Department of Biological Sciences

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Start date: 2025Subject: search.filters.subject.Plasmodium falciparum

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    IN VIVO IN VITRO ANTI-PLASMODIAL ACTIVITY OF CHEMICALLY SYNTHESISED IMIDAZOLE COMPOUNDS
    (Covenant University, Ota, 2026-09) OJO, Oluwaferanmi Esther; Covenant University, Dissertation
    Malaria remains a leading cause of morbidity and mortality globally, with the continued emergence of Plasmodium falciparum resistance to artemisinin-based therapies rendering the identification of novel chemotherapeutic scaffolds an urgent priority. The imidazole family of compounds, with their adaptable framework and ability to engage parasite-specific targets such as falcipain-2 and hemozoin biosynthesis machinery, represent compelling synthetic leads. This study evaluates the in vitro anti-plasmodial activity and in vivo efficacy and safety profiles of two newly synthesised compounds: 4,5-diphenyl-2-(m-tolyl)-1H-imidazole (IM1) and 4,5-diphenyl-2- (m-tolyl)-1-tosyl-1H-imidazole (IM2). In vitro susceptibility was assessed using a schizont maturation inhibition assay against the chloroquine-sensitive P. falciparum 3D7 strain. In vivo evaluation employed Peter's 4-d suppressive test in P. berghei ANKA-infected Swiss albino mice administered oral doses of 20–400 mg/kg. Acute toxicity was assessed according to the OECD 423 guidelines through haematological, biochemical, oxidative stress, and histopathological analyses. In vitro, IM1 demonstrated higher intrinsic potency, exhibiting a half-maximal inhibitory concentration (IC50) of 3.6 ± 0.2 μg/mL compared to 7.8 ± 0.5 μg/mL for IM2. However, in vivo evaluation revealed a distinct efficacy paradox: IM2 demonstrated superior systemic efficacy, achieving up to 68% parasitaemia suppression at 400 mg/kg, surpassing the 52% suppression observed with IM1. IM2 also significantly extended the mean survival time of infected mice to 12.3 d, compared with 8.1 d for untreated controls. Systemically, IM2 maintained physiological homeostasis, preserved hepatic and renal architecture, and induced significant modulation and stabilization of circulating lymphocytes (p=0.049), compared with the abnormal increase observed in untreated infections. A strong positive correlation between malondialdehyde and glutathione (r=0.839, p=0.005) indicated a well-tolerated, reactive oxygen species-mediated parasiticidal mechanism for IM2. On the other hand, high-dose IM1 (400 mg/kg) induced dose-dependent hepatotoxicity, as evidenced by elevated alanine aminotransferase (44.47 U/L) and histopathological evidence of hepatocyte vacuolation. Ultimately, whilst IM1's highly lipophilic core necessitates structural optimization to mitigate hepatic stress, IM2 represents a promising lead compound that requires further pre-clinical investigations.
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    The Impact of Plasmodium falciparum Adenosine Triphosphatase-6 Gene (PfATPase6) Mutations in Artemisinin Resistance
    (Journal of Pure and Applied Microbiology, 2025) Obafemi, Dorcas Yemisi; Atokolo, Austine
    The World Health Organization (WHO) recorded an estimated 263 million malaria cases globally in 2023, leading to about 597,000 mortalities. Most of this burden occurred in the WHO African Region, which accounted for approximately 94% of cases and 95% of malaria-related deaths. Artemisininbased combination therapies (ACTs) remain the mainstay of malaria treatment globally; however, the emergence of Plasmodium falciparum resistance compromises their sustained efficacy. Although mutations in the Plasmodium falciparum Kelch 13 (Pfk13) propeller domain are largely proven to be markers of partial artemisinin resistance, greater focus has turned to Plasmodium falciparum Adenosine Triphosphatase 6 (PfATPase6) as a potential supplementary determinant. This review compiled evidence from published articles between 2015 and 2025, sourced from Google Scholar, PubMed, ProQuest, and ScienceDirect, with a focus on PfATPase6 polymorphisms, their distribution, functional role, detection techniques, and implications for malaria prevention. Notable nonsynonymous single-nucleotide polymorphisms (SNPs) such as E431K, S769N, A623E, S769M, and M699V have been reported spanning Asia, the Americas, and Africa. Several studies reveal a correlation with decreased in vitro susceptibility or enhanced artemether Half Maximal Inhibitory Concentration (IC50), although findings are inconsistent due to interrelated resistance markers, environmental differences, and deviations in methodology. Recent improvements in molecular monitoring techniques, like nextgeneration sequencing, high-resolution melting analysis, and advanced real-time polymerase chain reaction (PCR) techniques, have broadened the ability to detect uncommon variants and have reinforced surveillance systems. Despite inconsistency in findings, there is evidence that PfATPase6 reduces sensitivity to artemisinin; therefore, it should be taken into consideration in resistance surveillance schemes. It is recommended to incorporate PfATPase6 genotyping alongside Pfk13 surveillance and treatment efficacy studies to offer more insights into the emergence of resistance. These approaches are vital to expound the underexplored role of the PfATPase6 in resistance patterns and encourage the sustainability of antimalarial drugs.
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    SINGLE NUCLEOTIDE POLYMORPHISMS OF Pfdhfr RESISTANCE GENE AMONG SYMPTOMATIC PATIENTS’ ISOLATES FROM SELECTED HOSPITALS IN IFO LGA, OGUN STATE
    (Covenant University Ota, 2025-10) SULE, Queen Elizabeth; Covenant University Dissertation
    Malaria remains a primary universal health concern, particularly in endemic areas where drug resistance poses a serious threat to the effectiveness of key treatment and prevention strategies. Sulfadoxine-pyrimethamine (SP), commonly used for malaria prophylaxis, is increasingly compromised by resistance associated with mutations in the Plasmodium falciparum dihydrofolate reductase (Pfdhfr) gene. This study aimed to assess the prevalence of P. falciparum infection and identify the single-nucleotide polymorphisms (SNPs) in the Pfdhfr resistance gene among symptomatic patients in Ifo Local Government Area, Ogun State, Nigeria. Five hundred patients with severe P. falciparum infection were recruited, and demographic data were recorded. Blood samples were analysed for P. falciparum stages and parasitemia levels using microscopy. DNA was extracted from samples with high parasitemia and genotyped for Pfdhfr mutations using PCR, followed by visualisation on 1% agarose gel electrophoresis. Microscopy confirmed P. falciparum malaria in 300 patients (60%). A significantly higher prevalence (71.05%) was recorded in the 0–4 years’ age group, while males accounted for 64.31% of cases (p < 0.05). Parasitemia levels (greater than 200 parasites/100 μL) were more pronounced in males than in females, and were highest among individuals aged 0–4 years. Among the 10.67% Pfdhfr genotypes identified, males exhibited a higher frequency (6.0%) than females. The overall prevalence of pfdhfr SNPs in N51I, C59R, S108, and I64L was (96%), (96%), (100%), and (0%), respectively. tripple mutant halotype (N51I+ C59R+S108), prevance was 92%. Males have a higher mutation rate (60%) than females (40%). The overall prevalence of pfdhfr SNPs in N51I, C59R, S108, and I164L was (96%), (96%), (100%), and (0%), respectively. tripple mutant halotype (N51I+ C59R+S108), prevance was 92%. Males have a higher mutation rate (60%) than females (40%). Also, individuals aged 0-4 years (20%) and 15-20 years (20%) show higher SNPs than the other age groups. The study highlights a high prevalence of P. falciparum and emerging Pfdhfr resistance mutations, emphasising the need for continuous surveillance and targeted interventions in malaria-endemic regions, such as Ifo LGA, Nigeria.