The hybrid antimalarial approach

Gupta, Poonam; Singh, Lovepreet; Singh, Kamaljit

doi:10.1016/bs.armc.2019.05.002

Cited by 8 publications

(14 citation statements)

References 150 publications

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“…Plasmodium falciparum has developed resistance to antiplasmodial agents over the years and has been reported to acquire resistance to currently used anti-malarial drugs [22]. Growing evidence of the resistance of P. falciparum to even artemisinin derivatives calls for the urgent need for more efficient and safer anti-malarials and nature remains a key source for such novel anti-malarial agents [23].…”

Section: Discussionmentioning

confidence: 99%

Xylopic acid-amodiaquine and xylopic acid-artesunate combinations are effective in managing malaria in Plasmodium berghei-infected mice

Osei

Biney

Obese

et al. 2021

Malar J

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Background Evidence of Plasmodium resistance to some of the current anti-malarial agents makes it imperative to search for newer and effective drugs to combat malaria. Therefore, this study evaluated whether the co-administrations of xylopic acid-amodiaquine and xylopic acid-artesunate combinations will produce a synergistic anti-malarial effect. Methods Antiplasmodial effect of xylopic acid (XA: 3, 10, 30, 100, 150 mg kg−1), artesunate (ART: 1, 2, 4, 8, 16 mg kg−1), and amodiaquine (AQ: 1.25, 2.5, 5, 10, 20 mg kg−1) were evaluated in Plasmodium berghei (strain ANKA)-infected mice to determine respective ED50s. Artemether/lumefantrine was used as the positive control. XA/ART and XA/AQ were subsequently administered in a fixed-dose combination of their ED50s (1:1) and the combination fractions of their ED50s (1/2, 1/4, 1/8, 1/16, and 1/32) to determine the experimental ED50s (Zexp). An isobologram was constructed to determine the nature of the interaction between XA/ART, and XA/AQ combinations by comparing Zexp with the theoretical ED50 (Zadd). Bodyweight and 30-day survival post-treatment were additionally recorded. Results ED50s for XA, ART, and AQ were 9.0 ± 3.2, 1.61 ± 0.6, and 3.1 ± 0.8 mg kg−1, respectively. The Zadd, Zexp, and interaction index for XA/ART co-administration was 5.3 ± 2.61, 1.98 ± 0.25, and 0.37, respectively while that of XA/AQ were 6.05 ± 2.0, 1.69 ± 0.42, and 0.28, respectively. The Zexp for both combination therapies lay significantly (p < 0.001) below the additive isoboles showing XA acts synergistically with both ART and AQ in clearing the parasites. High doses of XA/ART combination significantly (p < 0.05) increased the survival days of infected mice with a mean hazard ratio of 0.40 while all the XA/AQ combination doses showed a significant (p < 0.05) increase in the survival days of infected mice with a mean hazard ratio of 0.27 similar to AL. Both XA/ART and XA/AQ combined treatments significantly (p < 0.05) reduced weight loss. Conclusion Xylopic acid co-administration with either artesunate or amodiaquine produces a synergistic anti-plasmodial effect in mice infected with P. berghei.

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Section: Discussionmentioning

confidence: 99%

Xylopic acid-amodiaquine and xylopic acid-artesunate combinations are effective in managing malaria in Plasmodium berghei-infected mice

Osei

Biney

Obese

et al. 2021

Malar J

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“…Plasmodium falciparum has developed resistance to antiplasmodial agents over the years and has been reported to acquire resistance to currently used antimalarial drugs (20). Growing evidence of the resistance of P. falciparum to even artemisinin derivatives calls for the urgent need for more efficient and safer antimalarials and nature remains a key source for such novel antimalaria agents (21).…”

Section: Discussionmentioning

confidence: 99%

Xylopic Acid-Amodiaquine and Xylopic Acid-Artesunate Combinations are Effective in Managing Malaria in Plasmodium Berghei-infected Mice.

Osei

Biney

Obese

et al. 2020

Preprint

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Background: Evidence of plasmodium resistance to some of the current antimalarial agents makes it imperative to search for newer and effective drugs to combat malaria. Therefore, this study evaluated whether the co-administrations of xylopic acid-amodiaquine and xylopic acid-artesunate combinations will produce synergistic antimalarial effect. Methods: Antiplasmodial effect of xylopic acid (XA: 3, 10, 30, 100, 150 mg kg -1 ), artesunate (ART: 1, 2, 4, 8, 16 mg kg -1 ), and amodiaquine (AQ: 1.25, 2.5, 5, 10, 20 mg kg -1 ) were evaluated in Plasmodium berghei ANKA-infected mice to determine respective ED 50 s. Artemether/lumefantrine (AL: 1.14/6.9) p.o. was used as the positive control. XA/ART and XA/AQ were subsequently administered in a fixed-dose combination of their ED 50 s (1:1) and the combination fractions of their ED 50 s (1/2, 1/4, 1/8, 1/16, and 1/32) to determine the experimental ED 50 s (Z exp ). An isobologram was constructed to determine the nature of the interaction between XA/ART, and XA/AQ combinations by comparing Z exp with the theoretical ED 50 (Z add ). Body weight and 30-day survival post-treatment were additionally recorded. Results: ED 50 s for XA, ART, and AQ were 9.0 ± 3.2, 1.61 ± 0.6, and 3.1 ± 0.8 mg kg -1 respectively. The Z add , Z exp and interaction index for XA/ART co-administration was 5.3 ± 2.61, 1.98 ± 0.25 and 0.37, respectively while that of XA/AQ were 6.05 ± 2.0, 1.69 ± 0.42, and 0.28 respectively. The Z exp for both combination therapies lay significantly (p<0.001) below the additive isoboles showing XA acts synergistically with both ART and AQ in clearing the parasites. High doses of XA/ART combination significantly (p<0.05) increased the survival days of infected mice with a mean hazard ratio of 0.40 while all the XA/AQ combination doses showed a significant (p<0.05) increase in the survival days of infected mice with a mean hazard ratio of 0.27 similar to AL. Both XA/ART and XA/AQ combined treatments significantly (p<0.05) reduced weight loss. Conclusion: Xylopic acid co-administration with either artesunate or amodiaquine produces a synergistic anti-plasmodial effect in mice infected with Plasmodium berghei ANKA.

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“…At the same time, there is a need to design drugs, which can target more than one stage of the complex life cycle of malaria parasite, as evidenced by the "hybrid drugs", a strategy that not only provides new drugs but may also potentially delay the development of resistance. [16] In this direction, we [17][18][19][20] and others, [21][22][23] in the past have reported efficacy of several types of rational designs of hybrid drugs and their antimalarial activity.…”

Section: Introductionmentioning

confidence: 99%

“…[32] Phosphoramides are isosteres of phosphorodiamidates, a link also used in potent antiviral agents active against chikungunya. [33] During our ongoing research on the synthesis of hybrid antimalarials, [17][18][19][20] we realized that incorporation of a phosphoramide link to connect DHPMs and a CQ based fragment may be a good strategy to design new antimalarials, which at the same time could show antiviral activity.…”

Section: Introductionmentioning

confidence: 99%

Quinoline‐Dihydropyrimidin‐2(1H)‐one Hybrids: Synthesis, Biological Activity, and Mechanistic Studies

et al. 2022

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A novel class of quinoline-dihydropyrimidin-2(1H)-one (DHPM) hybrids was synthesized and in vitro antiplasmodial activity was evaluated against chloroquine sensitive (D10) and chloroquine resistant (Dd2) strains of Plasmodium falciparum, the human malaria parasite. The antiplasmodial activity was compared to previously reported DHPM based molecular hybrids. Dual mode of antiplasmodial action of the most active member has been evaluated through heme binding study and in silico docking in the active site of dihydrofolate enzymes (wild-type as well as mutant). Favourable pharmacokinetic parameters were pre-dicted in the ADMET evaluation. The new hybrids were also tested against a number of DNA and RNA viruses. No antiviral activity was found, except for one hybrid that showed mild inhibitory activity against two strains of cytomegalovirus (AD-169 and Davis), The most active hybrid was found to be a selective inhibitor of the growth of P. falciparum as well as a modest inhibitor of varicella zoster virus in HEL cells. Cytotoxicity of all hybrids was assessed in HEL, HeLa, Vero, MDCK, and CRFK cell cultures.

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The hybrid antimalarial approach

Cited by 8 publications

References 150 publications

Xylopic acid-amodiaquine and xylopic acid-artesunate combinations are effective in managing malaria in Plasmodium berghei-infected mice

Xylopic acid-amodiaquine and xylopic acid-artesunate combinations are effective in managing malaria in Plasmodium berghei-infected mice

Xylopic Acid-Amodiaquine and Xylopic Acid-Artesunate Combinations are Effective in Managing Malaria in Plasmodium Berghei-infected Mice.

Quinoline‐Dihydropyrimidin‐2(1H)‐one Hybrids: Synthesis, Biological Activity, and Mechanistic Studies

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