Anti-Sporothrix Activity of Novel Copper-Itraconazole Complexes.

A series of new metal complexes, [Cu(ITZ)2Cl2] ⋅ 5H2O (1), [Cu(NO3)2(ITZ)2] ⋅ 3H2O ⋅ C4H10O (2) and [Cu(ITZ)2)(PPh3)2]NO3 ⋅ 5H2O (3) were synthesized by a reaction of itraconazole (ITZ) with the respective copper salts under reflux. The metal complexes were characterized by elemental analyses, molar conductivity, 1H and 13C{1H} nuclear magnetic resonance, UV-Vis, infrared and EPR spectroscopies. The antifungal activity of these metal complexes was evaluated against the main sporotrichosis agents: Sporothrix brasiliensis, Sporothrix schenkii, and Sporothrix globosa. All three new compounds inhibited the growth of S. brasiliensis and S. schenckii at lower concentrations than the free azole, with complex 2 able to kill all species at 4 µM and induce more pronounced alterations in fungal cells. Complexes 2 and 3 exhibited higher selectivity and no mutagenic effect at the concentration that inhibited fungal growth and affected fungal cells. The strategy of coordinating itraconazole (ITZ) to copper was successful, since the corresponding metal complexes were more effective than the parent drug. Particularly, the promising antifungal activity of the Cu-ITZ complexes makes them potential candidates for the development of an alternative drug to treat mycoses.

Implications of dominance hierarchy on hummingbird-plant interactions in a temperate forest in Northwestern Mexico.

The structuring of plant-hummingbird networks can be explained by multiple factors, including species abundance (i.e., the neutrality hypothesis), matching of bill and flower morphology, phenological overlap, phylogenetic constraints, and feeding behavior. The importance of complementary morphology and phenological overlap on the hummingbird-plant network has been extensively studied, while the importance of hummingbird behavior has received less attention. In this work, we evaluated the relative importance of species abundance, morphological matching, and floral energy content in predicting the frequency of hummingbird-plant interactions. Then, we determined whether the hummingbird species' dominance hierarchy is associated with modules within the network. Moreover, we evaluated whether hummingbird specialization (d') is related to bill morphology (bill length and curvature) and dominance hierarchy. Finally, we determined whether generalist core hummingbird species are lees dominant in the community. We recorded plant-hummingbird interactions and behavioral dominance of hummingbird species in a temperate forest in Northwestern Mexico (El Palmito, Mexico). We measured flowers' corolla length and nectar traits and hummingbirds' weight and bill traits. We recorded 2,272 interactions among 13 hummingbird and 10 plant species. The main driver of plant-hummingbird interactions was species abundance, consistent with the neutrality interaction theory. Hummingbird specialization was related to dominance and bill length, but not to bill curvature of hummingbird species. However, generalist core hummingbird species (species that interact with many plant species) were less dominant. The frequency of interactions between hummingbirds and plants was determined by the abundance of hummingbirds and their flowers, and the dominance of hummingbird species determined the separation of the different modules and specialization. Our study suggests that abundance and feeding behavior may play an important role in North America's hummingbird-plant networks.

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.

Silver(I) complexes containing N-heterocyclic carbene azole drugs: Synthesis, characterization, cytotoxic activity, and their BSA interactions.

Cancer is one of the main public health problems globally, there is a public demand for better drugs. Rational strategies or approaches are used to improve the success of drug discovery. Our strategy was to the repurposing of well-known antifungal agents as potential anticancer drugs, such as Clotrimazole (CTZ) and Ketoconazole (KTZ). We prepared the respective iodide imidazolium salt L1: (CTZ-Me)I and L2: (KTZ-Me)I to be the intermediates toward the synthesis of its respective NHC ligand and achieve the respective silver(I)-monoNHC and silver(I)-bisNHC derivatives: [Ag(L1)I] (1), [AgI(L2)] (2) [Ag(L1)2]I. (3), [Ag(L2)2]I. (4), as well as their corresponding coordination compounds [Ag(CTZ)2]NO3 (5) and [Ag(KTZ)2]NO3 (6) where these ligands (CTZ and KTZ) coordinate to silver through the N-imidazole atom. These compounds (L1, L2 and complexes 1-6) exhibited significant activity against the tested cancer cell lines (B16-F1, murine melanoma strains and CT26WT, murine colon carcinoma). The silver(I) complexes were more active than the free ligands, complexes 2 and 4 being the most selective in B16-F1 cancer cell line. Two possibles biological targets such as DNA and albumin were examined for the observed anticancer activity. Results show that DNA is not the main target, however, the interactions with albumin suggest it can transport/delivery the metal complexes.

Zinc(II)-Sterol Hydrazone Complex as a Potent Anti-Leishmania Agent: Synthesis, Characterization, and Insight into Its Mechanism of Antiparasitic Action.

Searching for new alternatives for treating leishmaniasis, we present the synthesis, characterization, and biological evaluation against Leishmania amazonensis of the new ZnCl2(H3)2 complex. H3 is 22-hydrazone-imidazoline-2-yl-chol-5-ene-3ß-ol, a well-known bioactive molecule functioning as a sterol Δ24-sterol methyl transferase (24-SMT) inhibitor. The ZnCl2(H3)2 complex was characterized by infrared, UV-vis, molar conductance measurements, elemental analysis, mass spectrometry, and NMR experiments. The biological results showed that the free ligand H3 and ZnCl2(H3)2 significantly inhibited the growth of promastigotes and intracellular amastigotes. The IC50 values found for H3 and ZnCl2(H3)2 were 5.2 µM and 2.5 µM for promastigotes, and 543 nM and 32 nM for intracellular amastigotes, respectively. Thus, the ZnCl2(H3)2 complex proved to be seventeen times more potent than the free ligand H3 against the intracellular amastigote, the clinically relevant stage. Furthermore, cytotoxicity assays and determination of selectivity index (SI) revealed that ZnCl2(H3)2 (CC50 = 5 µΜ, SI = 156) is more selective than H3 (CC50 = 10 µΜ, SI = 20). Furthermore, as H3 is a specific inhibitor of the 24-SMT, free sterol analysis was performed. The results showed that H3 was not only able to induce depletion of endogenous parasite sterols (episterol and 5-dehydroepisterol) and their replacement by 24-desalkyl sterols (cholesta-5,7,24-trien-3ß-ol and cholesta-7,24-dien-3ß-ol) but also its zinc derivative resulting in a loss of cell viability. Using electron microscopy, studies on the fine ultrastructure of the parasites showed significant differences between the control cells and parasites treated with H3 and ZnCl2(H3)2. The inhibitors induced membrane wrinkle, mitochondrial injury, and abnormal chromatin condensation changes that are more intense in the cells treated with ZnCl2(H3)2.

Silver and copper-benznidazole derivatives as potential antiparasitic metallodrugs: Synthesis, characterization, and biological evaluation.

Currently the only drug available to treat Chagas disease in Brazil is benznidazole (BZN). Therefore, there is an urgent need to discover and develop new anti- Trypanosoma cruzi candidates. In our continuous effort to enhance clinical antiparasitic drugs using synergistic strategy, BZN was coordinated to silver and copper ions to enhance its effectiveness to treat that illness. In this work, the syntheses of four novel metal-BZN complexes, [Ag(BZN)2]NO3·H2O (1), [CuCl2(BZN)(H2O)]·1/2CH3CN (2), [Ag(PPh3)2(BZN)2]NO3·H2O (3), and [Cu(PPh3)2(BNZ)2]NO3·2H2O (4), and their characterization using multiple analytical and spectroscopic techniques such as Infrared (FTIR), Nuclear Magnetic Resonance (1H, 13C, 31P), UV-Visible (UV-Vis), Electron Paramagnetic Resonance (EPR), conductivity and elemental analysis are described. IC50 (Half-maximal inhibitory concentration) values of Ag-BZN compounds are about five to ten times lower than benznidazole itself in both proliferation stages of the parasite (epimastigotes and amastigotes). The cytotoxicity of both compounds in human cells (fibroblasts and hepatocytes) are comparable to BZN, indicating that Ag-BZN complexes can be more selective than BZN.

Copper (I)-Chloroquine Complexes: Interactions with DNA and Ferriprotoporphyrin, Inhibition of ß-Hematin Formation and Relation to Antimalarial Activity.

A new Cu(I)-chloroquine (CQ) complex [Cu(CQ)(PPh3)2]NO3 (1) was synthesized and characterized, and its mechanism of action studied concomitant with the previously reported complex [Cu(CQ)2]Cl (2). These copper (I) coordination compounds can be considered as potential antimalarial agents because they show better inhibition of the CQ-resistant strain in in vitro studies than CQ alone. In comparison with other metal-CQ complexes, only the gold complex was similar to (1), i.e., more active than CQ against both CQ-susceptible (3D7) and CQ-resistant strains (W2). These two copper (I)-compounds also demonstrated higher antiplasmodial activity against W2 than other copper complexes reported to date. This suggests that the incorporation of the copper metal center enhanced the biological activity of CQ. To better understand their significant growth inhibition of the Plasmodium falciparum parasite, the interaction with two essential molecular targets for the survival and proliferation of the malarial parasite were studied. These were the ferriprotoporphyrin group and the DNA, both important targets for current antimalarial drugs at the asexual erythrocytic stages. Both compounds (1,2) exhibited significant interactions with these targets. In particular, interactions with the DNA were dominated by the intercalator properties of the CQ ligand but may have also been affected by the presence of copper. Overall, these compounds were better parasitic inhibitors than chloroquine diphosphate (CQDP) alone or other previously reported metal-CQ complexes such as platinum, ruthenium and gold.

Post-Coronavirus Disease 2019 Triggers the Appearance of Mixed Polyneuropathy and Brain Fog: A Case Report.

Coronavirus disease 2019 (COVID-19) can directly or indirectly affect the central and peripheral nervous systems, resulting in cognitive impairment, memory problems, and a wide range of neuromuscular involvement, including neuropathies. However, the long-term neurological complications of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection are not clear. The aim this study was to analyze a case report the presence of neurological sequelae due to post-Coronavirus disease 19 in a patient without apparent previous neurological symptoms. Clinical case: A 46-year-old patient, with no relevant history for the described condition, who, after severe COVID-19 infection, started a mixed neuropathy and mental fog syndrome as the main sequel. Multiple laboratory and imaging studies were performed during and after his hospital stay, and it was corroborated by an electromyography that it occurred from a neuropathy triggered by COVID-19 infection. Conclusions: This case provides additional evidence that mixed neuropathy and brain fog syndrome are potential complications of post-coronavirus disease 2019 syndrome. The neurological sequelae that manifest after a COVID-19 episode can be rapidly enhanced as a consequence of another alteration in some systems of the organism. However, future studies are necessary to elucidate the incidence of these neurological complications, their pathophysiological mechanisms and their therapeutic options.

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.

Promising fluconazole based zinc(II) and copper(II) coordination polymers against Chagas disease.

A series of new transition metal coordination polymers, [Zn(Ac)2(FLZ)2]n (1), [Zn(FLZ)2(Cl)2]n (2), {[Zn(FLZ)2](NO3)2}n (3), [Cu(FLZ)2(CH3COO)4]n (4), {[Cu(FLZ)2Cl2]}n (5) and {[Cu(FLZ)2](NO3)2}n (6), were synthesized by the reaction of fluconazole (FLZ) with the respective zinc or copper salts under mild conditions. The molecular structure of these compounds was elucidated by several analytical and spectroscopy techniques such as elemental analyses, 1H and 13C{1H} nuclear magnetic resonance, electronic paramagnetic resonance, and infrared spectroscopy. Single-crystal X-ray diffraction confirmed the structure of the compounds 2, 4, 5 and 6 in solid state. The antichagasic activity of these compounds was evaluated against different forms of Trypanosoma cruzi. Compound 2 exhibited the highest activity against intracellular amastigotes. The ultrastructural changes in epimastigotes and intracellular amastigotes were investigated. These promising biological results demonstrated that the zinc or copper coordination polymers can form very active anti-parasitic compounds. The resulting compounds are more effective than the free azole drug and, consequently, great candidates for the treatment of Chagas disease.

The role of wood anatomical traits in the coexistence of oak species along an environmental gradient.

Oaks (Quercus) are a dominant woody plant genus in the northern hemisphere, which occupy a wide range of habitats and are ecologically diverse. We analysed the wood anatomical traits, the variables derived and the relative hydraulic conductivity of 21 oak species to identify their performance according to abiotic factors, leaf phenological patterns and phylogenetic restrictions by analysing the interspecific variation along an environmental gradient. First, we determine the causes of anatomical trait variation in the oaks, analysing the functional trade-offs related to distribution along the environmental gradient. We measure the phenotypic plasticity of the anatomical traits to determine the role of environment and geographic distance in the range of phenotypic plasticity. Second, we examined if oaks co-occurred along the environmental gradient. Then we analysed if wood anatomical traits reflect differences among their phylogenetic section, leaf habit and a phylogenetic section/leaf habit category. Last, we tested the phylogenetic signal. Our results showed that vessel diameter, vessel frequency, wood density and relative hydraulic conductivity are the main axes of trait variation in the species analysed among leaf habit categories. The aridity index and seasonal precipitation drive the variation in the analysed traits. Higher environmental distance resulted in a higher relative distance plasticity index among traits. Co-occurrence of oak species with different leaf habits and phylogenetic trajectories may promote complementary resource acquisition. The phylogenetic signal in the oak species studied was low, which implies labile wood traits.

Antifungal promising agents of zinc(II) and copper(II) derivatives based on azole drug.

A series of new metal complexes, [Zn(KTZ)2(Ac)2]·H2O (1), [Zn(KTZ)2Cl2]·0.4CH3OH (2), [Zn(KTZ)2(H2O)(NO3)](NO3) (3), [Cu(KTZ)2(Ac)2]·H2O (4), [Cu(KTZ)2Cl2]·3.2H2O (5), [Cu(KTZ)2(H2O)(NO3)](NO3)·H2O (6), were synthesized by a reaction of ketoconazole (KTZ) with their respective zinc or copper salts under mild conditions. Similarly, six corresponding metal-CTZ (clotrimazole) complexes [Zn(CTZ)2(Ac)2]·4H2O (7), [Zn(CTZ)2Cl2] (8), [Zn(CTZ)2(H2O)(NO3)](NO3)·4H2O (9), [Cu(CTZ)2(Ac)2]·H2O (10), [Cu(CTZ)2Cl2]·2H2O (11), [Cu(CTZ)2(H2O)(NO3)](NO3)·2H2O (12), were obtained. These metal complexes were characterized by elemental analyses, molar conductivity, 1H and 13C{1H} nuclear magnetic resonance, UV/Vis, and infrared spectroscopies. Further, the crystal structure for complexes 7 and 10 was determined by single-crystal X-ray diffraction. The antifungal activity of these metal complexes was evaluated against three fungal species of medical relevance: Candida albicans, Cryptococcus neoformans, and Sporothrix brasiliensis. Complexes 1 and 3 exhibited the greatest antifungal activity with a broad spectrum of action at low concentrations and high selectivity. Some morphological changes induced by these metal complexes in S. brasiliensis cells included yeast-hyphae conversion, an increase in cell size and cell wall damage. The strategy of coordination of clinic drugs (KTZ and CTZ) to zinc and copper was successful, since the corresponding metal complexes were more effective than the parent drug. Particularly, the promising antifungal activities displayed by Zn-KTZ complexes make them potential candidates for the development of an alternative drug to treat mycoses.

In vitro and in vivo antiplasmodial activity of novel quinoline derivative compounds by molecular hybridization.

Chloroquine (CQ) has been the main treatment for malaria in regions where there are no resistant strains. Molecular hybridization techniques have been used as a tool in the search for new drugs and was implemented in the present study in an attempt to produce compound candidates to treat malarial infections by CQ-resistant strains. Two groups of molecules were produced from the 4-aminoquinoline ring in conjugation to hydrazones (HQ) and imines (IQ). Physicochemical and pharmacokinetic properties were found to be favorable when analyzed in silico and cytotoxicity and antiplasmodial activity were assayed in vitro and in vivo showing low cytotoxicity and selectiveness to the parasites. Candidates IQ5 and IQ6 showed important values of parasite growth inhibition in vivo on the 5th day after infection (IQ5 15 mg/kg = 72.64% and IQ6 15 mg/kg = 71.15% and 25 mg/kg = 93.7%). IQ6 also showed interaction with ferriprotoporphyrin IX similarly to CQ. The process of applying condensation reactions to yield imines is promising and capable of producing molecules with antiplasmodial activity.

Metallodrugs for the Treatment of Trypanosomatid Diseases: Recent Advances and New Insights.

Trypanosomatid parasites are responsible for many Neglected Tropical Diseases (NTDs). NTDs are a group of illnesses that prevail in low-income populations, such as in tropical and subtropical areas of Africa, Asia, and the Americas. The three major human diseases caused by trypanosomatids are African trypanosomiasis, Chagas disease and leishmaniasis. There are known drugs for the treatment of these diseases that are used extensively and are affordable; however, the use of these medicines is limited by several drawbacks such as the development of chemo-resistance, side effects such as cardiotoxicity, low selectivity, and others. Therefore, there is a need to develop new chemotherapeutic against these tropical parasitic diseases. Metal-based drugs against NTDs have been discussed over the years as alternative ways to overcome the difficulties presented by approved antiparasitic agents. The study of late transition metal-based drugs as chemotherapeutics is an exciting research field in chemistry, biology, and medicine due to the ability to develop multitarget antiparasitic agents. The evaluation of the late transition metal complexes for the treatment of trypanosomatid diseases is provided here, as well as some insights about their mechanism of action.

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.

Synthesis and Biological Activity of Novel Zinc-Itraconazole Complexes in Protozoan Parasites and Sporothrix spp.

The new complexes Zn(ITZ)2Cl2 (1) and Zn(ITZ)2(OH)2 (2) were synthetized by a reaction of itraconazole with their respective zinc salts under reflux. These Zn-ITZ complexes were characterized by elemental analyses, molar conductivity, mass spectrometry, 1H and 13C{1H} nuclear magnetic resonance, and UV-vis and infrared spectroscopies. The antiparasitic and antifungal activity of Zn-ITZ complexes was evaluated against three protozoans of medical importance, namely, Leishmania amazonensis, Trypanosoma cruzi, and Toxoplasma gondii, and two fungi, namely, Sporothrix brasiliensis and Sporothrix schenckii The Zn-ITZ complexes exhibited a broad spectrum of action, with antiparasitic and antifungal activity in low concentrations. The strategy of combining zinc with ITZ was efficient to enhance ITZ activity since Zn-ITZ-complexes were more active than the azole alone. This study opens perspectives for future applications of these Zn-ITZ complexes in the treatment of parasitic diseases and sporotrichosis.

Activity of Metal-Azole Complexes Against Biofilms of Candida albicans and Candida glabrata.

BACKGROUND: Onychomycosis is a chronic nail infection caused by fungi frequently resistant to antifungal treatments. Recalcitrance in nail infections is a result of reduced antifungal penetration due to biofilm formation, combined with poor patient compliance with the treatment, which can be as long as 18 months. OBJECTIVE: Metal-drug complexation is a widely used strategy to increase drug efficacy. Therefore, the aim of this work was to evaluate the antifungal and anti-biofilm activity of several metal-azole complexes against Candida albicans and Candida glabrata. METHODS: Susceptibility assays and scanning electron microscopy were performed to determine the anti-biofilm activity of eight metal-azole complexes in vitro and ex-vivo, using human nail fragments. RESULTS: In vitro susceptibility assays showed that complexation of both Au(I) and Zn(II) to clotrimazole and ketoconazole improved the anti-biofilm activity compared to the azole alone. Using an ex-vivo model of biofilm formation on fragments of human nails, we also demonstrate the improved efficacy of metal-azole complexes against biofilms of C. albicans and C. glabrata that resembles the onychomycosis structure. Noteworthy, biofilms of C. glabrata were more susceptible to the optimized complexes than those of C. albicans. CONCLUSION: In conclusion, metal-azole complexes used in this work show promising anti-biofilm activity and further clinical studies should confirm its potential for the treatment of Candida-associated onychomycosis.

Zinc-clotrimazole complexes are effective against Trichomonas vaginalis.

Trichomonas vaginalis is a protozoan parasite that causes trichomoniasis in humans, the most prevalent non-viral sexually transmitted disease (STD). Imidazole compounds are used for the treatment of trichomoniasis, and metronidazole is the most commonly prescribed. However, these compounds can lead to parasite resistance and unwanted side effects. Therefore, there is a need for an alternative treatment for this disease. Here, we explored the potential of clotrimazole (CTZ) and zinc compounds, as well as CTZ complexed with zinc salts ([1] acetate [Zn(CTZ)2(Ac)2] and [2] a chloride [Zn(CTZ)2Cl2] complexes) against T. vaginalis. We synthesized the zinc complexed CTZ compounds and determined their concentration values that inhibited parasite growth by 50% (IC50). We used scanning and transmission electron microscopy to visualize the ultrastructural alterations induced by CTZ and their zinc complexes. The incubation of the parasites with [Zn(CTZ)2(Ac)2] complex inhibited their growth, yielding an IC50 of 4.9 µm. Moreover, there were changes in the shape of treated parasites, including the formation of surface projections that subsequently detached from the cell, in addition to changes in the hydrogenosomes, endoplasmic reticulum and Golgi complex. We found [Zn(CTZ)2(Ac)2] to be a highly effective compound against T. vaginalis in vitro, suggesting its potential utility as an alternative chemotherapy for trichomoniasis.

Hummingbird migration and flowering synchrony in the temperate forests of northwestern Mexico.

BACKGROUND: Many species of birds are morphologically and physiologically adapted for migration. Migratory movements of birds can range from thousands of kilometers, such as when birds migrate from wintering to breeding sites in summer, to several kilometers, such as when birds migrate among habitats in a single mountain system. The main factor that influences bird migration is the seasonal fluctuation of food resources; climate, predation, competition for resources and endogenous programming are also important factors. Hummingbirds are highly dependent on nectar, so their migration is likely correlated with the blooming of plant species. The ecological implications of altitudinal migration in the mountains of North America as well as the latitudinal migration of Selasphorus rufus through Mexico are still poorly understood. To explore these issues, over three non-consecutive years, we evaluated interannual variation in the phenologies of a latitudinal migrant (S. rufus) and an altitudinal migrant (Amazilia beryllina) and their visited plants. METHODS: We assessed the relationship between two migratory hummingbirds and flower abundance in 20 fixed-radius plots (25 m radius). All available flowers were counted along transects (40 × 5 m) inside each fixed-radius plot. Sampling was performed every 10 days from November 12 through February 20 of 2010-2011, 2013-2014 and 2015-2016, resulting in a total of 11 samples of each plot per period. Phenological variation and the relationships among hummingbird abundance, flower abundance and vegetation type were evaluated using a generalized additive mixed model. RESULTS: S. rufus abundance was related to sampling time in the first and third periods; this relationship was not significant in the second period. A. beryllina abundance was related with the sampling time over all three periods. The abundance of S. rufus hummingbirds was significantly related to the number of Salvia iodantha flowers. The abundance of A. beryllina hummingbirds was related to the number of S. iodantha and Cestrum thyrsoideum flowers and the total number of flowers. We found a non-significant correlation between S. rufus and A. beryllina abundance and vegetation types. CONCLUSION: Contrary to expectations, the long-distance migration of S. rufus was not consistent over the sampling periods. The migration of S. rufus through the study region may be altered by changes in climate, as has occurred with other species of migratory birds. In the present study, the migration of S. rufus was correlated with the blooming of S. iodantha. In comparison, the altitudinal migrant A. beryllina responded to the availability of floral resources but was not associated with a particular plant. The migration of this latter species in the area probably depends on multiple factors, including climatic and demographic factors, but is particularly dependent on the supply of floral resources and competition for these resources.

Platinum(ii)-chloroquine complexes are antimalarial agents against blood and liver stages by impairing mitochondrial function.

Chloroquine is an antimalarial agent with strong activity against the blood stage of Plasmodium infection, but with low activity against the parasite's liver stage. In addition, the resistance to chloroquine limits its clinical use. The discovery of new molecules possessing multistage activity and overcoming drug resistance is needed. One possible strategy to achieve this lies in combining antimalarial quinolones with the pharmacological effects of transition metals. We investigated the antimalarial activity of four platinum(ii) complexes composed of chloroquine and phosphine ligands, denoted as WV-90, WV-92, WV-93 and WV-94. In comparison with chloroquine, the complexes were less potent against the chloroquine-sensitive 3D7 strain but they were as active as chloroquine in inhibiting the chloroquine-resistant W2 strain of P. falciparum. Regarding selectivity, the complexes WV-90 and WV-93 displayed higher indexes. Unlike chloroquine, the complexes act as irreversible parasiticidal agents against trophozoites and the WV-93 complex displayed activity against the hepatic stage of P. berghei. The in vivo suppression activity against P. berghei in the Peters 4 day test displayed by the complexes was similar to that of chloroquine. However, the efficacy in an established P. berghei infection in the Thompson test was superior for the WV-93 complex compared to chloroquine. The complexes' antimalarial mechanism of action is initiated by inhibiting the hemozoin formation. While chloroquine efficiently inhibits hemozoin, parasites treated with the platinum complexes display residual hemozoin crystals. This is explained since the interaction of the platinum complexes with ferriprotoporphyrin is weaker than that of chloroquine. However, the complexes caused a loss of mitochondrial integrity and subsequent reduction in mitochondrial activity, and their effects on mitochondria were more pronounced than those in the chloroquine-treated parasites. The dual effect of the platinum complexes may explain their activity against the hemozoin-lacking parasites (hepatic stage), where chloroquine has no activity. Our findings indicate that the platinum(ii)-chloroquine complexes are multifunctional antimalarial compounds and reinforce the importance of metal complexes in antimalarial drug discovery.