Synthesis, pharmacological and physicochemical profiling of antimalarial and antischistosomal N-aryl 3-trifluoromethyl pyrido [1,2-α] benzimidazoles

Malaria and schistosomiasis represent the two most prevalent parasitic infections with grievous repercussions on the socio-economic development of affected countries, mainly in sub-Saharan Africa and South-East Asia. Despite their ravaging effects, the treatments of these two diseases have been committed to a limited arsenal of drugs that are threatened by resistance. This scenario, therefore, calls for decisive steps being taken towards the discovery and development of novel drugs with the ability to target multiple parasite stages and be efficacious against resistant parasite strains to achieve effective control and treatment of malaria and schistosomiasis. Originating from a World Health Organisation-Tropical Disease Research initiative, a phenotypic whole cell screening was conducted on a commercial library against Plasmodium falciparum whereupon novel hits exemplified by compound 1, embodying a pyridobenzimidazole (PBI) scaffold, were found to portray in vitro potency against both chloroquine sensitive and resistant parasites. Initial medicinal chemistry iterations generated analogues including 2 from which improved in vitro potency and demonstrable in vivo efficacy in a mouse model were observed. In this thesis, further structural diversity around the PBI motif 3 (Figure 1) was pursued with the aim of generating analogues for structure-activity and structure-property relationship studies. Beyond the asexual blood stage activity, the library of compounds generated was also evaluated for activity against the liver and gametocyte stages of Plasmodium. In exploring the probable mechanism of antimalarial action based on their planar morphology and existence of basic centres, the compounds were evaluated for their capacity to disrupt the heme detoxification process, a recognised druggable target in antimalarial drug discovery. Prioritised compounds, based on in vitro potency, were progressed for in vitro drug metabolism and pharmacokinetics assessment, including metabolic stability and cytotoxicity against Chinese hamster ovarian cell lines. Representative compounds were evaluated for their interaction potential with the human ether-a-go-go-related gene (hERG), a potassium ion channel whose inhibition can cause potentially fatal irregular heartbeats due to perturbed repolarisation of the myocardial action potential. In vivo proof-of-concept efficacy and pharmacokinetics studies were carried out on the most promising leads according to a predetermined screening cascade. Arising from this work, structure-activity relationship (SAR) trends were discernible with electron withdrawing substituents on the aromatic side appendage providing active analogues compared to compounds comprising hydrophilic electron-releasing or donating substituents. Following in vitro microsomal metabolic stability analysis, the series displayed moderate to good metabolic stability with compounds incorporating heteroaromatic side groups showing increased susceptibility to biotransformation usually arising from the aromatic ring. In a P. berghei mouse model at an oral dose of 50mg/kg over four consecutive days, two compounds 1j/GMP-19 and 4i/GMP-75 achieved 98% and 99.9% reduction in parasitaemia and led to mean survival days of 12 and 14, respectively, compared to the untreated infected mice which survived for only 6 days. A drug repositioning approach was pursued, exploiting the cellular and biological similarities in the haemoglobin degradation pathways existent in both Plasmodium parasites and schistosomes. Out of the 57 analogues tested, 12 were found to be potent inhibitors of the adult worms (IC50 ≤ 2 µM), with several compounds also displaying potency against the newly transformed schistosomula. Structural features consistent with good antischistosomal potency, interestingly, overlapped with those present in some compounds that also showed good antiplasmodial activity. Prioritised compounds subjected to in vivo efficacy studies in mice infected with schistosomes identified 1b/GMP-09, 1j/GMP-19 and 4i/GMP-75 with modest antischistosomal activity (55- 70% total worm reduction). Metabolic stability and physicochemical properties correlated with observed in vivo efficacy and solubility- limited absorption was implicated to contribute to low in vivo exposure of the compounds. Further profiling of physicochemical parameters revealed the interdependence of the properties and that crystallinity, as measured by the melting point, influenced compound solubility. In summary, the work pursued in this thesis has unravelled the structural features compatible with potent antimalarial and antischistosomal activities of N-aryl substituted 3- trifluoromethyl PBI derivatives. Additionally, structure-property trends of generated analogues have been delineated. The evolvable nature of the structure-activity and structureproperty relationship trends make these compounds appealing as candidates for further optimisation campaigns to impart improvements in physicochemical properties and drug metabolism and pharmacokinetics attributes without abrogating activity. Moreover, having identified the overlap as well as divergence in chemical spaces relating to antimalarial and antischistosomal potencies of these series inspire further investigations into the mechanisms of observed antiparasitic actions. Finally, that this work has identified targets which are panactive across multiple stages of both Plasmodium and schistosomes, and possessing favourable safety profiles, provide an exciting opportunity for pursuing these analogues as antimalarial and antischistosomal leads with the potential for malaria chemoprevention and transmission blocking

Knowledge and practices toward COVID-19 among healthcare students: A cross-sectional study at the University of Zambia

BACKGROUND: The COVID-19 pandemic led to the disruption of physical classes for university students globally, as large gatherings fuelled the transmission of the virus. In the efforts to mitigate its transmission and return to normality, prevention measures, including vaccination, have been encouraged. Therefore, it is critical to understand the knowledge and practices of students regarding COVID-19. This study assessed the knowledge and practices toward COVID-19 among healthcare students at the University of Zambia. MATERIALS AND METHODS: This questionnaire-based cross-sectional study was carried out from August 2021 to October 2021 among 478 healthcare students (pharmacy, physiotherapy, nursing, biomedical, medicine, and radiography). We used a previously validated questionnaire to measure knowledge and practice. The predictors of knowledge and practices were assessed using logistic regression with robust estimation of standard errors. Statistical analysis was conducted using Stata/BE version 17.0. RESULTS: Of the 478 respondents, 243 (50.8%) were females. A larger proportion, 175 (36.6%) were in Pharmacy training, and 156 (32.6%) were in their fifth year of study. The overall mean knowledge score of the participants was 87.9 (SD = 16.1), being higher at 89.6 (SD = 14.3) among medical students and the lowest at 86.7 (SD = 17.1) among Pharmacy students, although this was statistically non-significant (p = 0.488). The overall mean practice score was 60.0 (SD = 24.7), being significantly higher at 63.5 (23.4) among nursing, physiotherapy and environmental students compared to other students (p = 0.048). In multivariable analysis, the participant training program was non-significantly associated with knowledge and practice toward COVID-19. However, increased age (AOR = 1.09, 95% CI: 1.01-1.117) and residing in urban areas (AOR = 1.79, 95% CI: 1.07-3.01) than in rural areas were associated with higher odds of good practice toward COVID-19. CONCLUSION: The healthcare students generally showed good knowledge levels and poor practices toward COVID-19. Further, there was no evidence of a difference in knowledge of COVID-19 among healthcare students. These findings suggest the need for implementation strategies to be centered on improving the practices of students toward COVID-19

Student’s perspectives, satisfaction and experiences with online and classroom learning during the COVID-19 pandemic : findings and implications on blended learning

Objectives: The coronavirus disease 2019 (COVID-19) pandemic disrupted classroom-based learning, necessitating the adoption of online learning in most universities. However, there has been a lack of information on university students' perspectives regarding online learning during the COVID-19 pandemic. This study assessed the perspectives, satisfaction, and experiences with online and classroom learning among human health students at the University of Zambia. Methods: This cross-sectional study was conducted among 737 students at the University of Zambia from October 2022 to April 2023. Data were analysed using Stata version 16.1. Results: Of the 737 participants, 51.6% were female and 56.5% agreed that blended learning should continue even after the COVID-19 pandemic. However, 78.4% of the students believed that group discussions were more suitable in the classroom than online learning. Most students (67.1%) disagreed that they preferred online learning to classroom learning. Further, 77.6% of the students disagreed that online learning gave more satisfaction than classroom learning. Conclusions: This study found that most students recommended the continuation of blended learning after the pandemic. However, they believed that follow-up tutorials and assessments were better undertaken in physical classrooms than online learning. These findings are important in sensitising stakeholders in the education sector and governments to consider blended learning as a teaching strategy in the future. There is a need to develop and implement curricula that offer blended learning to students as well as ensure the students have the necessary facilities and equipment to support such learning

Structure-activity relationship and in vitro absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies of N-aryl 3-trifluoromethyl pyrido[1,2-a]benzimidazoles that are efficacious in a mouse model of Schistosomiasis

We have previously reported on the antischistosomal activity of pyrido[1,2- a]benzimidazole (PBI) derivatives. As a follow-up, we designed and prosecuted further structure-activity relationship (SAR) studies that incorporate N-aryl substitutions on the PBI scaffold. Investigations into the in vitro antischistosomal activity against newly transformed schistosomula (NTS) and adult worms revealed several leads with promising potency. Active compounds with a good cytotoxicity profile were tested in vivo whereby 6 and 44 induced noteworthy reduction (62-69%) in the worm load in the Schistosoma mansoni mouse model. Pharmacokinetic analysis on 44 pointed to slow absorption, low volume of distribution, and low plasma clearance indicating the potential of these compounds to achieve a long duration of action. Overall, our work demonstrates that PBI chemotype is a promising scaffold in the discovery of new antischistosomal leads

The Role of Natural Products in Drug Discovery and Development against Neglected Tropical Diseases

Endemic in 149 tropical and subtropical countries, neglected tropical diseases (NTDs) affect more than 1 billion people annually, including 875 million children in developing economies. These diseases are also responsible for over 500,000 deaths per year and are characterized by long-term disability and severe pain. The impact of the combined NTDs closely rivals that of malaria and tuberculosis. Current treatment options are associated with various limitations including widespread drug resistance, severe adverse effects, lengthy treatment duration, unfavorable toxicity profiles, and complicated drug administration procedures. Natural products have been a valuable source of drug regimens that form the cornerstone of modern pharmaceutical care. In this review, we highlight the potential that remains untapped in natural products as drug leads for NTDs. We cover natural products from plant, marine, and microbial sources including natural-product-inspired semi-synthetic derivatives which have been evaluated against the various causative agents of NTDs. Our coverage is limited to four major NTDs which include human African trypanosomiasis (sleeping sickness), leishmaniasis, schistosomiasis and lymphatic filariasis

Emerging Drug Targets for Antimalarial Drug Discovery: Validation and Insights into Molecular Mechanisms of Function

Approximately 619,000 malaria deaths were reported in 2021, and resistance to recommended drugs, including artemisinin-combination therapies (ACTs), threatens malaria control. Treatment failure with ACTs has been found to be as high as 93% in northeastern Thailand, and parasite mutations responsible for artemisinin resistance have already been reported in some African countries. Therefore, there is an urgent need to identify alternative treatments with novel targets. In this Perspective, we discuss some promising antimalarial drug targets, including enzymes involved in proteolysis, DNA and RNA metabolism, protein synthesis, and isoprenoid metabolism. Other targets discussed are transporters, Plasmodium falciparum acetyl-coenzyme A synthetase, N-myristoyltransferase, and the cyclic guanosine monophosphate-dependent protein kinase G. We have outlined mechanistic details, where these are understood, underpinning the biological roles and hence druggability of such targets. We believe that having a clear understanding of the underlying chemical interactions is valuable to medicinal chemists in their quest to design appropriate inhibitors

Data_Sheet_1_Knowledge and practices toward COVID-19 among healthcare students: A cross-sectional study at the University of Zambia.PDF

BackgroundThe COVID-19 pandemic led to the disruption of physical classes for university students globally, as large gatherings fuelled the transmission of the virus. In the efforts to mitigate its transmission and return to normality, prevention measures, including vaccination, have been encouraged. Therefore, it is critical to understand the knowledge and practices of students regarding COVID-19. This study assessed the knowledge and practices toward COVID-19 among healthcare students at the University of Zambia.Materials and methodsThis questionnaire-based cross-sectional study was carried out from August 2021 to October 2021 among 478 healthcare students (pharmacy, physiotherapy, nursing, biomedical, medicine, and radiography). We used a previously validated questionnaire to measure knowledge and practice. The predictors of knowledge and practices were assessed using logistic regression with robust estimation of standard errors. Statistical analysis was conducted using Stata/BE version 17.0.ResultsOf the 478 respondents, 243 (50.8%) were females. A larger proportion, 175 (36.6%) were in Pharmacy training, and 156 (32.6%) were in their fifth year of study. The overall mean knowledge score of the participants was 87.9 (SD = 16.1), being higher at 89.6 (SD = 14.3) among medical students and the lowest at 86.7 (SD = 17.1) among Pharmacy students, although this was statistically non-significant (p = 0.488). The overall mean practice score was 60.0 (SD = 24.7), being significantly higher at 63.5 (23.4) among nursing, physiotherapy and environmental students compared to other students (p = 0.048). In multivariable analysis, the participant training program was non-significantly associated with knowledge and practice toward COVID-19. However, increased age (AOR = 1.09, 95% CI: 1.01–1.117) and residing in urban areas (AOR = 1.79, 95% CI: 1.07–3.01) than in rural areas were associated with higher odds of good practice toward COVID-19.ConclusionThe healthcare students generally showed good knowledge levels and poor practices toward COVID-19. Further, there was no evidence of a difference in knowledge of COVID-19 among healthcare students. These findings suggest the need for implementation strategies to be centered on improving the practices of students toward COVID-19.</p

The impact of haptic and visual secondary tasks on drivers' visual behaviour and driving performance : a qualitative analysis

Godkänd; 2008; 20100428 (pebn

Structure-activity relationship studies and Plasmodium life cycle profiling identifies pan-active N-aryl-3-trifluoromethyl pyrido[1,2-a]benzimidazoles which are efficacious in an in vivo mouse model of malaria

Structure-activity relationship studies involving N-aryl-3-trifluoromethyl pyrido[1,2-a] benzimidazoles (PBI) identified several compounds possessing potent in vitro activities against the asexual blood, liver and gametocyte stages of the Plasmodium parasite with no cross-resistance to chloroquine. Frontrunner lead compounds with good in vitro absorption, distribution, metabolism and excretion (ADME) profiles were subjected to in vivo proof-of-concept studies in NMRI mice harboring the rodent P. berghei infection. This led to the identification of compounds 10 and 49, effecting 98% and 99.93% reduction in parasitemia with mean survival days of 12 and 14, respectively, at an oral dose of 4x50 mg/kg. In vivo pharmacokinetics studies on 10 revealed slow absorption, low volume of distribution and low clearance profiles. Furthermore, this series displayed low propensity to inhibit the human ether-a-go-go-related gene (hERG) potassium ion channel whose inhibition is associated with cardiotoxicity