Peter M. Njogu

Recent developments in rationally designed multitarget antiprotozoan agents.

Protozoan infections are the leading cause of morbidity and mortality among parasitic infections of humans, accounting for approximately 800 thousand mortalities and a loss of more than 30 million disability-adjusted life years annually. The major protozoan infections of humans, namely malaria, Chagas disease, human African trypanosomiasis, and leishmaniasis, are primarily centered in the tropics, with a reach into some subtropical regions of the world. Though globally massive in their impact, these diseases mostly afflict the least economically endowed and geographically marginalized populations in low-income countries. As such, there is no sufficient market incentive for industrial business-driven antiprotozoal drug discovery due to poor marketing prospects and low returns on investment. Consequently, the pharmacopoeia for majority of these diseases, composed mainly of agents with poor efficacy and unsatisfactory safety profiles, has essentially remained unchanged for decades, creating a compelling need for more efficacious and better tolerated medicines. The policy makers and the scientific community are seeking effective ways to meet this need. So far, two approaches have emerged promising in this regard: combination chemotherapy and drug repositioning. Molecular hybridization has been cited as a potential third approach that could be used to deliver new antiprotozoal chemical entities. In this review article, recent applications of this novel strategy in antimalarial, antichagasic, antitrypanosomal, and antileishmanial drug discovery research and development over the last five years will be presented and discussed.

Design, Synthesis, and Antiplasmodial Activity of Hybrid Compounds Based on (2R,3S)-N-Benzoyl-3-phenylisoserine.

A series of hybrid compounds based on (2R,3S)-N-benzoyl-3-phenylisoserine, artemisinin, and quinoline moieties was synthesized and tested for in vitro antiplasmodial activity against erythrocytic stages of K1 and W2 strains of Plasmodium falciparum. Two hybrid compounds incorporating (2R,3S)-N-benzoyl-3-phenylisoserine and artemisinin scaffolds were 3- to 4-fold more active than dihydroartemisinin, with nanomolar IC50 values against Plasmodium falciparum K1 strain.

Ethnobotanical survey of food and medicinal plants of the Ilkisonko Maasai community in Kenya

AIM OF THE STUDY Pastoralist communities such as the Maasai are heavily reliant on traditional foods and medicines. This survey sought to identify traditional foods and/or medicinal plants of the Ilkisonko Maasai community living in Kenya. MATERIALS AND METHODS Ethnobotanical knowledge of traditional plants used as food and human/veterinary medicine was obtained using structured and semi-structured questionnaires administered through face to face interviews of key informants. RESULTS A total of 30 species from 21 families and 25 genera were reportedly used as food and/or medicine by 48 respondents. The most commonly encountered genus was the Fabaceae. The growth forms encountered were tree (47%), shrub (33%) and herb (20%). Plants that were commonly mentioned by respondents were Salvadora persica (85%), Grewia villosa (52%), Ximenia americana (52%), Albizia anthelmintica (50%), Acacia robusta (46%) and Acacia nilotica (42%). The root/root bark was the most commonly used plant part (35%), followed by the stem/stem bark (30%), fruit (15%), leaves (11%) and whole plant (9%). Common ailments treated were stomach aches, constipation, back aches, joint aches, body pains and sexually transmitted infections. The plants were also used as tonics, digestives, and restoratives. CONCLUSION It was evident that traditional medicine was the preferred health care system for the Ilkisonko Maasai community. It is important to document and use this knowledge in producing novel products that could improve nutrition and healthcare in rural communities.

Computer-Aided Drug Discovery Approaches against the Tropical Infectious Diseases Malaria, Tuberculosis, Trypanosomiasis, and Leishmaniasis

Despite the tremendous improvement in overall global health heralded by the adoption of the Millennium Declaration in the year 2000, tropical infections remain a major health problem in the developing world. Recent estimates indicate that the major tropical infectious diseases, namely, malaria, tuberculosis, trypanosomiasis, and leishmaniasis, account for more than 2.2 million deaths and a loss of approximately 85 million disability-adjusted life years annually. The crucial role of chemotherapy in curtailing the deleterious health and economic impacts of these infections has invigorated the search for new drugs against tropical infectious diseases. The research efforts have involved increased application of computational technologies in mainstream drug discovery programs at the hit identification, hit-to-lead, and lead optimization stages. This review highlights various computer-aided drug discovery approaches that have been utilized in efforts to identify novel antimalarial, antitubercular, antitrypanosomal, and antileishmanial agents. The focus is largely on developments over the past 5 years (2010-2014).

Antimalarial Pyrido[1,2-a]benzimidazoles: Lead Optimization, Parasite Life Cycle Stage Profile, Mechanistic Evaluation, Killing Kinetics, and in Vivo Oral Efficacy in a Mouse Model

Further structure-activity relationship (SAR) studies on the recently identified pyrido[1,2-a]benzimidazole (PBI) antimalarials have led to the identification of potent, metabolically stable compounds with improved in vivo oral efficacy in the P. berghei mouse model and additional activity against parasite liver and gametocyte stages, making them potential candidates for preclinical development. Inhibition of hemozoin formation possibly contributes to the mechanism of action.

Designed Hybrid Compounds for Tropical Parasitic Diseases

Abstract Over the last century, the world has experienced a gradual but steady epidemiological transition in the pattern of diseases hallmarked by a shift in the causes of mortality and morbidity from communicable infections to noncommunicable pathologies. However, in some parts of the globe, communicable diseases are still the major contributors to disability-adjusted life years. Among these diseases is a cluster of 18 christened neglected tropical diseases due to their occurrence among the world’s poorest and marginalized populations and a dearth of effective medicines for their treatment. A number of strategies have been proposed and utilized as part of concerted efforts at drug discovery and development for tropical parasitic infections. In this chapter, application of the molecular hybridization strategy in antimalarial, antitrypanosomal, antileishmanial, and antischistosomal drug discovery research and development will be presented and discussed.

Antischistosomal Activity of Pyrido[1,2-a]benzimidazole Derivatives and Correlation with Inhibition of β-Hematin Formation

The extensive use of praziquantel against schistosomiasis raises concerns about drug resistance. New therapeutic alternatives targeting critical pathways within the parasite are therefore urgently needed. Hemozoin formation in Schistosoma presents one such target. We assessed the in vitro antischistosomal activity of pyrido[1,2-a]benzimidazoles (PBIs) and investigated correlations with their ability to inhibit β-hematin formation. We further evaluated the in vivo efficacy of representative compounds in experimental mice and conducted pharmacokinetic analysis on the most potent. At 10 μM, 48/57 compounds resulted in >70% mortality of newly transformed schistosomula, whereas 37 of these maintained >60% mortality of adult S. mansoni. No correlations were observed between β-hematin inhibitory and antischistosomal activities against both larval and adult parasites, suggesting possible presence of other target(s) or a mode of inhibition of crystal formation that is not adequately modeled by the assay. The most active compound in vivo showed 58.7 and 61.3% total and female worm burden reduction, respectively. Pharmacokinetic analysis suggested solubility-limited absorption and high hepatic clearance as possible contributors to the modest efficacy despite good in vitro activity. The PBIs evaluated in this report thus merit further optimization to improve their efficacy and to elucidate their possible mode of action.