New antimalarial 3-methoxy-1,2-dioxanes: optimization of cellular pharmacokinetics and pharmacodynamics properties by incorporation of amino and N-heterocyclic moieties at C4
Sonawane, DP; Persico, M; Corbett, Y; Chianese, G; Di Dato, A; Fattorusso, C; Taglialatela-Scafati, O; Taramelli, D; Trombini, C; Dhavale, DD; Quintavalla, A; Lombardo, M
| HERO ID | 3829850 |
|---|---|
| In Press | No |
| Year | 2015 |
| Title | New antimalarial 3-methoxy-1,2-dioxanes: optimization of cellular pharmacokinetics and pharmacodynamics properties by incorporation of amino and N-heterocyclic moieties at C4 |
| Authors | Sonawane, DP; Persico, M; Corbett, Y; Chianese, G; Di Dato, A; Fattorusso, C; Taglialatela-Scafati, O; Taramelli, D; Trombini, C; Dhavale, DD; Quintavalla, A; Lombardo, M |
| Journal | RSC Advances |
| Volume | 5 |
| Issue | 89 |
| Page Numbers | 72995-73010 |
| Abstract | A new series of nineteen 3-methoxy-1,2-dioxanes containing an amino moiety at C4 was designed, synthesized and tested for in vitro antimalarial activity against chloroquine sensitive (CQ-S) D10 and chloroquine resistant (CQ-R) W2 strains of Plasmodium falciparum (Pf). Cytotoxicity against the human endothelial cell line (HMEC-1) was also evaluated. The introduced modifications resulted in a notable improvement of the antimalarial activity. In particular, compound 9a with an amino-imidazole side-chain at C4 displays antimalarial activity in the high nanomolar range against the CQ-R Pf strain (W2 IC50 = 200 nM), being more active against CQ-R than CQ-S Pf strains and devoid of cytotoxicity against human HMEC-1 cells. On the other hand, some of the hybrids with 4-amino-7-chloroquinoline (9k-p) show an IC50 comparable to that of chloroquine against the CQ-S Pf strain (9k-p, D10 IC50 = 50-90 nM) but without losing potency against the CQ-R Pf strain (9k-p, resistance index = 1.2-2.6), with low cytotoxicity against HMEC-1. Structure-activity relationship studies show that the improved antimalarial activity of the new compounds is the result of a combination of cellular pharmacokinetics and pharmacodynamics effects. |
| Doi | 10.1039/c5ra10785g |
| Wosid | WOS:000360552000064 |
| Is Certified Translation | No |
| Dupe Override | No |
| Is Public | Yes |
| Keyword | Plasmodium falciparum; chloroquine; cytotoxicity; dioxane; endothelial cells; inhibitory concentration 50; moieties; pharmacodynamics; pharmacokinetics; structure-activity relationships |