Synthesis of novel amodiaquine analogs and evaluation of their in vitro and in vivo antimalarial activities
Background & objectives: Due to the rapid increase of drug resistance in Plasmodium parasites, there is a pressing need of developing new antiplasmodial drugs. In this study, new amodiaquine (AQ) analogs were synthesized, followed by an evaluation of their antiplasmodial activity. Methods: A new...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Wolters Kluwer Medknow Publications
2019-01-01
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| Series: | Journal of Vector Borne Diseases |
| Subjects: | |
| Online Access: | http://www.jvbd.org/article.asp?issn=0972-9062;year=2019;volume=56;issue=3;spage=221;epage=230;aulast=Tahghighi |
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| author | Azar Tahghighi Arezoo Rafie Parhizgar Safoura Karimi Mahboubeh Irani |
| author_facet | Azar Tahghighi Arezoo Rafie Parhizgar Safoura Karimi Mahboubeh Irani |
| author_sort | Azar Tahghighi |
| collection | DOAJ |
| description | Background & objectives: Due to the rapid increase of drug resistance in Plasmodium parasites, there is a pressing need of developing new antiplasmodial drugs. In this study, new amodiaquine (AQ) analogs were synthesized, followed by an evaluation of their antiplasmodial activity.
Methods: A new series of quinoline derivatives containing N-alkyl (piperazin-1-yl)methyl benzamidine moiety was synthesized by reacting 4-[(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl]benzonitrile with appropriate primary amines. The synthesized compounds were investigated for inhibitory activity by inhibition test of heme detoxification (ITHD). Their antiplasmodial activity was then evaluated using the classical 4-day suppressive test (Peter’s test) against Plasmodium berghei-infected mice (ANKA strain).
Results: The results showed that the percentage of heme detoxification inhibition in the active compounds was 90%. The most promising analogs, N-butyl-4-[(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl]benzamidine (compound 1e), and 4-[(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl)]-N-(4-methylpentan-2-yl)benzamidine (compound 1f) displayed 97.65 and 99.18% suppressions at the doses of 75 and 50 mg/kg/day, respectively. Further, the mean survival time of the mice treated with these compounds was higher than that of the negative control group.
Interpretation & conclusion: The newly synthesized amodiaquine analogs presented sufficient antiplasmodial activity with excellent suppressions and high in vitro heme detoxification inhibition. Higher mean survival time of the mice treated with synthetic compounds further confirmed the in vivo antimalarial activity of these new AQ analogs. Therefore, these compounds have the potential to replace common drugs from 4-aminoquinoline class. However, further investigations such as pharmacokinetic evaluations, cytotoxicity, toxicity, and formulation seem to be necessary. |
| first_indexed | 2024-12-13T03:33:24Z |
| format | Article |
| id | doaj.art-766c23df61f543be8872ad337d095993 |
| institution | Directory Open Access Journal |
| issn | 0972-9062 |
| language | English |
| last_indexed | 2024-12-13T03:33:24Z |
| publishDate | 2019-01-01 |
| publisher | Wolters Kluwer Medknow Publications |
| record_format | Article |
| series | Journal of Vector Borne Diseases |
| spelling | doaj.art-766c23df61f543be8872ad337d0959932022-12-22T00:01:06ZengWolters Kluwer Medknow PublicationsJournal of Vector Borne Diseases0972-90622019-01-0156322123010.4103/0972-9062.289395Synthesis of novel amodiaquine analogs and evaluation of their in vitro and in vivo antimalarial activitiesAzar TahghighiArezoo Rafie ParhizgarSafoura KarimiMahboubeh IraniBackground & objectives: Due to the rapid increase of drug resistance in Plasmodium parasites, there is a pressing need of developing new antiplasmodial drugs. In this study, new amodiaquine (AQ) analogs were synthesized, followed by an evaluation of their antiplasmodial activity. Methods: A new series of quinoline derivatives containing N-alkyl (piperazin-1-yl)methyl benzamidine moiety was synthesized by reacting 4-[(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl]benzonitrile with appropriate primary amines. The synthesized compounds were investigated for inhibitory activity by inhibition test of heme detoxification (ITHD). Their antiplasmodial activity was then evaluated using the classical 4-day suppressive test (Peter’s test) against Plasmodium berghei-infected mice (ANKA strain). Results: The results showed that the percentage of heme detoxification inhibition in the active compounds was 90%. The most promising analogs, N-butyl-4-[(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl]benzamidine (compound 1e), and 4-[(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl)]-N-(4-methylpentan-2-yl)benzamidine (compound 1f) displayed 97.65 and 99.18% suppressions at the doses of 75 and 50 mg/kg/day, respectively. Further, the mean survival time of the mice treated with these compounds was higher than that of the negative control group. Interpretation & conclusion: The newly synthesized amodiaquine analogs presented sufficient antiplasmodial activity with excellent suppressions and high in vitro heme detoxification inhibition. Higher mean survival time of the mice treated with synthetic compounds further confirmed the in vivo antimalarial activity of these new AQ analogs. Therefore, these compounds have the potential to replace common drugs from 4-aminoquinoline class. However, further investigations such as pharmacokinetic evaluations, cytotoxicity, toxicity, and formulation seem to be necessary.http://www.jvbd.org/article.asp?issn=0972-9062;year=2019;volume=56;issue=3;spage=221;epage=230;aulast=Tahghighiamodiaquine; antimalarial activity; heme detoxification; malaria; peter’s test; plasmodium berghei; quinoline |
| spellingShingle | Azar Tahghighi Arezoo Rafie Parhizgar Safoura Karimi Mahboubeh Irani Synthesis of novel amodiaquine analogs and evaluation of their in vitro and in vivo antimalarial activities Journal of Vector Borne Diseases amodiaquine; antimalarial activity; heme detoxification; malaria; peter’s test; plasmodium berghei; quinoline |
| title | Synthesis of novel amodiaquine analogs and evaluation of their in vitro and in vivo antimalarial activities |
| title_full | Synthesis of novel amodiaquine analogs and evaluation of their in vitro and in vivo antimalarial activities |
| title_fullStr | Synthesis of novel amodiaquine analogs and evaluation of their in vitro and in vivo antimalarial activities |
| title_full_unstemmed | Synthesis of novel amodiaquine analogs and evaluation of their in vitro and in vivo antimalarial activities |
| title_short | Synthesis of novel amodiaquine analogs and evaluation of their in vitro and in vivo antimalarial activities |
| title_sort | synthesis of novel amodiaquine analogs and evaluation of their in vitro and in vivo antimalarial activities |
| topic | amodiaquine; antimalarial activity; heme detoxification; malaria; peter’s test; plasmodium berghei; quinoline |
| url | http://www.jvbd.org/article.asp?issn=0972-9062;year=2019;volume=56;issue=3;spage=221;epage=230;aulast=Tahghighi |
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