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The late stage functionalization (LSF) of complex biorelevant compounds is a powerful tool to speed up the identification of structure-activity relationships (SARs) and to optimize ADME profiles. To this end, visible-light photocatalysis offers unique opportunities to achieve smooth and clean functionalization of drugs by unlocking site-specific reactivities under generally mild reaction conditions. This review offers a critical assessment of current literature, pointing out the recent developments in the field while emphasizing the expected future progress and potential applications. Along with paragraphs discussing the visible-light photocatalytic synthetic protocols so far available for LSF of drugs and drug candidates, useful and readily accessible synoptic tables of such transformations, divided by functional groups, will be provided, thus enabling a useful, fast, and easy reference to them.
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Luz , Preparações Farmacêuticas/síntese química , Catálise , Composição de Medicamentos , Preparações Farmacêuticas/química , Processos Fotoquímicos , Relação Estrutura-AtividadeRESUMO
Molecule interacting with CasL 2 (MICAL2), a cytoskeleton dynamics regulator, are strongly expressed in several human cancer types, especially at the invasive front, in metastasizing cancer cells and in the neo-angiogenic vasculature. Although a plethora of data exist and stress a growing relevance of MICAL2 to human cancer, it is worth noting that only one small-molecule inhibitor, named CCG-1423 (1), is known to date. Herein, with the aim to develop novel MICAL2 inhibitors, starting from CCG-1423 (1), a small library of new compounds was synthetized and biologically evaluated on human dermal microvascular endothelial cells (HMEC-1) and on renal cell adenocarcinoma (786-O) cells. Among the novel compounds, 10 and 7 gave interesting results in terms of reduction in cell proliferation and/or motility, whereas no effects were observed in MICAL2-knocked down cells. Aside from the interesting biological activities, this work provides the first structure-activity relationships (SARs) of CCG-1423 (1), thus providing precious information for the discovery of new MICAL2 inhibitors.
Assuntos
Anilidas , Benzamidas , Inibidores Enzimáticos , Proteínas dos Microfilamentos , Oxirredutases , Bibliotecas de Moléculas Pequenas , Humanos , Anilidas/química , Anilidas/farmacologia , Benzamidas/química , Benzamidas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Proteínas dos Microfilamentos/antagonistas & inibidores , Proteínas dos Microfilamentos/metabolismo , Estrutura Molecular , Oxirredutases/antagonistas & inibidores , Oxirredutases/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
A visible-light-promoted three-component isocyanide-based synthesis of iminofurans is herein reported. The reaction proved to be general in scope and proceeds through a triple domino process. Control experiments with 18O-labeled water and TEMPO provided key mechanistic insights for delineating the reactivity paradigms crucial to design efficient photoredox isocyanide-based domino transformations.
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The pandemic evolution of SARS-CoV-2 infection is forcing the scientific community to unprecedented efforts to explore all possible approaches against COVID-19. In this context, targeting virus entry is a promising antiviral strategy for controlling viral infections. The main strategies pursued to inhibit the viral entry are considering both the virus and the host factors involved in the process. Primarily, direct-acting antivirals rely on inhibition of the interaction between ACE2 and the receptor binding domain (RBD) of the Spike (S) protein or targeting the more conserved heptad repeats (HRs), involved in the membrane fusion process. The inhibition of host TMPRSS2 and cathepsins B/L may represent a complementary strategy to be investigated. In this review, we discuss the development entry inhibitors targeting the S protein, as well as the most promising host targeting strategies involving TMPRSS2 and CatB/L, which have been exploited so far against CoVs and other related viruses.
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Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Inibidores de Serina Proteinase/farmacologia , Internalização do Vírus/efeitos dos fármacos , Animais , Betacoronavirus/metabolismo , Betacoronavirus/fisiologia , Humanos , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/metabolismoRESUMO
Considering aryl azides as electrophilic partners for the TosMIC mediated Van Leusen reaction, a novel multicomponent synthesis of 4-tosyl-1-arylimidazoles is reported. In this transformation, two molecules of TosMIC participate in the reaction mechanism in two different ways, with the second molecule undergoing a novel type of fragmentation resulting in the incorporation of a C-H into the final product.
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A novel one-pot multicomponent reaction to synthesize substituted imidazopyrazines is described. In brief, 1H-(imidazol-5-yl)-N-substituted methanamines react with aldehydes and isocyanides in methanol at room temperature to give imidazopyrazine derivatives in excellent yields. The imidazole nitrogen atom was able to intercept the nascent nitrilium ion, channeling the reaction toward to the sole formation of imidazopyrazines, suppressing the competitive formation of other possible side products deriving from the reaction with the high-energy nitrilium ion. The number of examples and the variability of the nature of isocyanides, aldehydes, and amine components herein employed, witness the robustness of this novel methodology.
Assuntos
Cianetos/química , Imidazóis/síntese química , Nitrogênio/química , Pirazinas/síntese química , Aldeídos/química , Imidazóis/química , Estrutura Molecular , Pirazinas/químicaRESUMO
Dengue virus (DENV) is the leading mosquito-transmitted viral infection in the world. With more than 390 million new infections annually, and up to 1 million clinical cases with severe disease manifestations, there continues to be a need to develop new antiviral agents against dengue infection. In addition, there is no approved anti-DENV agents for treating DENV-infected patients. In the present study, we identified new compounds with anti-DENV replication activity by targeting viral replication enzymes - NS5, RNA-dependent RNA polymerase (RdRp) and NS3 protease, using cell-based reporter assay. Subsequently, we performed an enzyme-based assay to clarify the action of these compounds against DENV RdRp or NS3 protease activity. Moreover, these compounds exhibited anti-DENV activity in vivo in the ICR-suckling DENV-infected mouse model. Combination drug treatment exhibited a synergistic inhibition of DENV replication. These results describe novel prototypical small anti-DENV molecules for further development through compound modification and provide potential antivirals for treating DENV infection and DENV-related diseases.
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Antivirais/farmacologia , Vírus da Dengue/efeitos dos fármacos , Dengue/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Serina Endopeptidases/metabolismo , Animais , Antivirais/síntese química , Antivirais/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dengue/virologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , RNA Polimerase Dependente de RNA/metabolismo , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
Cannabinoid (CB) and opioid systems are both involved in analgesia, food intake, mood and behavior. Due to the co-localization of µ-opioid (MOR) and CB1 receptors in various regions of the central nervous system (CNS) and their ability to form heterodimers, bivalent ligands targeting to both these systems may be good candidates to investigate the existence of possible cross-talking or synergistic effects, also at sub-effective doses. In this work, we selected from a small series of new Rimonabant analogs one CB1R reverse agonist to be conjugated to the opioid fragment Tyr-D-Ala-Gly-Phe-NH2. The bivalent compound (9) has been used for in vitro binding assays, for in vivo antinociception models and in vitro hypothalamic perfusion test, to evaluate the neurotransmitters release.
Assuntos
Peptídeos Opioides/farmacologia , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Receptores Opioides/metabolismo , Animais , Humanos , Ligantes , Camundongos , Peptídeos Opioides/química , Peptídeos Opioides/metabolismo , Piperidinas/metabolismo , Pirazóis/metabolismo , RimonabantoRESUMO
Old multicomponent reactions are still a source of inspiration for discovering novel combinations of three or more reactants. A simple idea is to replace one of the educts of a known multicomponent reaction with another functional group and still be able to mimic the same reactivity. Following this line of thought, we report a three-component reaction in which isocyanides are able to open the epoxide intermediate of the Bargellini reaction affording 3-carboxamido-isobutyric acids in yields of 47-95%.
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Bacterial infections represent a key public health issue due to the occurrence of multidrug-resistant bacteria. Recently, the amount of data supporting the dynamic control of epigenetic pathways by environmental cues has triggered research efforts toward the clarification of their role in microbial infections. Among protein post-translational modifications, reversible acetylation is the most implicated in the feedback to environmental stimuli and in cellular homeostasis. Accordingly, the latest studies identified the histone deacetylase 6 (HDAC6) enzyme as a crucial player in the complex molecular machinery underlying bacterial clearance or killing. A very important milestone for the elucidation of the consequence of HDAC6 activity in bacterial infections is herein described, unveiling for the first time the role of a potent HDAC6 inhibitor in interfering with biofilm formation and modulating virulence factors of P. aeruginosa. We demonstrated that compound F2F-2020202 affected the production of some important virulence factors in P. aeruginosa, namely pyocyanin and rhamnolipids, clearly impairing its ability to form biofilm. Furthermore, evidence of possible QS involvement is supported by differential regulation of specific genes, namely RhlI, phAz1, and qsrO. The data herein obtained also complement and in part explain our previous results with selective HDAC6 inhibitors able to reduce inflammation and bacterial load in chronic infection models recapitulating the cystic fibrosis (CF) phenotype. This study fosters future in-depth investigation to allow the complete elucidation of the molecular mechanisms underlying HDAC6's role in bacterial infections.
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Photochemistry has emerged as a transformative force in organic chemistry, significantly expanding the chemical space accessible for medicinal chemistry. Light-induced reactions enable the efficient synthesis of intricate organic structures and have found applications throughout the different stages of the drug discovery and development processes. Moreover, photochemical techniques provide innovative solutions in chemical biology, allowing precise spatiotemporal drug activation and targeted delivery. In this Perspective, we highlight the already numerous remarkable applications and the even more promising future of photochemistry in medicinal chemistry and chemical biology.
Assuntos
Química Farmacêutica , Descoberta de Drogas , Fotoquímica , Química Farmacêutica/métodos , Descoberta de Drogas/métodos , BiologiaRESUMO
The widespread and irrational use of azole antifungal agents has led to an increase of azole-resistant Candida albicans strains with an urgent need for combination drug therapy, enhancing the treatment efficacy. Here, we report the discovery of a first-in-class pyrazole-isoxazole, namely, 5b, that showed remarkable growth inhibition against the C. albicans ATCC 10231 strain in combination with voriconazole, acting as a downregulator of ERG 11 (Cyp51) gene expression with a significant reduction of the yeast-to-hypha morphological transition. Furthermore, C. albicans CYP51 enzyme assay and in-depth molecular docking studies unveiled the unique ability of the combination of 5b and voriconazole to completely fill the CYP51 binding sites. In vivo studies using a Galleria mellonella model confirmed the previously in vitro observed synergistic effect of 5b with voriconazole. Also considering its biocompatibility in a cellular model of human keratinocytes, these results indicate that 5b represents a promising compound for a further optimization campaign.
Assuntos
Antifúngicos , Candida albicans , Farmacorresistência Fúngica , Isoxazóis , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Pirazóis , Voriconazol , Antifúngicos/farmacologia , Antifúngicos/química , Voriconazol/farmacologia , Candida albicans/efeitos dos fármacos , Pirazóis/farmacologia , Pirazóis/química , Animais , Humanos , Isoxazóis/farmacologia , Isoxazóis/química , Sinergismo Farmacológico , Mariposas/microbiologia , Mariposas/efeitos dos fármacos , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Modelos Animais de Doenças , Relação Estrutura-Atividade , Azóis/farmacologia , Azóis/química , Azóis/uso terapêuticoRESUMO
The efficacy, safety, and scale-up of several chemical rearrangements remain unsolved problems due to the associated handling of hazardous, toxic, and pollutant chemicals and high-risk intermediates. For many years batch processes have been considered the only possibility to drive these reactions, but continuous-flow technology has emerged, for both academic laboratories and pharmaceutical companies, as a powerful tool for easy, controlled, and safer chemistry protocols, helping to minimize the formation of side products and increase reaction yields. This Technology Note summarizes recently reported chemical rearrangements using continuous-flow approaches, with a focus on Curtius, Hofmann, and Schmidt reactions. Flow protocols, general advantages and safety aspects, and reaction scope for the generation of both privileged scaffolds and active pharmaceutical ingredients will be showcased.
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In recent years, photochemistry has increasingly emerged as an enabling methodology in both academia and the pharmaceutical industry. Long photolysis times and the gradual reduction of light penetration remained for many years unsolved issues for photochemical rearrangements, triggering the generation of highly reactive species in an uncontrolled fashion and causing the formation of multiple side products. The emergence of continuous-flow chemistry significantly helped to overcome these issues, thus prompting the implementation of photo-flow-based approaches for the generation of pharmaceutically relevant substructures. This Technology Note highlights the benefits of flow chemistry for photochemical rearrangements, including Wolff, Favorskii, Beckmann, Fries, and Claisen rearrangements. We showcase recent advances for photo-rearrangements in continuous flow applied to the synthesis of privileged scaffolds and active pharmaceutical ingredients.
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The [1,2,3]-triazolo [1,5-a] quinoxalin-4(5H)-one scaffold and its analogues triazole-fused heterocyclic compounds are relevant structural templates in both natural and synthetic biologically active compounds. However, their medicinal chemistry applications are often limited due to the lack of synthetic protocols combining straightforward generation of the central core while also allowing extensive decoration activity for drug discovery purposes. Herein, we report a "refreshed" synthesis of the [1,2,3]-triazolo [1,5-a]quinoxalin-4(5H)-one core, encompassing the use of eco-compatible catalysts and reaction conditions. We have also performed a sustainable and extensive derivatization campaign at both the endocyclic amide nitrogen and the ester functionality, comprehensively exploring the reaction scope and overcoming some of the previously reported difficulties in introducing functional groups on this structural template. Finally, we unveiled a preliminary biological investigation for the newly generated chemical entities. Our assessment of the compounds on different bacterial species (two S. aureus strains, three P. aeruginosa strains, K. pneumonia), and two fungal C. albicans strains, as well as the evaluation of their activity on S. epidermidis biofilm formation, foster further optimization for the retrieved hit compounds 9, 14, and 20.
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Despite the approval of vaccines, monoclonal antibodies and restrictions during the pandemic, the demand for new efficacious and safe antivirals is compelling to boost the therapeutic arsenal against the COVID-19. The viral 3-chymotrypsin-like protease (3CLpro) is an essential enzyme for replication with high homology in the active site across CoVs and variants showing an almost unique specificity for Leu-Gln as P2-P1 residues, allowing the development of broad-spectrum inhibitors. The design, synthesis, biological activity, and cocrystal structural information of newly conceived peptidomimetic covalent reversible inhibitors are herein described. The inhibitors display an aldehyde warhead, a Gln mimetic at P1 and modified P2-P3 residues. Particularly, functionalized proline residues were inserted at P2 to stabilize the ß-turn like bioactive conformation, modulating the affinity. The most potent compounds displayed low/sub-nM potency against the 3CLpro of SARS-CoV-2 and MERS-CoV and inhibited viral replication of three human CoVs, i.e. SARS-CoV-2, MERS-CoV, and HCoV 229 in different cell lines. Particularly, derivative 12 exhibited nM-low µM antiviral activity depending on the virus, and the highest selectivity index. Some compounds were co-crystallized with SARS-CoV-2 3CLpro validating our design. Altogether, these results foster future work toward broad-spectrum 3CLpro inhibitors to challenge CoVs related pandemics.
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COVID-19 , Coronavírus da Síndrome Respiratória do Oriente Médio , Peptidomiméticos , Humanos , SARS-CoV-2 , Inibidores de Proteases/química , Peptidomiméticos/farmacologia , Peptidomiméticos/química , Raios X , Peptídeo Hidrolases , Antivirais/químicaRESUMO
SARS-CoV-2 caused worldwide the current outbreak called COVID-19. Despite multiple countermeasures implemented, there is an urgent global need for new potent and efficient antiviral drugs against this pathogen. In this context, the main protease (Mpro) of SARS-CoV-2 is an essential viral enzyme and plays a pivotal role in viral replication and transcription. Its specific cleavage of polypeptides after a glutamine residue has been considered as a key element to design novel antiviral drugs. Herein, we reported the design, synthesis and structure-activity relationships of novel α-ketoamides as covalent reversible inhibitors of Mpro, exploiting the PADAM oxidation route. The reported compounds showed µM to nM activities in enzymatic and in the antiviral cell-based assays against SARS-CoV-2 Mpro. In order to assess inhibitors' binding mode, two co-crystal structures of SARS-CoV-2 Mpro in complex with our inhibitors were solved, which confirmed the covalent binding of the keto amide moiety to the catalytic Cys145 residue of Mpro. Finally, in order to interrogate potential broad-spectrum properties, we assessed a selection of compounds against MERS Mpro where they showed nM inhibitory potency, thus highlighting their potential as broad-spectrum coronavirus inhibitors.
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Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Humanos , Proteases 3C de Coronavírus , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Proteínas não Estruturais Virais , Cisteína Endopeptidases/metabolismo , Antivirais/farmacologia , Antivirais/química , Simulação de Acoplamento MolecularRESUMO
In the search for new drug-like selective G-quadruplex binders, a bioinspired design focused on the use of nucleobases as synthons in a multicomponent reaction was herein proved to be viable and successful. Hence, a new class of multifunctionalized imidazo[2,1-i]purine derivatives, easily synthesized with a convergent approach, allowed for the identification of the first dual BCL2/c-MYC gene promoter G-quadruplex ligand. Biophysical studies involving circular dichroism melting experiments, microscale thermophoresis measurements, NMR titrations, and computational docking calculations, as well as biological investigations including cytotoxicity and apoptotic assays, and quantitative polymerase chain reaction and Western blot analyses, were performed to assess the potency and to characterize the binding mode of the newly identified lead compound. The absence of toxicity toward normal cells, together with the small molecular weight (â 500 Da), the water solubility, the ease of functionalization, and the selectivity profile, are promising and desirable features to develop G-quadruplex binders as safe and effective anticancer agents.
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Antineoplásicos/metabolismo , Produtos Biológicos/química , Proteínas de Ligação a DNA/metabolismo , Desenho de Fármacos , Quadruplex G , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fatores de Transcrição/metabolismo , Antineoplásicos/química , Produtos Biológicos/metabolismo , Proteínas de Ligação a DNA/antagonistas & inibidores , Células HCT116 , Humanos , Imidazóis/química , Imidazóis/metabolismo , Células Jurkat , Células MCF-7 , Simulação de Acoplamento Molecular/métodos , Ligação Proteica/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Purinas/química , Purinas/metabolismo , Fatores de Transcrição/antagonistas & inibidoresRESUMO
The function of p53 protein, also known as "genome guardian", might be impaired by the overexpression of its primary cellular inhibitor, the murine double minute 2 protein (MDM2). However, the recent finding that MDM2-selective inhibitors induce high levels of its homologue MDM4, prompt us to identify, through a receptor-based virtual screening on an in house database, dual MDM2/MDM4 binders. Compound 1 turned out to possess an IC50 of 93.7 and of 4.6 nM on MDM2 and MDM4, respectively. A series of compounds were synthesized to optimize its activity on MDM2. As a result, compound 12 showed low nanomolar IC50 for both targets. NMR studies confirmed the pocket of binding of 12 as predicted by the Glide docking software. Notably, 12 was able to cause concentration-dependent inhibition of cell proliferation, yielding an IC50 value of 356 ± 21 nM in neuroblastoma SHSY5Y cells and proved even to efficiently block cancer stem cell growth.
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Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho Assistido por Computador , Desenho de Fármacos , Genes p53 , Ensaios de Triagem em Larga Escala , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Células-Tronco Neoplásicas , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
New 1,1'-biphenylsulfonamides were synthesized and evaluated as inhibitors of the ubiquitous human carbonic anhydrase isoforms I, II, IX, XII, and XIV using acetazolamide (AAZ) as reference compound. The sulfonamides 1-21 inhibited all the isoforms, with Ki values in the nanomolar range of concentration, and were superior to AAZ against all of them. X-ray crystallography and molecular modeling studies on the adducts that compound 20, the most potent hCA XIV inhibitor of the series (Ki = 0.26 nM), formed with the five hCAs, provided insight into the molecular determinants responsible for the high affinity of this molecule toward the target enzymes. The results pave the way to the development of 1.1'-biphenylsulfonamides as a new class of highy potent hCA XIV inhibitors.