Antitrypanosomal Chloronitrobenzamides
Human African trypanosomiasis (HAT), a neglected tropical disease caused by Trypanosoma brucei gambiense (Tbg) or Trypanosoma brucei rhodesiense (Tbr), remains a significant public health concern with over 55 million people at risk of infection. Current treatments for HAT face the challenges of poor efficacy, drug resistance, and toxicity. This study presents the synthesis and evaluation of chloronitrobenzamides (CNBs) against Trypanosoma species, identifying previously reported compound 52 as a potent and selective orally bioavailable antitrypanosomal agent. 52 was well tolerated in vivo and demonstrated favorable oral pharmacokinetics, maintaining plasma concentrations surpassing the cellular EC50 for over 24 h and achieving peak brain concentrations exceeding 7 μM in rodents after single oral administration (50 mg/kg). Treatment with 52 significantly extended the lifespan of mice infected with Trypanosoma congolense and T. brucei rhodesiense. These results demonstrate that 52 is a strong antitrypanosomal lead with potential for developing treatments for both human and animal African trypanosomiasis.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:67 |
|---|---|
| Enthalten in: |
Journal of medicinal chemistry - 67(2024), 5 vom: 14. März, Seite 3437-3447 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Carrillo, Angela K [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| Anmerkungen: |
Date Completed 15.03.2024 Date Revised 15.03.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1021/acs.jmedchem.3c01680 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM36853152X |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM36853152X | ||
| 003 | DE-627 | ||
| 005 | 20240315233319.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240216s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1021/acs.jmedchem.3c01680 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1330.xml |
| 035 | |a (DE-627)NLM36853152X | ||
| 035 | |a (NLM)38363074 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Carrillo, Angela K |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Antitrypanosomal Chloronitrobenzamides |
| 264 | 1 | |c 2024 | |
| 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 15.03.2024 | ||
| 500 | |a Date Revised 15.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Human African trypanosomiasis (HAT), a neglected tropical disease caused by Trypanosoma brucei gambiense (Tbg) or Trypanosoma brucei rhodesiense (Tbr), remains a significant public health concern with over 55 million people at risk of infection. Current treatments for HAT face the challenges of poor efficacy, drug resistance, and toxicity. This study presents the synthesis and evaluation of chloronitrobenzamides (CNBs) against Trypanosoma species, identifying previously reported compound 52 as a potent and selective orally bioavailable antitrypanosomal agent. 52 was well tolerated in vivo and demonstrated favorable oral pharmacokinetics, maintaining plasma concentrations surpassing the cellular EC50 for over 24 h and achieving peak brain concentrations exceeding 7 μM in rodents after single oral administration (50 mg/kg). Treatment with 52 significantly extended the lifespan of mice infected with Trypanosoma congolense and T. brucei rhodesiense. These results demonstrate that 52 is a strong antitrypanosomal lead with potential for developing treatments for both human and animal African trypanosomiasis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Trypanocidal Agents |2 NLM | |
| 700 | 1 | |a Kadayat, Tara Man |e verfasserin |4 aut | |
| 700 | 1 | |a Hwang, Jong Yeon |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yizhe |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Fangyi |e verfasserin |4 aut | |
| 700 | 1 | |a Holbrook, Gloria |e verfasserin |4 aut | |
| 700 | 1 | |a Gillingwater, Kirsten |e verfasserin |4 aut | |
| 700 | 1 | |a Connelly, Michele C |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Kaiser, Marcel |e verfasserin |4 aut | |
| 700 | 1 | |a Guy, R Kiplin |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of medicinal chemistry |d 1963 |g 67(2024), 5 vom: 14. März, Seite 3437-3447 |w (DE-627)NLM000006602 |x 1520-4804 |7 nnns |
| 773 | 1 | 8 | |g volume:67 |g year:2024 |g number:5 |g day:14 |g month:03 |g pages:3437-3447 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1021/acs.jmedchem.3c01680 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 67 |j 2024 |e 5 |b 14 |c 03 |h 3437-3447 | ||