Antimalarial Agents Derived from Metal-Amodiaquine Complexes with Activity in Multiple Stages of the Plasmodium Life Cycle.

Malaria is the one of the deadliest infectious diseases worldwide. Chemically, quinolines are excellent ligands for metal coordination and are deployed as drugs for malaria treatment. There is a growing body of evidence indicating that metal complexes can be conjugated with antimalarial quinolines to be used as chemical tools to overcome the disadvantages of quinolines, improving their bioactive speciation, cellular distribution, and subsequently broadening the spectrum of activity to multiple stages of the complex Plasmodium life cycle. In this study, four novel complexes of ruthenium(II)- and gold(I)-containing amodiaquine (AQ) were synthesized, and a careful chemical characterization revealed the precise coordination site of AQ to the metals. Their speciation in solution was investigated, demonstrating the stability of the quinoline-metal bond. RuII - and AuI -AQ complexes were demonstrated to be potent and efficacious in inhibiting parasite growth in multiple stages of the Plasmodium life cycle as assayed in vitro and in vivo. These properties could be attributed to the ability of the metal-AQ complexes to reproduce the suppression of heme detoxification induced by AQ, while also inhibiting other processes in the parasite life cycle; this can be attributed to the action of the metallic species. Altogether, these findings indicate that metal coordination with antimalarial quinolines is a potential chemical tool for drug design and discovery in malaria and other infectious diseases susceptible to quinoline treatment.

A Hybrid of Amodiaquine and Primaquine Linked by Gold(I) Is a Multistage Antimalarial Agent Targeting Heme Detoxification and Thiol Redox Homeostasis.

Hybrid-based drugs linked through a transition metal constitute an emerging concept for Plasmodium intervention. To advance the drug design concept and enhance the therapeutic potential of this class of drugs, we developed a novel hybrid composed of quinolinic ligands amodiaquine (AQ) and primaquine (PQ) linked by gold(I), named [AuAQPQ]PF6. This compound demonstrated potent and efficacious antiplasmodial activity against multiple stages of the Plasmodium life cycle. The source of this activity was thoroughly investigated by comparing parasite susceptibility to the hybrid's components, the annotation of structure-activity relationships and studies of the mechanism of action. The activity of [AuAQPQ]PF6 for the parasite's asexual blood stages was influenced by the presence of AQ, while its activity against gametocytes and pre-erythrocytic parasites was influenced by both quinolinic components. Moreover, the coordination of ligands to gold(I) was found to be essential for the enhancement of potency, as suggested by the observation that a combination of quinolinic ligands does not reproduce the antimalarial potency and efficacy as observed for the metallic hybrid. Our results indicate that this gold(I) hybrid compound presents a dual mechanism of action by inhibiting the beta-hematin formation and enzymatic activity of thioredoxin reductases. Overall, our findings support the potential of transition metals as a dual chemical linker and an antiplasmodial payload for the development of hybrid-based drugs.

A Novel Hybrid of Chloroquine and Primaquine Linked by Gold(I): Multitarget and Multiphase Antiplasmodial Agent.

Plasmodium parasites kill 435 000 people around the world every year due to unavailable vaccines, a limited arsenal of antimalarial drugs, delayed treatment, and the reduced clinical effectiveness of current practices caused by drug resistance. Therefore, there is an urgent need to discover and develop new antiplasmodial candidates. In this work, we present a novel strategy to develop a multitarget metallic hybrid antimalarial agent with possible dual efficacy in both sexual and asexual erythrocytic stages. A hybrid of antimalarial drugs (chloroquine and primaquine) linked by gold(I) was synthesized and characterized by spectroscopic and analytical techniques. The CQPQ-gold(I) hybrid molecule affects essential parasite targets, it inhibits ß-hematin formation and interacts moderately with the DNA minor groove. Its interaction with PfTrxR was also examined in computational modeling studies. The CQPQ-gold(I) hybrid displayed an excellent in vitro antimalarial activity against the blood-stage of Plasmodium falciparum and liver-stage of Plasmodium berghei and efficacy in vivo against P. berghei, thereby demonstrating its multiple-stage antiplasmodial activity. This metallic hybrid is a promising chemotherapeutic agent that could act in the treatment, prevention, and transmission of malaria.

Physical Activity Decreases the Risk of Sarcopenia and Sarcopenic Obesity in Older Adults with the Incidence of Clinical Factors: 24-Month Prospective Study.

Background/Study: The occurrence of sarcopenia and sarcopenic obesity (SO) may be associated with modifiable behavioral factors such as insufficient physical activity (PA) and sedentary behavior. Thus, the aim of this study was to analyze the association of total physical activity (PA) and its different domains, as well as sedentary behavior with sarcopenia and SO in older adults with the incidence of clinical factors.Methods: Body composition was measured by dual energy X-ray absorptiometry (DXA), handgrip strength by dynamometer, physical function by physical tests, and PA and sedentary behavior were self-reported.Results: Older adults with low gait speed (HR = 5.99, 95%CI = 2.07-17.24 and HR = 4.44, 95%CI = 1.37-14.41) and insufficiently active in the occupational domain presented a higher risk of sarcopenia, independent of others PA domains, total PA and sedentary behavior. Older adults with low muscle mass (HR = 3.71, 95%CI = 1.15-11.96), low gait speed (HR = 4.15, 95%CI = 1.38-12.50), and high body fat (HR = 3.82; 95%CI = 1.18-12.37) and insufficiently active in the locomotion domain presented a higher risk of SO, independent of sex and age.Conclusion: The risk of sarcopenia and SO is higher in older adults with the incidence of clinical factors who are insufficiently active in the occupational and locomotion domains, respectively.

Effects of linear versus nonperiodized resistance training on isometric force and skeletal muscle mass adaptations in sarcopenic older adults.

The aim of this study was to compare the effects of linear periodization (LP) versus nonperiodized (NP) resistance training on upper-body isometric force and skeletal muscle mass (SMM) in sarcopenic older adults. Twenty sarcopenic older adults were randomly assigned into the LP and NP groups and performed 16 weeks of resistance training. The SMM was measured by octopolar bioelectrical impedance. The isometric force for handgrip and trunk were assessed by dynamometer. Evaluations were performed at baseline, after 4, 8, 12, and 16 weeks of resistance training. For total weight lifted, there was a main effect for time (F=126.986, P<0.001), statistically significant difference between condition (F=13.867, P=0.001) and interaction (F=8.778, P<0.001), whereby total weight lifted was greater for NP after 4 months of training. Isometric force for handgrip and trunk increased across time (P<0.001) but no significant differences between groups or interaction were observed (P>0.05). The SMM increased across time (P<0.05), however no significant difference between groups or interaction were observed (P>0.05). There were strong and significant correlations between handgrip maximum force and SMM (LP: rho=0.79, P=0.004 vs. NP: rho=-0.43, P=0.244) and handgrip mean force and SMM (LP: rho=0.68, P=0.021 vs. NP: rho=-0.37, P=0.332) only for the LP group. In conclusion, LP and NP resistance training induced similar benefits on upper-body isometric force and SMM in sarcopenic older adults. However, LP presented lower total weight lifted, suggesting that it is possible to obtain similar gains in isometric force and SMM with less total work.