Evaluation of ferrocenyl phosphines as potent antimalarials targeting the digestive vacuole function of Plasmodium falciparum

Owing to their lipophilic nature and chemical stability, ferrocene and its derivatives have been widely explored as antimicrobial agents, in combination with other active chemical 'war heads'. A prime example is ferroquine, an analogue of chloroquine obtained by covalently bonding ferrocen...

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Main Authors: Subramanian, Gowtham, Abdul Sadeer, Mukherjee, Kalyani, Kojima, Tadayuki, Tripathi, Pallavi, Naidu, Renugah, Tay, Shan Wen, Pang, Jia Hao, Pullarkat, Sumod A., Chandramohanadas, Rajesh
Other Authors: School of Physical and Mathematical Sciences
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Language:English
Published: 2021
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Online Access:https://hdl.handle.net/10356/150653
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spelling sg-ntu-dr.10356-1506532021-08-03T13:35:21Z Evaluation of ferrocenyl phosphines as potent antimalarials targeting the digestive vacuole function of Plasmodium falciparum Subramanian, Gowtham Abdul Sadeer Mukherjee, Kalyani Kojima, Tadayuki Tripathi, Pallavi Naidu, Renugah Tay, Shan Wen Pang, Jia Hao Pullarkat, Sumod A. Chandramohanadas, Rajesh School of Physical and Mathematical Sciences Science::Chemistry In-vitro Hemoglobin Degradation Owing to their lipophilic nature and chemical stability, ferrocene and its derivatives have been widely explored as antimicrobial agents, in combination with other active chemical 'war heads'. A prime example is ferroquine, an analogue of chloroquine obtained by covalently bonding ferrocene to 4-aminoquinoline, which possesses superior efficacy against multi-drug resistant malaria parasites. Herein, we explored the possibility of combining the ferrocenyl moiety with a phosphine unit and the subsequent inclusion of gold(i) to derive a molecular framework with demonstrated potential in inhibiting parasitic diseases. A library of 24 compounds consisting of 5 non-functionalized ferrocenyl enones and 19 ferrocenyl phosphine derivatives were synthesized, verified and tested against Plasmodium (P.) falciparum, which allowed us to identify compounds with low micromolar potency against both normal and chloroquine-resistant strains. Through flow cytometry combined with microscopic examination of Giemsa-stained thin smears, we observed that most of the active compounds interfered with trophozoite development as well as schizont maturation. The gold complex, namely G3, derived from the hydrophosphination of the terminal furan bearing an enone substrate showed the highest inhibitory potential. We demonstrate that G3 is affecting the parasite's metabolic processes as evident from the swollen digestive vacuole. Furthermore, G3 significantly affected heme de-toxification as determined through the β-hematin assay, which caused apparent oxidative stress on parasites leading to death. Collectively, these results point out the potential of gold-conjugated ferrocenyl phosphine derivatives as antimalarials targeting the digestive vacuole function and metabolism of parasites. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) Nanyang Technological University GS acknowledges the Ministry of Education (MoE), Singapore for the President's Graduate Fellowship. AS acknowledges Nanyang Technological University (NTU) for the Nanyang Presidents Graduate Scholarship (NPGS). AS, TK, SWT and JHP acknowledge support from IDR-URECA and SAP acknowledges support for this work via the MoE Tier I grant T1-001-175-01 awarded through NTU. Infrastructure support through the SUTD-MIT International Design Centre (IDC) is greatly acknowledged. GS, KM, PT, RN, and RC acknowledge the following grants: RGAST1503 (A*star-India Collaboration Grant) and T1MOE1702 (MoE Tier 1 Grant awarded through SUTD). Technical support on HUVEC cell culture by Dr Leo Chen Huei, Ms Rupambika Das and Ms Hu Yang (SUTD) is greatly acknowledged. 2021-08-03T13:35:21Z 2021-08-03T13:35:21Z 2019 Journal Article Subramanian, G., Abdul Sadeer, Mukherjee, K., Kojima, T., Tripathi, P., Naidu, R., Tay, S. W., Pang, J. H., Pullarkat, S. A. & Chandramohanadas, R. (2019). Evaluation of ferrocenyl phosphines as potent antimalarials targeting the digestive vacuole function of Plasmodium falciparum. Dalton Transactions, 48(3), 1108-1117. https://dx.doi.org/10.1039/c8dt04263b 1477-9226 https://hdl.handle.net/10356/150653 10.1039/c8dt04263b 30605200 2-s2.0-85060047479 3 48 1108 1117 en T1-001-175-01 Dalton Transactions © 2019 The Royal Society of Chemistry. All rights reserved.
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Chemistry
In-vitro
Hemoglobin Degradation
spellingShingle Science::Chemistry
In-vitro
Hemoglobin Degradation
Subramanian, Gowtham
Abdul Sadeer
Mukherjee, Kalyani
Kojima, Tadayuki
Tripathi, Pallavi
Naidu, Renugah
Tay, Shan Wen
Pang, Jia Hao
Pullarkat, Sumod A.
Chandramohanadas, Rajesh
Evaluation of ferrocenyl phosphines as potent antimalarials targeting the digestive vacuole function of Plasmodium falciparum
description Owing to their lipophilic nature and chemical stability, ferrocene and its derivatives have been widely explored as antimicrobial agents, in combination with other active chemical 'war heads'. A prime example is ferroquine, an analogue of chloroquine obtained by covalently bonding ferrocene to 4-aminoquinoline, which possesses superior efficacy against multi-drug resistant malaria parasites. Herein, we explored the possibility of combining the ferrocenyl moiety with a phosphine unit and the subsequent inclusion of gold(i) to derive a molecular framework with demonstrated potential in inhibiting parasitic diseases. A library of 24 compounds consisting of 5 non-functionalized ferrocenyl enones and 19 ferrocenyl phosphine derivatives were synthesized, verified and tested against Plasmodium (P.) falciparum, which allowed us to identify compounds with low micromolar potency against both normal and chloroquine-resistant strains. Through flow cytometry combined with microscopic examination of Giemsa-stained thin smears, we observed that most of the active compounds interfered with trophozoite development as well as schizont maturation. The gold complex, namely G3, derived from the hydrophosphination of the terminal furan bearing an enone substrate showed the highest inhibitory potential. We demonstrate that G3 is affecting the parasite's metabolic processes as evident from the swollen digestive vacuole. Furthermore, G3 significantly affected heme de-toxification as determined through the β-hematin assay, which caused apparent oxidative stress on parasites leading to death. Collectively, these results point out the potential of gold-conjugated ferrocenyl phosphine derivatives as antimalarials targeting the digestive vacuole function and metabolism of parasites.
author2 School of Physical and Mathematical Sciences
author_facet School of Physical and Mathematical Sciences
Subramanian, Gowtham
Abdul Sadeer
Mukherjee, Kalyani
Kojima, Tadayuki
Tripathi, Pallavi
Naidu, Renugah
Tay, Shan Wen
Pang, Jia Hao
Pullarkat, Sumod A.
Chandramohanadas, Rajesh
format Article
author Subramanian, Gowtham
Abdul Sadeer
Mukherjee, Kalyani
Kojima, Tadayuki
Tripathi, Pallavi
Naidu, Renugah
Tay, Shan Wen
Pang, Jia Hao
Pullarkat, Sumod A.
Chandramohanadas, Rajesh
author_sort Subramanian, Gowtham
title Evaluation of ferrocenyl phosphines as potent antimalarials targeting the digestive vacuole function of Plasmodium falciparum
title_short Evaluation of ferrocenyl phosphines as potent antimalarials targeting the digestive vacuole function of Plasmodium falciparum
title_full Evaluation of ferrocenyl phosphines as potent antimalarials targeting the digestive vacuole function of Plasmodium falciparum
title_fullStr Evaluation of ferrocenyl phosphines as potent antimalarials targeting the digestive vacuole function of Plasmodium falciparum
title_full_unstemmed Evaluation of ferrocenyl phosphines as potent antimalarials targeting the digestive vacuole function of Plasmodium falciparum
title_sort evaluation of ferrocenyl phosphines as potent antimalarials targeting the digestive vacuole function of plasmodium falciparum
publishDate 2021
url https://hdl.handle.net/10356/150653
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