Endoperoxide-8-aminoquinoline hybrids as dual-stage antimalarial agents with enhanced metabolic stability.

Hybrid compounds may play a critical role in the context of the malaria eradication agenda, which will benefit from therapeutic tools active against the symptomatic erythrocytic stage of Plasmodium infection, and also capable of eliminating liver stage parasites. To address the need for efficient multistage antiplasmodial compounds, a small library of 1,2,4,5-tetraoxane-8- aminoquinoline hybrids, with the metabolically labile C-5 position of the 8-aminoquinoline moiety blocked with aryl groups, was synthesized and screened for antiplasmodial activity and metabolic stability. The hybrid compounds inhibited development of intra-erythrocytic forms of the multidrug-resistant Plasmodium falciparum W2 strain, with EC50 values in the nM range, and with low cytotoxicity against mammalian cells. The compounds also inhibited the development of P. berghei liver stage parasites, with the most potent compounds displaying EC50 values in the low µM range. SAR analysis revealed that unbranched linkers between the endoperoxide and 8-aminoquinoline pharmacophores are most beneficial for dual antiplasmodial activity. Importantly, hybrids were significantly more potent than a 1:1 mixture of 8-aminoquinoline-tetraoxane, highlighting the superiority of the hybrid approach over the combination therapy. Furthermore, aryl substituents at C-5 of the 8-aminoquinoline moiety improve the compounds' metabolic stability when compared with their primaquine (i.e. C-5 unsubstituted) counterparts. Overall, this study reveals that blocking the quinoline C-5 position does not result in loss of dual-stage antimalarial activity, and that tetraoxane-8- aminoquinoline hybrids are an attractive approach to achieve elimination of exo- and intraerythrocytic parasites, thus with the potential to be used in malaria eradication campaigns.

Impact of nutritional iodine optimization on rates of thyroid hypoechogenicity and autoimmune thyroiditis: a cross-sectional, comparative study.

BACKGROUND: Since several countries have established mandatory food iodine fortification, there has been a decrease in rates of iodine deficiency disorders in parallel with an increase in prevalence of autoimmune thyroid diseases. This study compared the nutritional iodine status and the prevalence of autoimmune thyroiditis and thyroid hypoechogenicity on ultrasound in schoolchildren in São Paulo (Brazil) in two distinct periods of time in which fortified salt had different concentrations of iodine. METHODS: We conducted a cross-sectional study evaluating 206 children aged 7-14 years and without a history of thyroid disease. Assessments included measurements of thyrotropin (TSH), free thyroxine, antithyroperoxidase (anti-TPO), and antithyroglobulin (anti-TG) antibodies, urinary iodine concentration, and thyroid ultrasound. RESULTS: Mean urinary iodine concentration was 165.1 µg/L. Eleven children (5.3%) were diagnosed with autoimmune thyroiditis based on at least two of four criteria adopted in our study: positive anti-TPO or anti-TG antibody, hypoechogenicity of the thyroid parenchyma on ultrasound, and a TSH >4.0 µU/mL. Comparing our results with those from a similar study conducted during a period in which concentrations of iodine in the salt were higher (median urinary iodine concentration >300 µg/L), we observed a trend toward a lower prevalence of autoimmune thyroiditis, although no definitive conclusion could be established. CONCLUSION: The current nutritional iodine status in our cohort was within optimal levels and lower than levels found in 2003. The prevalence of autoimmune thyroiditis seems to be decreasing in parallel with a decrease in iodine intake, although we could not reach a definitive conclusion.