Godfrey Mayoka

Bio: Godfrey Mayoka is an academic researcher from University of Cape Town. The author has contributed to research in topics: Medicine & Malaria. The author has an hindex of 4, co-authored 5 publications receiving 129 citations. Previous affiliations of Godfrey Mayoka include Jomo Kenyatta University of Agriculture and Technology.

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

Abstract: 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.

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

Abstract: 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 ...

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.

Abstract: 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.

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.

Abstract: 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 4 × 50 mg/kg. In vivo pharmacokinetics studies on 10 revealed slow absorption, low volume of distribution, and low clearance profiles. Furthermore, this series displayed a low propensity to inhibit the human ether-a-go-go-related gene (hERG) potassium ion channel whose inhibition is associated with cardiotoxicity.

Medicinal chemistry progression of antimalarial hits from phenotypic whole cell screening of SoftFocus libraries

Abstract: Malaria continues to be endemic in tropical and subtropical regions of Africa, Central and South America, Asia and Oceania. In 2016, over 400,000 deaths and approximately 220 million cases were recorded according to the World Health Organization. Once effective and cheap drugs such as chloroquine and sulfadoxine-pyrimethamine have been rendered ineffective by widespread resistance. Sadly, in South-East Asia, there is growing evidence of emerging resistance to the current first-line treatments, the artemisinin-combination therapies. Therefore, there is a critical need to develop new and affordable antimalarials which are not prone to resistance mechanisms that have rendered current therapies ineffective. In this chapter, the epidemiology, pathophysiology and current malaria treatments including associated challenges are reviewed. Common approaches to antimalarial drug discovery such as target- and phenotypic whole-cell-based approaches with their merits and demerits are also discussed. We further discuss Plasmodium falciparum kinases as a promising family of enzymes that could be exploited in antimalarial drug discovery. We then review case studies involving phenotypic hit identification, hit-to-lead and lead optimization and mechanism of action studies of four antimalarial chemotypes derived from phenotypic whole cell screening of SoftFocus libraries—aminopyridines, aminopyrazines, imidazopyridines and imidazopyridazines. Although hurdles encountered during lead optimization phases (such as poor solubility, a hERG inhibition liability, lack of acceptable in vivo efficacy and atypical dose-response curves) have precluded the progression of the latter two chemotypes, studies on the aminopyridines and aminopyrazines have delivered clinical (MMV390048) and preclinical (UCT943) candidates, respectively.

Quinghaosu (artemisin): an antimalarial drug from china

Abstract: The herb Artemisia annua has been used for many centuries in Chinese traditional medicine as a treatment for fever and malaria. In 1971, Chinese chemists isolated from the leafy portions of the plant the substance responsible for its reputed medicinal action. This compound, called qinghaosu (QHS, artemisinin), is a sesquiterpene lactone that bears a peroxide grouping and, unlike most other antimalarials, lacks a nitrogen-containing heterocyclic ring system. The compound has been used successfully in several thousand malaria patients in China, including those with both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Derivatives of QHS, such as dihydroqinghaosu, artemether, and the water-soluble sodium artesunate, appear to be more potent than QHS itself. Sodium artesunate acts rapidly in restoring to consciousness comatose patients with cerebral malaria. Thus QHS and its derivatives offer promise as a totally new class of antimalarials.

Marine natural products as source of new drugs: a patent review (2015-2018).

Abstract: Introduction: Natural products from plants, animals, microbes, and minerals have long been a traditional source for the treatment of human diseases. In the past decades, research on natural product...

International Federation Of Pharmaceutical Manufacturers & Associations

Abstract: The International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) is a non-profit, non-governmental organization (NGO) that represents the interests of national pharmaceutical associations and companies. Member firms of the IFPMA are research-based pharmaceutical, biotechnology, and vaccine companies. The authorities of IFPMA are the Council, the Secretariat and the General Assembly. The Council consists of a President, two Vice Presidents and 34 members. The IFPMA is wholly financed through annual dues paid by its members-both companies and associations. Throughout the pharmaceutical industry IFPMA aims at promoting and supporting the development of ethical principles and practices voluntary agreed upon, as exemplified by the IFPMA Code of Pharmaceutical Marketing Practices, and the adoption of high standards of manufacturing practices and quality assurance for pharmaceutical products. The Federation has committed itself to an increased transparency with regard to pharmaceutical companies' activities in corporate social responsibility. Keywords: corporate social responsibility; IFPMA; IFPMA Code of Pharmaceutical Marketing Practices; pharmaceutical industry