Eric M. Guantai

Design, synthesis and in vitro antimalarial evaluation of triazole-linked chalcone and dienone hybrid compounds

A targeted series of chalcone and dienone hybrid compounds containing aminoquinoline and nucleoside templates was synthesized and evaluated for in vitro antimalarial activity. The Cu(I)-catalyzed cycloaddition of azides and terminal alkynes was applied as the hybridization strategy. Several chalcone-chloroquinoline hybrid compounds were found to be notably active, with compound 8b the most active, exhibiting submicromolar IC(50) values against the D10, Dd2 and W2 strains of Plasmodium falciparum.

Synthesis, antimalarial and antitubercular activity of acetylenic chalcones

A series of acetylenic chalcones were evaluated for antimalarial and antitubercular activity. The antimalarial data for this series suggests that growth inhibition of the W2 strain of Plasmodium falciparum can be imparted by the introduction of a methoxy group ortho to the acetylenic group. Most compounds were more active against non-replicating than replicating cultures of Mycobacterium tuberculosis H(37)Rv, an unusual pattern with respect to existing anti-TB agents.

Enone― and Chalcone―Chloroquinoline Hybrid Analogues: In Silico Guided Design, Synthesis, Antiplasmodial Activity, in Vitro Metabolism, and Mechanistic Studies

Analogues of the previously reported antimalarial hybrid compounds 8b and 12 were proposed with the aim of identifying compounds with improved solubility and retained antimalarial potency. In silico characterization predicted improved solubilities of the analogues, particularly at low pH; they retained acceptable predicted permeability properties but were predicted to be susceptible to hepatic metabolism. These analogues were synthesized and found to exhibit notable in vitro antimalarial activity. Compounds 25 and 27 were the most active of the analogues. In vitro metabolism studies indicated susceptibility of the analogues to hepatic metabolism. There was also evidence of primary glucuronidation for analogues 24-27. Presumed cis-trans isomerism of 12, 22, and 23 under in vitro metabolism assay conditions was also observed, with differences in the nature and rates of metabolism observed between isomers. Biochemical studies strongly suggested that inhibition of hemozoin formation is the primary mechanism of action of these analogues.

Effects of highly active novel artemisinin–chloroquinoline hybrid compounds on β-hematin formation, parasite morphology and endocytosis in Plasmodium falciparum

4-Aminoquinolines were hybridized with artemisinin and 1,4-naphthoquinone derivatives via the Ugi-four-component condensation reaction, and their biological activities investigated. The artemisinin-containing compounds 6a-c and its salt 6c-citrate were the most active target compounds in the antiplasmodial assays. However, despite the potent in vitro activities, they also displayed cytotoxicity against a mammalian cell-line, and had lower therapeutic indices than chloroquine. Morphological changes in parasites treated with these artemisinin-containing hybrid compounds were similar to those observed after addition of artemisinin. These hybrid compounds appeared to share mechanism(s) of action with both chloroquine and artemisinin: they exhibited potent β-hematin inhibitory activities; they caused an increase in accumulation of hemoglobin within the parasites that was intermediate between the increase observed with artesunate and chloroquine; and they also appeared to inhibit endocytosis as suggested by the decrease in the number of transport vesicles in the parasites. No cross-resistance with chloroquine was observed for these hybrid compounds, despite the fact that they contained the chloroquinoline moiety. The hybridization strategy therefore appeared to be borrowing the best from both classes of antimalarials.

Chloroquine resistance: proposed mechanisms and countermeasures.

Malaria has been, and remains, one of the biggest global health concerns as far as infectious diseases are concerned, with yearly incidence and mortality figures running into millions. One of the major drawbacks to the control of this disease has been the emergence of drug resistant strains of the causative agent, which limits the successful use of many clinically available antimalarial drugs. This review discusses chloroquine resistance; it highlights some of the proposed molecular mechanisms of chloroquine resistance, but dwells more on efforts at reversing chloroquine resistance and the concept of chloroquine resistance-reversal agents.

Antiplasmodial and antitumor activity of dihydroartemisinin analogs derived via the aza-Michael addition reaction

A series of dihydroartemisinin derivatives were synthesized via an aza-Michael addition reaction to a dihydroartemisinin-based acrylate and were evaluated for antiplasmodial and antitumor activity. The target compounds showed excellent antiplasmodial activity, with dihydroartemisinin derivatives 5, 7, 9 and 13 exhibiting IC(50) values of ≤10 nM against both D10 and Dd2 strains of Plasmodium falciparum. Derivative 4d was the most active against the HeLa cancer cell line, with an IC(50) of 0.37 μM and the highest tumor specificity.

Synthesis, Biological Evaluation And Mechanistic Studies Of Totarol Amino Alcohol Derivatives As Potential Antimalarial Agents.

Herein we report on the semisynthesis and biological evaluation of β-amino alcohol derivatives of the natural product totarol and other simple aromatic systems. All β-amino alcohol derivatives of totarol exhibited higher antiplasmodial activity than totarol [IC(50): 11.69 μM (K1, chloroquine and multi-drug resistant strain), and 11.78 μM (D10, chloroquine sensitive strain)]-12e was the most active [IC(50): 0.63 μM (K1), and 0.61 μM (D10)]. The phenyl and naphthyl β-amino alcohol derivatives were much less active than their corresponding totarol equivalents. The majority of the β-amino alcohol derivatives of totarol were more active against K1 than the D10 strains of Plasmodium falciparum, a trend similar to the inverse relationship observed with the established aryl-amino alcohol antimalarial mefloquine. Selected compounds were shown to affect erythrocyte morphology, inhibit erythrocyte invasion and trigger CQ accumulation.

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).

Prescription patterns and adequacy of blood pressure control among adult hypertensive patients in Kenya; findings and implications

ABSTRACT Background: Hypertension is a major cause of global morbidity and mortality, with high prevalence rates in Africa including Kenya. Consequently, it is imperative to understand current treatment approaches and their effectiveness in practice. Currently, there is paucity of such data in Kenya, which is a concern. The aim is to describe prescribing patterns and adequacy of blood pressure (BP) control in adult hypertensive patients to guide future practice. Method: Retrospective study of patients attending a sub-county outpatient clinic combined with qualitative interviews. Results: 247 hypertensive patients, predominantly female, mean age 55.8 years on antihypertensive therapy for 1–5 years, were analyzed. ACEIs and thiazide diuretics were the most commonly prescribed drugs, mainly as combination therapy. Treatment typically complied with guidelines, mainly for stage 2 hypertension (75%). BP control was observed in 46% of patients, with a significant reduction in mean systolic (155 to 144 mmHg) and diastolic (91 to 83 mmHg) BP (P < 0.001). Patients on ≥2 antihypertensive drugs were more likely to have uncontrolled BP (OR:1.9, p = 0.021). Conclusion: Encouragingly good adherence to guidelines was helped by training. Poor blood pressure control in the majority needs to be addressed. Additional training of prescribers and follow-up of measures to improve BP control will be introduced and followed up.

Natural Product-Based Drug Discovery in Africa: The Need for Integration into Modern Drug Discovery Paradigms

A myriad of infectious diseases continue to cause the death and suffering of millions of people in sub-Saharan Africa. Efforts to mitigate this suffering involve, among others, concerted efforts at discovering and developing new and more efficacious therapies for these diseases. To support these efforts, the full potential of Africa’s rich and vibrant biodiversity as a source of lead compounds and drug candidates needs to be harnessed. This would require a complete reevaluation of how natural product drug discovery is conducted on the continent, and in this chapter, we describe some of the components that could underpin this proposed transformation.