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Item IN VIVO IN VITRO ANTI-PLASMODIAL ACTIVITY OF CHEMICALLY SYNTHESISED IMIDAZOLE COMPOUNDS(Covenant University, Ota, 2026-09) OJO, Oluwaferanmi Esther; Covenant University, DissertationMalaria 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.Item 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, AustineThe 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.Item Inhibitors of Protein Targets of Plasmodium falciparum(Journal of Pure and Applied Microbiology, 2024-11-24) Oranusi, Solomon Uche; Mameh, Emmanuel Ojochegbe; Oyegbade, Samuel Adeniyi; Balogun, Daniel Oluwatobiloba; Aririguzoh, Victoria-Grace OnyekachiThe World Health Organization documented 247 million reported malaria cases worldwide resulting in 619,000 fatalities in 2021. More than 70% of these deaths are attributed to Children under five years of age and sub-Saharan Africa is the region in which the highest number of deaths occur. The Plasmodium falciparum parasite is the deadliest form of malaria, and treating falciparum infection is becoming more challenging due to the emergence of drug-resistant parasites, causing a decrease in the efficiency of antimalarial medications. Artemisinin combination therapy is now considered the gold standard for malaria treatment; however, this method is at risk due to parasites exhibiting delayed clearance to artemisinin and resistance to partner drugs such as lumefantrine, amodiaquine, mefloquine, piperaquine, and sulfadoxine/pyrimethamine. This review assessed drug targets in Plasmodium falciparum for the development of novel antimalarials. Over Eighty-five papers on malaria, Plasmodium falciparum protein targets, and protein inhibitors were gathered from Google Scholar, ProQuest, PubMed, and Science Direct, between 2012 and 2023. Only articles with comparable keywords on malaria drug targets concentrating on enzyme proteins, carrier molecules present in Plasmodium falciparum, and their inhibitors were retrieved for review, while articles within that range that did not provide definite data were excluded. Most recently, inhibitors of dihydroorotate dehydrogenase (DHODH), artefenomel (OZ439), and ferroquine have been reported and are being explored in combination with other partner medications to work against different stages of plasmodium parasite. In identifying target proteins for drug development, essentiality and vulnerability throughout the life cycle of the parasite, its druggability, and the availability of target-based assays are critical factors. The use of modern proteomics and cellular proteins from database search which assists in parasite proliferation delivers optimal information on the new generation of lead compounds. In addition, advances in in silico methods enable the identification of protein targets for drug development.Item Targeting invasion-associated proteins PfSUB2 and PfTRAMP in Plasmodium falciparum: identification of potential inhibitors via molecular docking(BMC Infectious Diseases, 2025) Okafor, Esther. O.; Bella-Omunagbe, Mercy; Elugbadebo, Temitope; Dokunmu, Titilope M.; Adebiyi, EzekielPlasmodium falciparum subtilisin-like protease 2 (PfSUB2) is responsible for processing Plasmodium falciparum thrombospondin-related apical merozoite protein (PfTRAMP). These proteins are essential for asexual blood stage growth and RBC invasion and have, therefore, been identified as potential drug targets. This study predicted the three-dimensional structure of PfSUB2 and PfTRAMP and identified potential inhibitors using molecular docking methods. Five hundred nineteen compounds were docked against both proteins with AutoDock Vina in PyRx. Compounds 139,974,934 and 154,414,021 exhibited better binding affinities when compared to the standard inhibitors, PMSF, which highlights them as suitable inhibitors and potential antimalarials targeting PfTRAMP and PfSUB2. It also highlights 155,204,487 as a compound with dual antimalarial target potential, exhibiting a better binding affinity to PfTRAMP and PfSUB2. The study recommends 139,974,934, 154,414,021, and 155,204,487 as possible compounds for antimalarial drug development.Item Ex Vivo Molecular Studies and In Silico Small Molecule Inhibition of Plasmodium falciparum Bromodomain Protein 1(Drugs Drug Candidates, 2025-06-22) Oladejo, David O.; Dokunmu, Titilope M.; Oduselu, Gbolahan O.; Oladejo, Daniel O.; Ogunlana, Olubanke O.; Iweala, Emeka E. J.Background: Malaria remains a significant global health burden, particularly in sub- Saharan Africa, accounting for high rates of illness and death. The growing resistance to frontline antimalarial therapies underscores the urgent need for novel drug targets and therapeutics. Bromodomain-containing proteins, which regulate gene expression through chromatin remodeling, have gained attention as potential targets. Plasmodium falciparum bromodomain protein 1 (Pf BDP1), a 55 kDa nuclear protein, plays a key role in recognizing acetylated lysine residues and facilitating transcription during parasite development. Methods: This study investigated ex vivo PfBDP1 gene mutations and identified potential small molecule inhibitors using computational approaches. Malariapositive blood samples were collected. Genomic DNA was extracted, assessed for quality, and amplified using Pf BDP1-specific primers. DNA sequencing and alignment were performed to determine single-nucleotide polymorphism (SNP). Structural modeling used the PfBDP1 crystal structure (PDB ID: 7M97), and active site identification was conducted using CASTp 3.0. Virtual screening and pharmacophore modeling were performed using Pharmit and AutoDock Vina, followed by ADME/toxicity evaluations with SwissADME, OSIRIS, and Discovery Studio. GROMACS was used for 100 ns molecular dynamics simulations. Results: The malaria prevalence rate stood at 12.24%, and the sample size was 165. Sequencing results revealed conserved PfBDP1 gene sequences compared to the 3D7 reference strain. Virtual screening identified nine lead compounds with binding affinities ranging from −9.8 to −10.7 kcal/mol. Of these, CHEMBL2216838 had a binding affinity of −9.9 kcal/mol, with post-screening predictions of favorable drug-likeness (8.60), a high drug score (0.78), superior pharmacokinetics, and a low toxicity profile compared to chloroquine. Molecular dynamics simulations confirmed its stable interaction within the PfBDP1 active site. Conclusions: Overall, this study makes a significant contribution to the ongoing search for novel antimalarial drug targets by providing both molecular and computational evidence for PfBDP1 as a promising therapeutic target. The prediction of CHEMBL2216838 as a lead compound with favorable binding affinity, drug-likeness, and safety profile, surpassing those of existing drugs like chloroquine, sets the stage for preclinical validation and further structure-based drug design efforts. These findings are supported by prior experimental evidence showing significant parasite inhibition and gene suppression capability of predicted hits.Item Plasmodium falciparum Transketolase as a Drug Target in Malaria: A Review of Current Research and Future Perspectives(Journal of Science and Technology, Research Vol. 7, Special Issue: Landmark University International Conference, 2025) Orogun, Yetunde; Fadare, Olatomide; Bajepade, Tobilola; Raimi, Olawale; Ogunlana, OlubankeMalaria is a severe infectious disease caused by Plasmodium species, primarily Plasmodium falciparum, which accounts for the most deaths globally. Africa bears the heaviest malaria burden, with countries like Nigeria, Congo, and Mozambique contributing to a significant percentage of global cases. It is transmitted through the bite of an infected female Anopheles mosquito. The fight against malaria has been challenged by the emergence of resistance to most antimalarial drugs, including Artemisinin-based Combination Therapies (ACTs). This highlights the urgent need for novel drug targets. Transketolase (Tk), a key enzyme in the pentose phosphate pathway (PPP) non-oxidative branch, plays a vital role in cellular metabolism and has been identified to support parasite survival. Plasmodium falciparum transketolase (PfTk) has been identified as an emerging drug target due to its essential role in the parasite's metabolism and low structural homology with human transketolase (HTk). This review aims to provide an overview of PfTk as a potential anti-malarial drug target and to highlight the key research direction for future drug development. It examines the current research on PfTk as a therapeutic target, focusing on its biochemical properties, structural and functional characteristics, and potential inhibitors' development as a therapeutic strategy while exploring future perspectives.Item 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 DissertationMalaria 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.Item EVALUATION OF SYNTHETIC FLAVONOID BASED COMPOUNDS AS INHIBITORS OF Plasmodium falciparum TRANSKETOLASE(Covenant University Ota, 2025-09) OROGUN, Yetunde Grace; Covenant University DissertationMalaria, primarily attributed to Plasmodium falciparum, remains a significant contributor to global mortality, with Africa experiencing the greatest burden, particularly in countries such as Nigeria, the Democratic Republic of Congo, and Mozambique. The rise in resistance to present therapies, including Artemisinin-based Combination Therapies (ACTs), underscores the urgent need for novel drug targets. Transketolase, a thiamine-dependent enzyme in the non-oxidative arm of the pentose phosphate pathway, is vital for parasite metabolism and structurally distinct from the human enzyme, making it a promising selective target. Twenty synthetic flavonoid-based compounds were evaluated as potential inhibitors of P. falciparum transketolase (PfTk). Molecular docking revealed strong binding affinities, while ADMET profiling showed that most compounds complied with Lipinski’s rule. Notably, Compounds 6, 7, 11, and 13 were predicted to be orally bioavailable with favorable pharmacokinetic and drug-likeness properties. The compounds were further tested in vitro against PfTk and human transketolase (hTk), with oxythiamine as the positive control, and cytotoxicity was assessed using hemolysis assays on human red blood cells. The results demonstrated that several compounds exhibited high potency and selective inhibition of PfTk with minimal activity on hTk. Among them, Compounds 6, 7, and 10 emerged as the most promising leads, combining high selectivity, oral bioavailability, and favorable safety margins. Additionally, Compounds 11 and 13, analogues of Compound 10, showed good drug-likeness and oral bioavailability, indicating potential for structural optimization. Hemolysis assays confirmed minimal red blood cell lysis across all compounds, supporting their safety. In conclusion, this study validates PfTk as a viable drug target and identifies Compounds 6, 7, and 10 as strong lead candidates, with Compounds 11 and 13 as promising analogues for further optimization and development of safe, effective antimalarial agents.Item DEVELOPMENT OF A MULTI-LABEL CLASSIFIER FOR PREDICTING GENETIC MARKERS ASSOCIATED WITH MULTI-DRUG RESISTANCE IN Plasmodium falciparum STRAINS(Covenant University Ota, 2025-08) OGUNDIMU, Temitayo Ayomikun; Covenant University DissertationMalaria is an infectious disease of global health importance caused by Plasmodium falciparum. It is highly complicated by parasite’s ability to gain resistance to multiple antimalarial drugs simultaneously, a phenomenon known as multidrug resistance (MDR). Single-label models only predict resistance to one drug at a time and as such would not capture these complex resistance patterns, limiting their utility for real-world surveillance. To bridge this gap, this study developed and evaluated four advanced multi-label classification models: Random Forest with Binary Relevance (RFDTBR), Ensemble of Classifier Chains (ECCJ48), Ensemble of Binary Relevance (EBRJ48), and a Backpropagation Neural Network (BPNN), using genomic and phenotypic data for five key antimalarials. Notably, RFDTBR and EBRJ48 outperformed others in predicting exact MDR profiles, while BPNN performed faster compared to the other models. Sulfadoxine-Pyrimethamine had the lowest performance across the models. Specific genomic features consistently emerged as key predictive factors across all models. These findings demonstrate the value of multi-label learning for comprehensive MDR prediction. Also, effective models and genomic regions were identified, warranting further investigation, thereby paving the way for improved resistance surveillanceItem GENOME-WIDE IDENTIFICATION OF SHORT TANDEM REPEATS ASSOCIATED WITH MULTI-DRUG RESISTANCE IN Plasmodium falciparum STRAINS(Covenant University Ota, 2025-08) EMMANUELLA EKURI MAMTUMAMBOH; Covenant University DissertationAntimalarial drug resistance in Plasmodium falciparum threatens global malaria control, and while single nucleotide polymorphisms (SNPs) are well-studied, the role of short tandem repeats (STRs) remains underexplored. This study investigates the contribution of pathogenic STRs to drug resistance using STR genotypes from HipSTR, phenotypic resistance data, and machine learning models. Allele frequency analysis revealed consistently lower alternative allele frequencies in resistant strains across all 14 chromosomes, with strong selective signals on chromosomes 2, 3, 4, 8, and 13. Population differentiation analyses (PCA, FST) identified key resistance loci near PfKelch13 and plasmepsin 2/3, along with potential novel resistance regions. A logistic regression model trained on STR alleles achieved perfect classification (AUC = 1.00), demonstrating the strong predictive power of STRs in distinguishing resistant from sensitive parasites. Top STRs showed both known and novel associations with resistance, reinforcing the polygenic nature of antimalarial resistance. These findings establish STRs as important genetic markers for resistance surveillance and highlight their potential utility in guiding malaria treatment strategies.