Repurposing a polymer precursor: Synthesis and in vitro medicinal potential of ferrocenyl 1, 3-benzoxazine derivatives
- Mbaba, Mziyanda, Dingle, Laura M K, Cash, Devon, de la Mare, Jo-Anne, Laming, Dustin, Taylor, Dale, Hoppe, Heinrich C, Edkins, Adrienne L, Khanye, Setshaba D
- Authors: Mbaba, Mziyanda , Dingle, Laura M K , Cash, Devon , de la Mare, Jo-Anne , Laming, Dustin , Taylor, Dale , Hoppe, Heinrich C , Edkins, Adrienne L , Khanye, Setshaba D
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165395 , vital:41240 , https://doi.org/10.1016/j.ejmech.2019.111924
- Description: Cancer and malaria remain relevant pathologies in modern medicinal chemistry endeavours. This is compounded by the threat of development of resistance to existing clinical drugs in use as first-line option for treatment of these diseases. To counter this threat, strategies such as drug repurposing and hybridization are constantly adapted in contemporary drug discovery for the expansion of the drug arsenal and generation of novel chemotypes with potential to avert or delay resistance. In the present study, a polymer precursor scaffold, 1,3-benzoxazine, has been repurposed by incorporation of an organometallic ferrocene unit to produce a novel class of compounds showing in vitro biological activity against breast cancer, malaria and trypanosomiasis.
- Full Text:
- Date Issued: 2020
- Authors: Mbaba, Mziyanda , Dingle, Laura M K , Cash, Devon , de la Mare, Jo-Anne , Laming, Dustin , Taylor, Dale , Hoppe, Heinrich C , Edkins, Adrienne L , Khanye, Setshaba D
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165395 , vital:41240 , https://doi.org/10.1016/j.ejmech.2019.111924
- Description: Cancer and malaria remain relevant pathologies in modern medicinal chemistry endeavours. This is compounded by the threat of development of resistance to existing clinical drugs in use as first-line option for treatment of these diseases. To counter this threat, strategies such as drug repurposing and hybridization are constantly adapted in contemporary drug discovery for the expansion of the drug arsenal and generation of novel chemotypes with potential to avert or delay resistance. In the present study, a polymer precursor scaffold, 1,3-benzoxazine, has been repurposed by incorporation of an organometallic ferrocene unit to produce a novel class of compounds showing in vitro biological activity against breast cancer, malaria and trypanosomiasis.
- Full Text:
- Date Issued: 2020
The in vitro antiplasmodial and antiproliferative activity of new ferrocene-based α-aminocresols targeting hemozoin inhibition and DNA interaction:
- Mbaba, Mziyanda, Dingle, Laura M K, Swart, Tarryn, Cash, Devon, Laming, Dustin, de la Mare, Jo-Anne, Taylor, Dale, Hoppe, Heinrich C, Biot, Christophe, Edkins, Adrienne L, Khanye, Setshaba D
- Authors: Mbaba, Mziyanda , Dingle, Laura M K , Swart, Tarryn , Cash, Devon , Laming, Dustin , de la Mare, Jo-Anne , Taylor, Dale , Hoppe, Heinrich C , Biot, Christophe , Edkins, Adrienne L , Khanye, Setshaba D
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/149347 , vital:38827 , https://0-doi.org.wam.seals.ac.za/10.1002/cbic.202000132
- Description: Compounds incorporating ferrocene in a aminocresol scaffold showed antiplasmodial and anticancer activity. SAR studies revealed that an OH group and rotatable C–NH bond are vital for biological activity, with spectrophotometric techniques and docking simulations suggesting a dual mode of action involving hemozoin inhibition and DNA interaction. Targeting multiple pathways could delay the development of clinical resistance.
- Full Text:
- Date Issued: 2020
- Authors: Mbaba, Mziyanda , Dingle, Laura M K , Swart, Tarryn , Cash, Devon , Laming, Dustin , de la Mare, Jo-Anne , Taylor, Dale , Hoppe, Heinrich C , Biot, Christophe , Edkins, Adrienne L , Khanye, Setshaba D
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/149347 , vital:38827 , https://0-doi.org.wam.seals.ac.za/10.1002/cbic.202000132
- Description: Compounds incorporating ferrocene in a aminocresol scaffold showed antiplasmodial and anticancer activity. SAR studies revealed that an OH group and rotatable C–NH bond are vital for biological activity, with spectrophotometric techniques and docking simulations suggesting a dual mode of action involving hemozoin inhibition and DNA interaction. Targeting multiple pathways could delay the development of clinical resistance.
- Full Text:
- Date Issued: 2020
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:
- Date Issued: 2018
- 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:
- Date Issued: 2018
Ferrocenyl and organic novobiocin derivatives: synthesis and their in vitro biological activity
- Mbaba, Mziyanda, Mabhula, Amanda N, Boel, Natasha, Edkins, Adrienne L, Isaacs, Michelle, Hoppe, Heinrich C, Khanye, Setshaba D
- Authors: Mbaba, Mziyanda , Mabhula, Amanda N , Boel, Natasha , Edkins, Adrienne L , Isaacs, Michelle , Hoppe, Heinrich C , Khanye, Setshaba D
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66189 , vital:28914 , https://doi.org/10.1016/j.jinorgbio.2017.04.014
- Description: publisher version , A focused series of novobiocin derivatives containing a ferrocene unit together with their corresponding organic novobiocin analogues have been synthesized in modest to good yields. These compounds were screened for biological activity against a chloroquine-sensitive strain of Plasmodium falciparum (3D7) and human breast cancer cell line (HCC38). With the exception of compounds 5c and 5d, the general trend observed is that incorporation of the ferrocene moiety into novobiocin scaffold resulted in compounds 6a–d/6f showing enhanced activity compared to organic analogues 5a–b and 5e–f.
- Full Text: false
- Date Issued: 2017
- Authors: Mbaba, Mziyanda , Mabhula, Amanda N , Boel, Natasha , Edkins, Adrienne L , Isaacs, Michelle , Hoppe, Heinrich C , Khanye, Setshaba D
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66189 , vital:28914 , https://doi.org/10.1016/j.jinorgbio.2017.04.014
- Description: publisher version , A focused series of novobiocin derivatives containing a ferrocene unit together with their corresponding organic novobiocin analogues have been synthesized in modest to good yields. These compounds were screened for biological activity against a chloroquine-sensitive strain of Plasmodium falciparum (3D7) and human breast cancer cell line (HCC38). With the exception of compounds 5c and 5d, the general trend observed is that incorporation of the ferrocene moiety into novobiocin scaffold resulted in compounds 6a–d/6f showing enhanced activity compared to organic analogues 5a–b and 5e–f.
- Full Text: false
- Date Issued: 2017
Facile synthesis and biological evaluation of assorted indolyl-3-amides and esters from a single, stable carbonyl nitrile intermediate
- Veale, Clinton G L, Edkins, Adrienne L, de la Mare, Jo-Anne, de Kock, Carmen, Smith, Peter J, Khanye, Setshaba D
- Authors: Veale, Clinton G L , Edkins, Adrienne L , de la Mare, Jo-Anne , de Kock, Carmen , Smith, Peter J , Khanye, Setshaba D
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66221 , vital:28919 , https://doi.org/10.1016/j.tetlet.2015.02.090
- Description: publisher version , The synthesis of biologically relevant amides and esters is routinely conducted under complex reaction conditions or requires the use of additional catalysts in order to generate sensitive electrophilic species for attack by a nucleophile. Here we present the synthesis of different indolic esters and amides from indolyl-3-carbonyl nitrile, without the requirement of anhydrous reaction conditions or catalysts. Additionally, we screened these compounds for potential in vitro antimalarial and anticancer activity, revealing 1H-indolyl-3-carboxylic acid 3-(indolyl-3-carboxamide)aminobenzyl ester to have moderate activity against both lines.
- Full Text: false
- Date Issued: 2015
- Authors: Veale, Clinton G L , Edkins, Adrienne L , de la Mare, Jo-Anne , de Kock, Carmen , Smith, Peter J , Khanye, Setshaba D
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66221 , vital:28919 , https://doi.org/10.1016/j.tetlet.2015.02.090
- Description: publisher version , The synthesis of biologically relevant amides and esters is routinely conducted under complex reaction conditions or requires the use of additional catalysts in order to generate sensitive electrophilic species for attack by a nucleophile. Here we present the synthesis of different indolic esters and amides from indolyl-3-carbonyl nitrile, without the requirement of anhydrous reaction conditions or catalysts. Additionally, we screened these compounds for potential in vitro antimalarial and anticancer activity, revealing 1H-indolyl-3-carboxylic acid 3-(indolyl-3-carboxamide)aminobenzyl ester to have moderate activity against both lines.
- Full Text: false
- Date Issued: 2015
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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