Discovery of spirooxadiazoline oxindoles with dual-stage antimalarial activity
Copyright © 2022. Published by Elsevier Masson SAS..
Malaria remains a prevalent infectious disease in developing countries. The first-line therapeutic options are based on combinations of fast-acting artemisinin derivatives and longer-acting synthetic drugs. However, the emergence of resistance to these first-line treatments represents a serious risk, and the discovery of new effective drugs is urgently required. For this reason, new antimalarial chemotypes with new mechanisms of action, and ideally with activity against multiple parasite stages, are needed. We report a new scaffold with dual-stage (blood and liver) antiplasmodial activity. Twenty-six spirooxadiazoline oxindoles were synthesized and screened against the erythrocytic stage of the human malaria parasite P. falciparum. The most active compounds were also tested against the liver-stage of the murine parasite P. berghei. Seven compounds emerged as dual-stage antimalarials, with IC50 values in the low micromolar range. Due to structural similarity with cipargamin, which is thought to inhibit blood-stage P. falciparum growth via inhibition of the Na + efflux pump PfATP4, we tested one of the most active compounds for anti-PfATP4 activity. Our results suggest that this target is not the primary target of spirooxadiazoline oxindoles and further studies are ongoing to identify the main mechanism of action of this scaffold.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:236 |
|---|---|
| Enthalten in: |
European journal of medicinal chemistry - 236(2022) vom: 05. Juni, Seite 114324 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Lopes, Elizabeth A [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Antimalarials |
|---|
| Anmerkungen: |
Date Completed 17.05.2022 Date Revised 17.05.2022 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.ejmech.2022.114324 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM339204176 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM339204176 | ||
| 003 | DE-627 | ||
| 005 | 20231226002358.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.ejmech.2022.114324 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1130.xml |
| 035 | |a (DE-627)NLM339204176 | ||
| 035 | |a (NLM)35390711 | ||
| 035 | |a (PII)S0223-5234(22)00226-4 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Lopes, Elizabeth A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Discovery of spirooxadiazoline oxindoles with dual-stage antimalarial activity |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 17.05.2022 | ||
| 500 | |a Date Revised 17.05.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022. Published by Elsevier Masson SAS. | ||
| 520 | |a Malaria remains a prevalent infectious disease in developing countries. The first-line therapeutic options are based on combinations of fast-acting artemisinin derivatives and longer-acting synthetic drugs. However, the emergence of resistance to these first-line treatments represents a serious risk, and the discovery of new effective drugs is urgently required. For this reason, new antimalarial chemotypes with new mechanisms of action, and ideally with activity against multiple parasite stages, are needed. We report a new scaffold with dual-stage (blood and liver) antiplasmodial activity. Twenty-six spirooxadiazoline oxindoles were synthesized and screened against the erythrocytic stage of the human malaria parasite P. falciparum. The most active compounds were also tested against the liver-stage of the murine parasite P. berghei. Seven compounds emerged as dual-stage antimalarials, with IC50 values in the low micromolar range. Due to structural similarity with cipargamin, which is thought to inhibit blood-stage P. falciparum growth via inhibition of the Na + efflux pump PfATP4, we tested one of the most active compounds for anti-PfATP4 activity. Our results suggest that this target is not the primary target of spirooxadiazoline oxindoles and further studies are ongoing to identify the main mechanism of action of this scaffold | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Dual-stage antiplasmodial activity | |
| 650 | 4 | |a Malaria | |
| 650 | 4 | |a Oxadiazoline | |
| 650 | 4 | |a Resistance | |
| 650 | 4 | |a Spirooxindoles | |
| 650 | 7 | |a Antimalarials |2 NLM | |
| 650 | 7 | |a Folic Acid Antagonists |2 NLM | |
| 650 | 7 | |a Oxindoles |2 NLM | |
| 700 | 1 | |a Mestre, Raquel |e verfasserin |4 aut | |
| 700 | 1 | |a Fontinha, Diana |e verfasserin |4 aut | |
| 700 | 1 | |a Legac, Jenny |e verfasserin |4 aut | |
| 700 | 1 | |a Pei, Jinxin V |e verfasserin |4 aut | |
| 700 | 1 | |a Sanches-Vaz, Margarida |e verfasserin |4 aut | |
| 700 | 1 | |a Mori, Mattia |e verfasserin |4 aut | |
| 700 | 1 | |a Lehane, Adele M |e verfasserin |4 aut | |
| 700 | 1 | |a Rosenthal, Philip J |e verfasserin |4 aut | |
| 700 | 1 | |a Prudêncio, Miguel |e verfasserin |4 aut | |
| 700 | 1 | |a Santos, Maria M M |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t European journal of medicinal chemistry |d 1994 |g 236(2022) vom: 05. Juni, Seite 114324 |w (DE-627)NLM106608835 |x 1768-3254 |7 nnns |
| 773 | 1 | 8 | |g volume:236 |g year:2022 |g day:05 |g month:06 |g pages:114324 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.ejmech.2022.114324 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 236 |j 2022 |b 05 |c 06 |h 114324 | ||