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In response to the spread of artemisinin (ART) resistance, ART-based hybrid drugs were developed, and their activity profile was characterized against drug-sensitive and drug-resistant Plasmodium falciparum parasites. Two hybrids were found to display parasite growth reduction, stage-specificity, speed of activity, additivity of activity in drug combinations, and stability in hepatic microsomes of similar levels to those displayed by dihydroartemisinin (DHA). Conversely, the rate of chemical homolysis of the peroxide bonds is slower in hybrids than in DHA. From a mechanistic perspective, heme plays a central role in the chemical homolysis of peroxide, inhibiting heme detoxification and disrupting parasite heme redox homeostasis. The hybrid exhibiting slow homolysis of peroxide bonds was more potent in reducing the viability of ART-resistant parasites in a ring-stage survival assay than the hybrid exhibiting fast homolysis. However, both hybrids showed limited activity against ART-induced quiescent parasites in the quiescent-stage survival assay. Our findings are consistent with previous results showing that slow homolysis of peroxide-containing drugs may retain activity against proliferating ART-resistant parasites. However, our data suggest that this property does not overcome the limited activity of peroxides in killing non-proliferating parasites in a quiescent state.
Assuntos
Antimaláricos , Artemisininas , Plasmodium falciparum , Artemisininas/farmacologia , Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Resistência a Medicamentos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Humanos , Testes de Sensibilidade Parasitária , Animais , Peróxidos/farmacologiaRESUMO
Drug modification by a fluorescent label is a common tool for studying its mechanism of action with fluorescence microscopy techniques. However, the attachment of a fluorescent label can significantly alter the polarity, solubility, and biological activity of the investigated drug, and, as a result, the studied mechanism of action can be misrepresented. Therefore, developing efficient drugs, which are inherently fluorescent and can be tracked directly in the cell is highly favorable. Here an easy formation of fluorescent hybrid drugs is presented, generated by a combination of two readily available non-fluorescent pharmacophores via a non-cleavable linker using a Ramachary-Bressy-Wang organocatalyzed azide-carbonyl [3+2] cycloaddition (organo-click) reaction. All newly prepared fluorescent compounds showed strong anti-HCMV activity (EC50 down to 0.07±0.00â µM), thus presenting a very promising drug developmental basis compared to the approved drug ganciclovir (EC50 2.60±0.50â µM). Remarkably, inâ vitro fluorescent imaging investigation of new compounds revealed induced changes in mitochondrial structures, which is a phenotypical hallmark of antiviral activity. This approach opens up new vistas for the easy formation of potent fluorescent drugs from readily available non-fluorescent parent compounds and might facilitate insight into their mode of action in living cells, avoiding the requirement of linkage to external fluorescent markers.
Assuntos
Antivirais , Artemisininas , Antivirais/farmacologia , Artemisininas/farmacologia , Microscopia de Fluorescência , Corantes , Benzimidazóis , Reação de Cicloadição , Química ClickRESUMO
Invited for the cover of this issue are Manfred Marschall, Svetlanaâ B. Tsogoeva and co-workers at Friedrich-Alexander University of Erlangen-Nürnberg. The image depicts a new anti-SARS-CoV-2 compound in front of SARS-CoV-2 viruses. Read the full text of the article at 10.1002/chem.202103861.
Assuntos
COVID-19 , Quinolinas , Técnicas de Cultura de Células , Humanos , SARS-CoV-2RESUMO
The presently ongoing pandemic of human SARS-CoV-2 infections (COVID-19) presents an enormous challenge in surveillance, vaccine and antiviral drug development. Here we report the synthesis of new bioactive quinoline-morpholine hybrid compounds and their virological evaluation, which proves pronounced cell culture-based inhibitory profile against SARS-CoV-2. Thus, selected quinoline compounds may suggest specific hit-to-lead development.
Assuntos
COVID-19 , Quinolinas , Antivirais/farmacologia , Técnicas de Cultura de Células , Humanos , Pandemias , Quinolinas/farmacologia , SARS-CoV-2RESUMO
Considerable progress has been made with the rather recently developed dimer approach, which has already found applications in the development of new effective artemisinin-derived antimalarial, anticancer, and antiviral agents. One observation common to these potential applications is the significant (i.e., much more than double) improvement in activity of artemisinin based dimers, which are not toxic to normal cells and have fewer or less harmful side effects, with respect to monomers against parasites, cancer cells and viruses. Due to the high potential of the dimerization concept, many new artemisinin-derived dimer compounds and their biological activities have been recently reported. In this review an overview of the synthesis of dimer drug candidates based on the clinically used drug artemisinin and its semisynthetic derivatives is given. Besides the highlighting of biological activities of the selected dimers, the main focus is set on different synthetic approaches toward the dimers containing a broad variety of symmetric and nonsymmetric linking moieties.
Assuntos
Antimaláricos , Antineoplásicos , Artemisininas , Antimaláricos/química , Antineoplásicos/química , Antivirais/química , Artemisininas/química , Dimerização , HumanosRESUMO
Enhanced electromagnetic fields in nanometer gaps of plasmonic structures increase the optical interaction with matter, including Raman scattering and optical absorption. Quantum electron tunneling across sub-1 nm gaps, however, lowers these effects again. Understanding these phenomena requires controlled variation of gap sizes. Mechanically actuated plasmonic antennas enable repeatable tuning of gap sizes from the weak-coupling over the quantum-electron-tunneling to the direct-electrical-contact regime. Gap sizes are controlled electrically via leads that only weakly disturb plasmonic modes. Conductance signals show a near-continuous transition from electron tunneling to metallic contact. As the antenna's absorption cross-section is reduced, thermal expansion effects are negligible, in contrast to conventional break-junctions. Optical scattering spectra reveal first continuous red shifts for decreasing gap sizes and then blue shifts below gaps of 0.3 nm. The approach provides pathways to study opto- and electromolecular processes at the limit of plasmonic sensing.
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Human cytomegalovirus (HCMV) is a major pathogenic herpesvirus that is prevalent worldwide and it is associated with a variety of clinical symptoms. Current antiviral therapy options do not fully satisfy the medical needs; thus, improved drug classes and drug-targeting strategies are required. In particular, host-directed antivirals, including pharmaceutical kinase inhibitors, might help improve the drug qualities. Here, we focused on utilizing PROteolysis TArgeting Chimeras (PROTACs), i.e., hetero-bifunctional molecules containing two elements, namely a target-binding molecule and a proteolysis-inducing element. Specifically, a PROTAC that was based on a cyclin-dependent kinase (CDK) inhibitor, i.e., CDK9-directed PROTAC THAL-SNS032, was analyzed and proved to possess strong anti-HCMV AD169-GFP activity, with values of EC50 of 0.030 µM and CC50 of 0.175 µM (SI of 5.8). Comparing the effect of THAL-SNS032 with its non-PROTAC counterpart SNS032, data indicated a 3.7-fold stronger anti-HCMV efficacy. This antiviral activity, as illustrated for further clinically relevant strains of human and murine CMVs, coincided with the mid-nanomolar concentration range necessary for a drug-induced degradation of the primary (CDK9) and secondary targets (CDK1, CDK2, CDK7). In addition, further antiviral activities were demonstrated, such as the inhibition of SARS-CoV-2 replication, whereas other investigated human viruses (i.e., varicella zoster virus, adenovirus type 2, and Zika virus) were found insensitive. Combined, the antiviral quality of this approach is seen in its (i) mechanistic uniqueness; (ii) future options of combinatorial drug treatment; (iii) potential broad-spectrum activity; and (iv) applicability in clinically relevant antiviral models. These novel data are discussed in light of the current achievements of anti-HCMV drug development.
Assuntos
Antivirais , Citomegalovirus , Inibidores de Proteínas Quinases , Animais , Humanos , Camundongos , Antivirais/farmacologia , Linhagem Celular , Quinase 9 Dependente de Ciclina , Citomegalovirus/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Inibidores de Proteínas Quinases/farmacologia , Replicação Viral/efeitos dos fármacos , ProteóliseRESUMO
Structural hybridization of preclinically and clinically validated pharmacologically active molecules has emerged as a promising tool to develop new generations of safe and highly efficient drug candidates against various diseases including microbial infections, virus infections and cancer. Strategies of drug-drug combinations have been adopted to generate hybrid conjugates of many clinically used drugs, designed to address inherent problems associated with these drugs. Thus, the design of hybrids was aimed to achieve higher efficacy through possible multi-target interactions, selective delivery of the drug to the site of action with the aim to improve bioavailability, alleviate toxicity and circumvent drug resistances. In this review article, we summarize the progress made in recent years in the rapidly growing field of drug discovery, focusing on the rationality of the hybrid design with particular emphasis on the linker architecture, which plays a crucial role in the overall success of a hybrid drug.
Assuntos
Anti-Infecciosos/química , Antineoplásicos/química , Desenho de Fármacos , Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Bactérias/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Testes de Sensibilidade Microbiana , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Vírus/efeitos dos fármacosRESUMO
Human cytomegalovirus (HCMV) is a major human pathogen associated with severe pathology. Current options of antiviral therapy only partly satisfy the needs of a well-tolerated long-term treatment/prophylaxis free from drug-induced viral resistance. Recently, we reported the strong antiviral properties in vitro and in vivo of the broad-spectrum anti-infective drug artesunate and its optimized derivatives. NF-κB signaling was described as a targeting mechanism and additional target proteins have recently been identified. Here, we analyzed the autofluorescent hybrid compound BG95, which could be utilized for intracellular visualization by confocal imaging and a tracking analysis in virus-infected primary human fibroblasts. As an important finding, BG95 accumulated in mitochondria visualized by anti-prohibitin and MitoTracker staining, and induced statistically significant changes of mitochondrial morphology, distinct from those induced by HCMV infection. Notably, mitochondrial membrane potential was found substantially reduced by BG95, an effect apparently counteracting efficient HCMV replication, which requires active mitochondria and upregulated energy levels. This finding was consistent with binding properties of artesunate-like compounds to mitochondrial proteins and thereby suggested a new mechanistic aspect. Combined, the present study underlines an important role of mitochondria in the multifaceted, host-directed antiviral mechanism of this drug class, postulating a new mitochondria-specific mode of protein targeting.
Assuntos
Antivirais/farmacologia , Artemisininas/farmacologia , Infecções por Citomegalovirus/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Antivirais/química , Artemisininas/química , Artesunato/análogos & derivados , Artesunato/farmacologia , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/virologia , Farmacorresistência Viral/efeitos dos fármacos , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Humanos , Mitocôndrias/genética , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/genética , Replicação Viral/efeitos dos fármacosRESUMO
Gold nanoparticles are separated above a planar gold film by 1.1 nm thick self-assembled molecular monolayers of different conductivities. Incremental replacement of the nonconductive molecules with a chemically equivalent conductive version differing by only one atom produces a strong 50 nm blue-shift of the coupled plasmon. With modeling this gives a conductance of 0.17G(0) per biphenyl-4,4'-dithiol molecule and a total conductance across the plasmonic junction of 30G(0). Our approach provides a reliable tool quantifying the number of molecules in each plasmonic hotspot, here <200.
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Au nanoparticles (NPs) deposited on a substrate function as ring shaped colloidal shadow masks. Using e-beam evaporation of gold, nanometer sized gaps are formed as a result. The size of these gaps can be accurately tuned by controlling the thickness of the gold deposition, thereby tuning the plasmonic coupling of the NPs with the substrate. The clean cavity produced between the Au NPs and the Au film provides an excellent SERS platform for trace molecule detection.
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We present a detailed theoretical analysis of the optical response of threaded plasmonic nanoparticle strings, chains of metallic nanoparticles connected by cylindrical metallic bridges (threads), based on full-electrodynamic calculations. The extinction spectra of these complex metallic nanostructures are dominated by large resonances in the near infrared, which are associated with charge transfer along the entire string. By analysing contour plots of the electric field amplitude and phase we show that such strings can be interpreted as an intermediate situation between metallic nanoparticle chains and metallic nanorods, exhibiting characteristics of both. Modifying the dielectric environment, the number of nanoparticles within the strings, and the dimensions of the threads, allows for tuning the optical response of the strings within a very broad region in the visible and near infrared.
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Malaria is one of the most widespread diseases worldwide. Besides a growing number of people potentially threatened by malaria, the consistent emergence of resistance against established antimalarial pharmaceuticals leads to an urge toward new antimalarial drugs. Hybridization of two chemically diverse compounds into a new bioactive product is a successful concept to improve the properties of a hybrid drug relative to the parent compounds and also to overcome multidrug resistance. 1,2,3-Triazoles are a significant pharmacophore system among nitrogen-containing heterocycles with various applications, such as antiviral, antimalarial, antibacterial, and anticancer agents. Several marketed drugs possess these versatile moieties, which are used in a wide range of medical indications. While the synthesis of hybrid compounds containing a 1,2,3-triazole unit was described using Cu- and Ru-catalyzed azide-alkyne cycloaddition, an alternative metal-free pathway has never been reported for the synthesis of antimalarial hybrids. However, a metal-free pathway is a green method that allows toxic and expensive metals to be replaced with an organocatalyst. Herein, we present the synthesis of new artemisinin-triazole antimalarial hybrids via a facile Ramachary-Bressy-Wang organocatalyzed azide-carbonyl [3 + 2] cycloaddition (organo-click) reaction. The prepared new hybrid compounds are highly potent in vitro against chloroquine (CQ)-resistant and multi-drug-resistant Plasmodium falciparum strains (IC50 (Dd2) down to 2.1 nM; IC50 (K1) down to 1.8 nM) compared to CQ (IC50 (Dd2) = 165.3 nM; IC50 (K1) = 302.8 nM). Moreover, the most potent hybrid drug was more efficacious in suppressing parasitemia and extending animal survival in Plasmodium berghei-infected mice (up to 100% animal survival and up to 40 days of survival time) than the reference drug artemisinin, illustrating the potential of the hybridization concept as an alternative and powerful drug-discovery approach.
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A fast dark-field scattering technique capturing full broadband spectra with millisecond time-resolution enables us to monitor the growth or assembly of single nano-objects in situ and in real time. Applying this technique to study the growth of single gold nanorods, together with scanning electron microscopy and finite-difference time-domain simulations, reveals precise quantitative information about gold nanorod growth kinetics.
Assuntos
Ouro/química , Nanopartículas Metálicas/química , Nanopartículas Metálicas/ultraestrutura , Análise Espectral/métodos , Microscopia de Força Atômica , Microscopia Eletrônica de Varredura , Modelos Teóricos , Nanotecnologia/métodosRESUMO
Following the impact of a single femtosecond light pulse on nickel nanostripes, material deformations-or "nanobumps"-are created. We have studied the dependence of these nanobumps on the length of nanostripes and verified the link with plasmons. More specifically, local electric currents can melt the nanostructures in the hotspots, where hydrodynamic processes give rise to nanobumps. This process is further confirmed by independently simulating local magnetic fields, since these are produced by the same local electric currents.
Assuntos
Elétrons , Nanoestruturas , Níquel/química , Condutividade ElétricaRESUMO
Malaria is one of our planet's most widespread and deadliest diseases, and there is an ever-consistent need for new and improved pharmaceuticals. Natural products have been an essential source of hit and lead compounds for drug discovery. Antimalarial drug artemisinin (ART), a highly effective natural product, is an enantiopure sesquiterpene lactone and occurs in Artemisia annua L. The development of improved antimalarial drugs, which are highly potent and at the same time inherently fluorescent is particularly favorable and highly desirable since they can be used for live-cell imaging, avoiding the requirement of the drug's linkage to an external fluorescent label. Herein, we present the first antimalarial autofluorescent artemisinin-coumarin hybrids with high fluorescence quantum yields of up to 0.94 and exhibiting excellent activity in vitro against CQ-resistant and multidrug-resistant P. falciparum strains (IC50 (Dd2) down to 0.5 nM; IC50 (K1) down to 0.3 nM) compared to reference drugs CQ (IC50 (Dd2) 165.3 nM; IC50 (K1) 302.8 nM) and artemisinin (IC50 (Dd2) 11.3 nM; IC50 (K1) 5.4 nM). Furthermore, a clear correlation between in vitro potency and in vivo efficacy of antimalarial autofluorescent hybrids was demonstrated. Moreover, deliberately designed autofluorescent artemisinin-coumarin hybrids, were not only able to overcome drug resistance, they were also of high value in investigating their mode of action via time-dependent imaging resolution in living P. falciparum-infected red blood cells.
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Starting in 2019, the spread of respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated pandemic of the corona virus disease (COVID-19) has led to enormous efforts in the development of medical countermeasures. Although innovative vaccines have scaled back the number of severe COVID cases, the emergence of the omicron variant (B.1.1.529) illustrates how vaccine development struggles to keep pace with viral evolution. On the other hand, while the recently approved antiviral drugs remdesivir, molnupiravir, and Paxlovid are considered as broadly acting anti-coronavirus therapeutics, only molnupiravir and Paxlovid are orally available and none of these drugs are recommended for prophylactic use. Thus, so far unexploited small molecules, targeting strategies, and antiviral mechanisms are urgently needed to address issues in the current pandemic and in putative future outbreaks of newly emerging variants of concern. Recently, we and others have described the anti-infective potential and particularly the pronounced antiviral activity of artesunate and related compounds of the trioxane/sesquiterpene class. In particular, the trimeric derivative TF27 demonstrated strong anti-cytomegalovirus activity at nanomolar concentrations in vitro as well as in vivo efficacy after oral administration in therapeutic and even prophylactic treatment settings. Here, we extended this analysis by evaluating TF27 for its anti-SARS-CoV-2 potential. Our main findings are as follows: (i) compound TF27 exerted strong anti-SARS-CoV-2 activity in vitro (EC50 = 0.46 ± 0.20 µM), (ii) antiviral activity was clearly distinct from the induction of cytotoxicity, (iii) pretreatment with TF27 prevented virus replication in cultured cells, (iv) antiviral activity has likewise been demonstrated in Calu-3 human lung and Caco-2 human colon cells infected with wild-type, delta, or omicron SARS-CoV-2, respectively, and (v) analysis of TF27 combination treatments has revealed synergistic interaction with GC376, but antagonistic interaction with EIDD-1931. Combined, the data demonstrated the pronounced anti-SARS-CoV-2 activity of TF27 and thus highlight the potential of trioxane compounds for further pharmacologic development towards improved options for COVID-specific medication.
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The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause life-threatening diseases in millions of people worldwide, in particular, in patients with cancer, and there is an urgent need for antiviral agents against this infection. While inâ vitro activities of artemisinins against SARS-CoV-2 and cancer have recently been demonstrated, no study of artemisinin and/or synthetic peroxide-based hybrid compounds active against both cancer and SARS-CoV-2 has been reported yet. However, the hybrid drug's properties (e. g., activity and/or selectivity) can be improved compared to its parent compounds and effective new agents can be obtained by modification/hybridization of existing drugs or bioactive natural products. In this study, a series of new artesunic acid and synthetic peroxide based new hybrids were synthesized and analyzed inâ vitro for the first time for their inhibitory activity against SARS-CoV-2 and leukemia cell lines. Several artesunic acid-derived hybrids exerted a similar or stronger potency against K562 leukemia cells (81-83 % inhibition values) than the reference drug doxorubicin (78 % inhibition value) and they were also more efficient than their parent compounds artesunic acid (49.2 % inhibition value) and quinoline derivative (5.5 % inhibition value). Interestingly, the same artesunic acid-quinoline hybrids also show inhibitory activity against SARS-CoV-2 inâ vitro (EC50 13-19â µm) and no cytotoxic effects on Vero E6 cells (CC50 up to 110â µM). These results provide a valuable basis for design of further artemisinin-derived hybrids to treat both cancer and SARS-CoV-2 infections.
Assuntos
Artemisininas , Tratamento Farmacológico da COVID-19 , Leucemia , Neoplasias , Quinolinas , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Artemisininas/farmacologia , Chlorocebus aethiops , Humanos , Leucemia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Peróxidos , Quinolinas/uso terapêutico , SARS-CoV-2 , Células VeroRESUMO
A recently developed artemisinin-quinoline hybrid, named 163A, has been shown to display potent activity against the asexual blood stage of Plasmodium, the malaria parasite. In this study, we determined its in vitro cytotoxicity to mammalian cells, its potency to suppress P. berghei hepatic infection and to decrease the viability of P. falciparum gametocytes, in addition to determining whether the drug exhibits efficacy of a P. berghei infection in mice. This hybrid compound has a low level of cytotoxicity to mammalian cells and, conversely, a high level of selectivity. It is potent in the prevention of hepatic stage development as well as in killing gametocytes, denoting a potential blockage of malaria transmission. The hybrid presents a potent inhibitory activity for beta-hematin crystal formation, in which subsequent assays revealed that its endoperoxide component undergoes bioactivation by reductive reaction with ferrous heme towards the formation of heme-drug adducts; in parallel, the 7-chloroquinoline component has binding affinity for ferric hemin. Both structural components of the hybrid co-operate to enhance the inhibition of beta-hematin, and this bitopic ligand property is essential for arresting the growth of asexual blood parasites. We demonstrated the in vivo efficacy of the hybrid as an erythrocytic schizonticide agent in comparison to a chloroquine/artemisinin combination therapy. Collectively, the findings suggest that the bitopic property of the hybrid is highly operative on heme detoxification suppression, and this provides compelling evidence for explaining the action of the hybrid on the asexual blood stage. For sporozoite and gametocyte stages, the hybrid conserves the potency typically observed for endoperoxide drugs, and this is possibly achieved due to the redox chemistry of endoperoxide components with ferrous heme.