Expanding the SAR of Nontoxic Antiplasmodial Indolyl-3-ethanone Ethers and Thioethers:
- Lunga, Mayibongwe J, Chisango, Ruramai L, Weyers, Carli, Isaacs, Michelle, Taylor, Dale, Edkins, Adrienne L, Khanye, Setshaba D, Hoppe, Heinrich C, Veale, Clinton G L
- Authors: Lunga, Mayibongwe J , Chisango, Ruramai L , Weyers, Carli , Isaacs, Michelle , Taylor, Dale , Edkins, Adrienne L , Khanye, Setshaba D , Hoppe, Heinrich C , Veale, Clinton G L
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164389 , vital:41114 , DOI: 10.1002/cmdc.201800235
- Description: Despite major strides in reducing Plasmodium falciparum infections, this parasite still accounts for roughly half a million annual deaths. This problem is compounded by the decreased efficacy of artemisinin combination therapies. Therefore, the development and optimisation of novel antimalarial chemotypes is critical. In this study, we describe our strategic approach to optimise a class of previously reported antimalarials, resulting in the discovery of 1-(5-chloro-1H-indol-3-yl)-2-[(4-cyanophenyl)thio]ethanone (13) and 1-(5-chloro-1H-indol-3-yl)-2-[(4-nitrophenyl)thio]ethanone (14), whose activity was equipotent to that of chloroquine against the P. falciparum 3D7 strain.
- Full Text:
- Authors: Lunga, Mayibongwe J , Chisango, Ruramai L , Weyers, Carli , Isaacs, Michelle , Taylor, Dale , Edkins, Adrienne L , Khanye, Setshaba D , Hoppe, Heinrich C , Veale, Clinton G L
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164389 , vital:41114 , DOI: 10.1002/cmdc.201800235
- Description: Despite major strides in reducing Plasmodium falciparum infections, this parasite still accounts for roughly half a million annual deaths. This problem is compounded by the decreased efficacy of artemisinin combination therapies. Therefore, the development and optimisation of novel antimalarial chemotypes is critical. In this study, we describe our strategic approach to optimise a class of previously reported antimalarials, resulting in the discovery of 1-(5-chloro-1H-indol-3-yl)-2-[(4-cyanophenyl)thio]ethanone (13) and 1-(5-chloro-1H-indol-3-yl)-2-[(4-nitrophenyl)thio]ethanone (14), whose activity was equipotent to that of chloroquine against the P. falciparum 3D7 strain.
- Full Text:
Expanding the SAR of Nontoxic Antiplasmodial Indolyl-3-ethanone Ethers and Thioethers.
- Lunga, Mayibongwe J, Chisango, Ruramai Lissa, Weyers, Carli, Isaacs, Michelle, Taylor, Dale, Edkins, Adrienne L, Khanye, Setshaba D, Hoppe, Heinrich C, Veale, Clinton G L
- Authors: Lunga, Mayibongwe J , Chisango, Ruramai Lissa , Weyers, Carli , Isaacs, Michelle , Taylor, Dale , Edkins, Adrienne L , Khanye, Setshaba D , Hoppe, Heinrich C , Veale, Clinton G L
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/122908 , vital:35370 , https://doi.org/10.1002/cmdc.201800235
- Description: Despite major strides in reducing Plasmodium falciparum infections, this parasite still accounts for roughly half a million annual deaths. This problem is compounded by the decreased efficacy of artemisinin combination therapies. Therefore, the development and optimisation of novel antimalarial chemotypes is critical. In this study, we describe our strategic approach to optimise a class of previously reported antimalarials, resulting in the discovery of 1‐(5‐chloro‐1H‐indol‐3‐yl)‐2‐[(4‐cyanophenyl)thio]ethanone (13) and 1‐(5‐chloro‐1H‐indol‐3‐yl)‐2‐[(4‐nitrophenyl)thio]ethanone (14), whose activity was equipotent to that of chloroquine against the P. falciparum 3D7 strain. Furthermore, these compounds were found to be nontoxic to HeLa cells as well as being non‐haemolytic to uninfected red blood cells. Intriguingly, several of our most promising compounds were found to be less active against the isogenic NF54 strain, highlighting possible issues with long‐term dependability of malarial strains. Finally compound 14 displayed similar activity against both the NF54 and K1 strains, suggesting that it inhibits a pathway that is uncompromised by K1 resistance.
- Full Text:
- Authors: Lunga, Mayibongwe J , Chisango, Ruramai Lissa , Weyers, Carli , Isaacs, Michelle , Taylor, Dale , Edkins, Adrienne L , Khanye, Setshaba D , Hoppe, Heinrich C , Veale, Clinton G L
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/122908 , vital:35370 , https://doi.org/10.1002/cmdc.201800235
- Description: Despite major strides in reducing Plasmodium falciparum infections, this parasite still accounts for roughly half a million annual deaths. This problem is compounded by the decreased efficacy of artemisinin combination therapies. Therefore, the development and optimisation of novel antimalarial chemotypes is critical. In this study, we describe our strategic approach to optimise a class of previously reported antimalarials, resulting in the discovery of 1‐(5‐chloro‐1H‐indol‐3‐yl)‐2‐[(4‐cyanophenyl)thio]ethanone (13) and 1‐(5‐chloro‐1H‐indol‐3‐yl)‐2‐[(4‐nitrophenyl)thio]ethanone (14), whose activity was equipotent to that of chloroquine against the P. falciparum 3D7 strain. Furthermore, these compounds were found to be nontoxic to HeLa cells as well as being non‐haemolytic to uninfected red blood cells. Intriguingly, several of our most promising compounds were found to be less active against the isogenic NF54 strain, highlighting possible issues with long‐term dependability of malarial strains. Finally compound 14 displayed similar activity against both the NF54 and K1 strains, suggesting that it inhibits a pathway that is uncompromised by K1 resistance.
- Full Text:
Novobiocin–ferrocene conjugates possessing anticancer and antiplasmodial activity independent of HSP90 inhibition.
- Mbaba, Mziyanda, de la Mare, Jo-Anne, Sterrenberg, Jason N, Kajewole, Deborah, Maharaj, Shantal, Edkins, Adrienne L, Isaacs, Michelle, Hoppe, Heinrich C, Khanye, Setshaba D
- Authors: Mbaba, Mziyanda , de la Mare, Jo-Anne , Sterrenberg, Jason N , Kajewole, Deborah , Maharaj, Shantal , Edkins, Adrienne L , Isaacs, Michelle , Hoppe, Heinrich C , Khanye, Setshaba D
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/122858 , vital:35359 , https://doi.org/10.1007/s00775-018-1634-9
- Description: A series of tailored novobiocin–ferrocene conjugates was prepared in moderate yields and investigated for in vitro anticancer and antiplasmodial activity against the MDA-MB-231 breast cancer line and Plasmodium falciparum 3D7 strain, respectively. While the target compounds displayed moderate anticancer activity against the breast cancer cell line with IC50 values in the mid-micromolar range, compounds 10a–c displayed promising antiplasmodial activity as low as 0.889 µM. Furthermore, the most promising compounds were tested for inhibitory effects against a postulated target, heat shock protein 90 (Hsp90).
- Full Text:
- Authors: Mbaba, Mziyanda , de la Mare, Jo-Anne , Sterrenberg, Jason N , Kajewole, Deborah , Maharaj, Shantal , Edkins, Adrienne L , Isaacs, Michelle , Hoppe, Heinrich C , Khanye, Setshaba D
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/122858 , vital:35359 , https://doi.org/10.1007/s00775-018-1634-9
- Description: A series of tailored novobiocin–ferrocene conjugates was prepared in moderate yields and investigated for in vitro anticancer and antiplasmodial activity against the MDA-MB-231 breast cancer line and Plasmodium falciparum 3D7 strain, respectively. While the target compounds displayed moderate anticancer activity against the breast cancer cell line with IC50 values in the mid-micromolar range, compounds 10a–c displayed promising antiplasmodial activity as low as 0.889 µM. Furthermore, the most promising compounds were tested for inhibitory effects against a postulated target, heat shock protein 90 (Hsp90).
- Full Text:
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