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New antimalarial agents derived from nonlinear phenoxazine ring system

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Abstract

In vivo antimalarial screening of nine nonlinear phenoxazine compounds was carried out on the blood stages of Plasmodium berghei using standard methods. The activities of the compounds were compared with that of quinine as a standard antimalarial drug. LD50 and histopathological studies were also done. Molecular docking studies were carried out on four different protein targets of Plasmodium spp. The effects of these compounds on the hematological parameters (Hemoglobin, Hb; packed cell volume, PCV; white blood cells, WBC; and red blood cells, RBC) were also evaluated. The in vivo antimalarial studies showed that all the synthesized compounds had significant parasitaemia load reduction (89.00–94.05%) at 200 mg/ml when compared with the control, with (2-aminophenoxyl)benzo[a]phenoxazin-5-one 3b showing the highest activity. There was no significant difference in the activities of these compounds compared with the standard drug used (96%). The LD50 was found to be ≥5000 mg/kg. Histopathological studies showed a significant restoration of the liver intoxicated with malaria parasite after 5 days. The hematological analysis showed normal values for Hb, PCV, WBC, and RBC in the course of the treatment. The compounds showed more binding affinities for the P. falciparum receptors than the standard drug. The nine synthesized nonliner phenoxazine compounds had significant antimalarial activities and did not significantly affect the hematological parameters. They showed strong binding affinity to the parasite receptors. Hence, they are good candidates for antimalarial drugs. More preclinical investigations are needed.

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Abbreviations

1CET:

lactate dehydrogenase

3QS1:

plasmepsin I

1LS5:

plasmepsin II

1SME:

plasmepsin IV

STD:

standard drug

MW:

molecular weight

NoRB:

number of rotatable bonds

logP:

partition coefficient

HBA:

number of hydrogen bond acceptors

HBD:

number of hydrogen bond donors

nViolation:

number of violation

TPSA:

total polar surface area

NC:

normal control

NP:

no parasitaemia

UG:

untreated group

Hb:

Hemoglobin

PCV:

packed cell volume

RBC:

red blood cell

WBC:

white blood cell

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Acknowledgements

The authors are grateful to the faculty of Veterinary Medicine Department of University of Nigeria, Nsukka for providing the malaria parasite—Plasmodium berghei used in the study.

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Authors and Affiliations

  1. Department of Pure and Industrial Chemistry, University of Nigeria, Nsukka, 410001, Enugu State, Nigeria

    Mercy A. Ezeokonkwo, Efeturi A. Onoabedje & Benjamin E. Ezema

  2. Department of Pharmaceutical and Medicinal Chemistry, University of Nigeria, Nsukka, 410001, Enugu State, Nigeria

    Sunday N. Okafor

  3. Evangel University, Akaeze, Ebonyi State, Nigeria

    Onyinyechi N. Ogbonna

  4. Natural Science Unit, School of General Studies, University of Nigeria, Nsukka, 410001, Enugu State, Nigeria

    Fidelia N. Ibeanu

  5. Department of Chemistry, Gregory University, Uturu, 441107, Abia State, Nigeria

    Evelyn U. Godwin-Nwakwasi

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  1. Mercy A. Ezeokonkwo
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  2. Sunday N. Okafor
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Correspondence to Mercy A. Ezeokonkwo.

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The authors declare that they have no conlict of interest.

Ethics approval

The ethical clearance to use rats was in accordance with the University of Nigeria Ethics Committee on the use of laboratory animals, registered by the National Health Research Ethics Committee (NHREC) of Nigeria, with the number; NHREC/05/01/2008B.

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Ezeokonkwo, M.A., Okafor, S.N., Ogbonna, O.N. et al. New antimalarial agents derived from nonlinear phenoxazine ring system. Med Chem Res 29, 63–74 (2020). https://doi.org/10.1007/s00044-019-02459-6

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