Evaluation of 4-Aminoquinoline Hydrazone Analogues as Potential Leads for Drug-Resistant Malaria
The emergence of resistance to first-line antimalarial drugs calls for the development of new therapies for drug-resistant malaria. The efficacy of quinoline-based antimalarial drugs has prompted the development of novel quinolines. A panel of 4-aminoquinoline hydrazone analogues were tested on the...
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MDPI AG
2023-09-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/18/6471 |
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| author | Rachael N. Magwaza Muna Abubaker Buthaina Hussain Michael Haley Kevin Couper Sally Freeman Niroshini J. Nirmalan |
| author_facet | Rachael N. Magwaza Muna Abubaker Buthaina Hussain Michael Haley Kevin Couper Sally Freeman Niroshini J. Nirmalan |
| author_sort | Rachael N. Magwaza |
| collection | DOAJ |
| description | The emergence of resistance to first-line antimalarial drugs calls for the development of new therapies for drug-resistant malaria. The efficacy of quinoline-based antimalarial drugs has prompted the development of novel quinolines. A panel of 4-aminoquinoline hydrazone analogues were tested on the multidrug-resistant K1 strain of <i>Plasmodium falciparum</i>: IC<sub>50</sub> values after a 48 h cycle ranged from 0.60 to 49 µM, while the 72 h cycle ranged from 0.026 to 0.219 μM. Time-course assays were carried out to define the activity of the lead compounds, which inhibited over 50% growth in 24 h and 90% growth in 72 h. Cytotoxicity assays with HepG2 cells showed IC<sub>50</sub> values of 0.87–11.1 μM, whereas in MDBK cells, IC<sub>50</sub> values ranged from 1.66 to 11.7 μM. High selectivity indices were observed for the lead compounds screened at 72 h on <i>P. falciparum</i>. Analyses of stage specificity revealed that the ring stages of the parasite life cycle were most affected. Based on antimalarial efficacy and in vitro safety profiles, lead compound 4-(2-benzylidenehydrazinyl)-6-methoxy-2-methylquinoline <b>2</b> was progressed to drug combination studies for the detection of synergism, with a combinatory index of 0.599 at IC<sub>90</sub> for the combination with artemether, indicating a synergistic antimalarial activity. Compound <b>2</b> was screened on different strains of <i>P. falciparum</i> (3D7, Dd2), which maintained similar activity to K1, suggesting no cross-resistance between multidrug resistance and sensitive parasite strains. In vivo analysis with <b>2</b> showed the suppression of parasitaemia with <i>P. yoelii</i> NL (non-lethal)-treated mice (20 mg/kg and 5 mg/kg). |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T22:25:08Z |
| publishDate | 2023-09-01 |
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| spelling | doaj.art-68f7c61eab1b421f9ba0483bedd133b62023-11-19T12:07:51ZengMDPI AGMolecules1420-30492023-09-012818647110.3390/molecules28186471Evaluation of 4-Aminoquinoline Hydrazone Analogues as Potential Leads for Drug-Resistant MalariaRachael N. Magwaza0Muna Abubaker1Buthaina Hussain2Michael Haley3Kevin Couper4Sally Freeman5Niroshini J. Nirmalan6Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester M13 9PT, UKSchool of Science, Engineering and Environment, University of Salford, Manchester M5 4WT, UKFaculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman 17138, JordanSchool of Biological Sciences, Lydia Becker Institute of Immunology and Infection, University of Manchester, Manchester M13 9PT, UKSchool of Biological Sciences, Lydia Becker Institute of Immunology and Infection, University of Manchester, Manchester M13 9PT, UKDivision of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester M13 9PT, UKSchool of Science, Engineering and Environment, University of Salford, Manchester M5 4WT, UKThe emergence of resistance to first-line antimalarial drugs calls for the development of new therapies for drug-resistant malaria. The efficacy of quinoline-based antimalarial drugs has prompted the development of novel quinolines. A panel of 4-aminoquinoline hydrazone analogues were tested on the multidrug-resistant K1 strain of <i>Plasmodium falciparum</i>: IC<sub>50</sub> values after a 48 h cycle ranged from 0.60 to 49 µM, while the 72 h cycle ranged from 0.026 to 0.219 μM. Time-course assays were carried out to define the activity of the lead compounds, which inhibited over 50% growth in 24 h and 90% growth in 72 h. Cytotoxicity assays with HepG2 cells showed IC<sub>50</sub> values of 0.87–11.1 μM, whereas in MDBK cells, IC<sub>50</sub> values ranged from 1.66 to 11.7 μM. High selectivity indices were observed for the lead compounds screened at 72 h on <i>P. falciparum</i>. Analyses of stage specificity revealed that the ring stages of the parasite life cycle were most affected. Based on antimalarial efficacy and in vitro safety profiles, lead compound 4-(2-benzylidenehydrazinyl)-6-methoxy-2-methylquinoline <b>2</b> was progressed to drug combination studies for the detection of synergism, with a combinatory index of 0.599 at IC<sub>90</sub> for the combination with artemether, indicating a synergistic antimalarial activity. Compound <b>2</b> was screened on different strains of <i>P. falciparum</i> (3D7, Dd2), which maintained similar activity to K1, suggesting no cross-resistance between multidrug resistance and sensitive parasite strains. In vivo analysis with <b>2</b> showed the suppression of parasitaemia with <i>P. yoelii</i> NL (non-lethal)-treated mice (20 mg/kg and 5 mg/kg).https://www.mdpi.com/1420-3049/28/18/64714-aminoquinolinehydrazoneantimalarialNQO2 inhibitorsantimalarial drug interactionSAR |
| spellingShingle | Rachael N. Magwaza Muna Abubaker Buthaina Hussain Michael Haley Kevin Couper Sally Freeman Niroshini J. Nirmalan Evaluation of 4-Aminoquinoline Hydrazone Analogues as Potential Leads for Drug-Resistant Malaria Molecules 4-aminoquinoline hydrazone antimalarial NQO2 inhibitors antimalarial drug interaction SAR |
| title | Evaluation of 4-Aminoquinoline Hydrazone Analogues as Potential Leads for Drug-Resistant Malaria |
| title_full | Evaluation of 4-Aminoquinoline Hydrazone Analogues as Potential Leads for Drug-Resistant Malaria |
| title_fullStr | Evaluation of 4-Aminoquinoline Hydrazone Analogues as Potential Leads for Drug-Resistant Malaria |
| title_full_unstemmed | Evaluation of 4-Aminoquinoline Hydrazone Analogues as Potential Leads for Drug-Resistant Malaria |
| title_short | Evaluation of 4-Aminoquinoline Hydrazone Analogues as Potential Leads for Drug-Resistant Malaria |
| title_sort | evaluation of 4 aminoquinoline hydrazone analogues as potential leads for drug resistant malaria |
| topic | 4-aminoquinoline hydrazone antimalarial NQO2 inhibitors antimalarial drug interaction SAR |
| url | https://www.mdpi.com/1420-3049/28/18/6471 |
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