]quinoline‐11‐carboxamides were evaluated for antiplasmodial activities, but none were more active than cryptolepine, possibly because these compounds lack the 5‐ N‐ methyl group that has been shown to be essential for potent antiplasmodial activity in cryptolepine (Wright et al 1996 ). The incorporation of amino groups into cryptolepine analogues may be expected to reduce lipophilicity, ameliorate the risk of hERG inhibition, and increase oral absorption.…”

Structure–activity relationship of antiparasitic and cytotoxic indoloquinoline alkaloids, and their tricyclic and bicyclic analogues

“…26 For normelinonine F an IC 50 of 13.6 ± 9.9 lM was reported, which is an order of magnitude less active than in our case. Nostocarboline (41) is a chloro-substituted quaternary bcarbolinium alkaloid isolated from the cyanobacterium Nostoc 78-12A.…”

Synthesis and Evaluation of Cryptolepine Analogues for Their Potential as New Antimalarial Agents

“…Toxicity appears to be related to the route of administration as no deaths were reported in previous studies in which subcutaneous (at 113 mg -1 kg -1 day) 11 or oral (50 mg kg -1 day -1 ) 2 routes were used. In the former study, no effect on parasitemia was observed, but oral administration of 1 at 50 mg kg -1 day -1 for 4 days suppressed parasitemia by 80.5% 2 .…”

Antiplasmodial Activity and Pharmacokinetic Profiling of Cryptolepine and 2,7‐Dibromocryptolepine With a View to Informing the Design of Novel Antimalarial Cryptolepine Analogues

“…Overall, this study has shown that 2 is superior to 1 with respect to antiplasmodial properties but its higher lipophilicity and potential hERG inhibitory activity are of concern and indicate that the development of cryptolepine analogues substituted with 1 halogen and an alkylamino group in place of the second halogen may be worthwhile, as it has been shown that a number of 11‐aminoalkyl‐cryptolepine analogues have enhanced antiplasmodial activities with improved selectivity in comparison to 1 (Lavrado et al 2011 ). In another study by Mudududdla et al ( 2018 ), a series of indolo[3,2‐ b ]quinoline‐11‐carboxamides were evaluated for antiplasmodial activities, but none were more active than cryptolepine, possibly because these compounds lack the 5‐ N‐ methyl group that has been shown to be essential for potent antiplasmodial activity in cryptolepine (Wright et al 1996 ). The incorporation of amino groups into cryptolepine analogues may be expected to reduce lipophilicity, ameliorate the risk of hERG inhibition, and increase oral absorption.…”

Structure–activity relationship of antiparasitic and cytotoxic indoloquinoline alkaloids, and their tricyclic and bicyclic analogues

“…26 For normelinonine F an IC 50 of 13.6 ± 9.9 lM was reported, which is an order of magnitude less active than in our case. Nostocarboline (41) is a chloro-substituted quaternary bcarbolinium alkaloid isolated from the cyanobacterium Nostoc 78-12A.…”

Synthesis and Evaluation of Cryptolepine Analogues for Their Potential as New Antimalarial Agents

“…Toxicity appears to be related to the route of administration as no deaths were reported in previous studies in which subcutaneous (at 113 mg -1 kg -1 day) 11 or oral (50 mg kg -1 day -1 ) 2 routes were used. In the former study, no effect on parasitemia was observed, but oral administration of 1 at 50 mg kg -1 day -1 for 4 days suppressed parasitemia by 80.5% 2 .…”

Antiplasmodial Activity and Pharmacokinetic Profiling of Cryptolepine and 2,7‐Dibromocryptolepine With a View to Informing the Design of Novel Antimalarial Cryptolepine Analogues

“…Overall, this study has shown that 2 is superior to 1 with respect to antiplasmodial properties but its higher lipophilicity and potential hERG inhibitory activity are of concern and indicate that the development of cryptolepine analogues substituted with 1 halogen and an alkylamino group in place of the second halogen may be worthwhile, as it has been shown that a number of 11‐aminoalkyl‐cryptolepine analogues have enhanced antiplasmodial activities with improved selectivity in comparison to 1 (Lavrado et al 2011 ). In another study by Mudududdla et al ( 2018 ), a series of indolo[3,2‐ b ]quinoline‐11‐carboxamides were evaluated for antiplasmodial activities, but none were more active than cryptolepine, possibly because these compounds lack the 5‐ N‐ methyl group that has been shown to be essential for potent antiplasmodial activity in cryptolepine (Wright et al 1996 ). The incorporation of amino groups into cryptolepine analogues may be expected to reduce lipophilicity, ameliorate the risk of hERG inhibition, and increase oral absorption.…”