Drugs and Drug Candidates最新文献

{"title":"MET-Targeting Anticancer Drugs—De Novo Design and Identification by Drug Repurposing","authors":"K. To, K. Leung, W. C. Cho","doi":"10.3390/ddc2030031","DOIUrl":"https://doi.org/10.3390/ddc2030031","url":null,"abstract":"The Met protein is a cell surface receptor tyrosine kinase predominantly expressed in epithelial cells. Aberrant regulation of MET is manifested by numerous mechanisms including amplification, mutations, deletion, fusion of the MET proto-oncogene, and protein overexpression. They represent the common causes of drug resistance to conventional and targeted chemotherapy in numerous cancer types. There is also accumulating evidence that MET/HGF signaling drives an immunosuppressive tumor microenvironment and dampens the efficacy of cancer immunotherapy. Substantial research effort has been invested in designing Met-targeting drugs with different mechanisms of action. In this review, we summarized the current preclinical and clinical research about the development of Met-targeting drugs for cancer therapeutics. Early attempts to evaluate Met-targeted therapies in clinical trials without selecting the appropriate patient population did not produce satisfactory outcomes. In the era of personalized medicine, cancer patients harboring MET exon 14 alterations or MET amplification have been found to respond well to Met-inhibitor therapy. The application of Met inhibitors to overcome drug resistance in cancer patients is discussed in this paper. Given that kinases play critical roles in cancer development, numerous kinase-mediated signaling pathways are attractive targets for cancer therapy. Existing kinase inhibitors have also been repurposed to new kinase targets or new indications in cancer. On the other hand, non-oncology drugs have also been repurposed for treating cancer through kinase inhibition as one of their reported anticancer mechanisms.","PeriodicalId":131152,"journal":{"name":"Drugs and Drug Candidates","volume":"1884 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123347119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug Candidates for the Treatment of Alzheimer’s Disease: New Findings from 2021 and 2022","authors":"Sujatha L. Motebennur, B. Nandeshwarappa, M. Katagi","doi":"10.3390/ddc2030030","DOIUrl":"https://doi.org/10.3390/ddc2030030","url":null,"abstract":"Alzheimer’s disease (AD), an ongoing neurodegenerative disorder among the elderly, is signalized by amnesia, progressive deficiency in cognitive roles, and behavioral deformity. Over the last ten years, its pathogenesis still remains unclear despite several efforts from various researchers across the globe. There are certain factors that seem to be involved in the progression of the disease such as the accumulation of β-amyloid, oxidative stress, the hyperphosphorylation of tau protein, and a deficit of acetylcholine (ACh). Ongoing therapeutics are mainly based on the cholinergic hypothesis, which suggests that the decrease in the ACh levels leads to the loss of memory. Therefore, increasing the cholinergic function seems to be beneficial. Acetylcholinesterase inhibitors (AChEIs) inhibit the enzyme by avoiding the cleavage of acetylcholine (ACh) and increasing the neurotransmitter acetylcholine (ACh) levels in the brain areas. Thus, the cholinergic deficit is the root cause of Alzheimer’s disease (AD). Currently, drugs such as tacrine, donepezil, rivastigmine, and galantamine have been launched on the market for a cholinergic approach to AD to increase neurotransmission at cholinergic synapses in the brain and to improve cognition. These commercialized medicines only provide supportive care, and there is a loss of medicinal strength over time. Therefore, there is a demand for investigating a novel molecule that overcomes the drawbacks of commercially available drugs. Therefore, butyrylcholinesterase (BChE), amyloid-β (Aβ), β-secretase-1 (BACE), metals Cu(II), Zn(II), or Fe(II), antioxidant properties, and the free radical scavenging capacity have been primarily targeted in the preceding five years along with targeting the AChE enzyme. A desired, well-established pharmacological profile with a number of hybrid molecules incorporating substructures within a single scaffold has been investigated. From distinct chemical categories such as acridine, quinoline, carbamate, huperzine, and other heterocyclic analogs, the main substructures used in developing these molecules are derived. The optimization of activity through structural modifications of the prototype molecules has been followed to develop the Structure Activity Relationship (SAR), which in turn facilitates the development of novel molecules with expected AChE inhibitory activity together with many more pharmacological properties. The present review outlines the current drug candidates in the advancement of these AChEIs in the last two years.","PeriodicalId":131152,"journal":{"name":"Drugs and Drug Candidates","volume":"32 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129833389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Algal Nanoparticles and Their Antibacterial Activity: Current Research Status and Future Prospectives","authors":"Maheswari Behera, Prateek Ranjan Behera, Prajna Paramita Bhuyan, Lakshmi Singh, Biswajita Pradhan","doi":"10.3390/ddc2030029","DOIUrl":"https://doi.org/10.3390/ddc2030029","url":null,"abstract":"Green nanotechnology is a promising technology that has a wide range of applications in pharmaceuticals today because they offer a higher surface-area-to-volume ratio. Algal-based nanoparticles (NPs) are the subject of intense research interest today for their potential to treat and prevent infections caused by infectious microorganisms that are antibiotic resistant. Algae contain a variety of therapeutically potential bioactive ingredients, including chlorophyll, phycobilin, phenolics, flavonoids, glucosides, tannins, and saponins. As a result, NPs made from algae could be used as therapeutic antimicrobials. Due to their higher surface-area-to-volume ratios compared to their macroscopic components, metallic nanoparticles are more reactive and have toxic effects on their therapy. For pharmaceutical and biomedical applications, green synthesis restricts the use of physical and chemical methods of metallic nanoparticle synthesis, and it can be carried out in an environmentally friendly and relatively low-cost manner. The majority of macroalgae and some microalgae have latent antimicrobial activity and are used in the synthesis of metallic nanoparticles. A potential application in the field of nanomedicine and the establishment of a potential pharmacophore against microorganisms may result from the synthesis of algal-based NPs. Only a few studies have been done on the potential antimicrobial, antifungal, and antibacterial activity of algae-based NPs. As a result, the study will concentrate on the environmentally friendly synthesis of various NPs and their therapeutic potential, with a focus on their antibacterial activity. Thus, the aim of this study is to review all the literature available on the synthesis and characterization of the algal nanoparticles and their potential application as an antibacterial agent.","PeriodicalId":131152,"journal":{"name":"Drugs and Drug Candidates","volume":"54 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122394664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drugs of the Kallikrein–Kinin System: An Overview","authors":"F. Marceau","doi":"10.3390/ddc2030028","DOIUrl":"https://doi.org/10.3390/ddc2030028","url":null,"abstract":"The kallikrein–kinin system consists of the two kininogen substrates present in the blood plasma, and two serine proteases: the plasma and tissue kallikreins. The action of the latter on kininogens produces small peptides, the kinins, short-lived, but endowed by powerful pharmacologic actions on blood vessels and other tissues. Many recent and exciting therapeutic developments in the field are briefly summarized. Notably, various novel strategies are being clinically developed to inhibit the formation of bradykinin or block its receptors in the management of hereditary angioedema. The interventions include orally bioavailable drugs, biotechnological proteins, and gene therapy. These approaches are currently explored in a variety of other inflammatory and thrombotic disorders. Harnessing controlled kinin formation is also of potential therapeutic interest, as shown by the clinical development of recombinant tissue kallikrein for ischemic stroke and renal disease. The biomarkers of kinin-mediated disorders, frequently implicating edemas, include the consumption of kininogen(s), plasma kallikrein activity, and the detection of circulating kinin metabolites such as fragments BK1–5 and BK2–9. Novel opportunities to clinically apply the underexploited drugs of the kallikrein–kinin system are briefly reviewed. This personal perspective is offered by an observer of and a participant in drug characterization throughout the last four decades.","PeriodicalId":131152,"journal":{"name":"Drugs and Drug Candidates","volume":"33 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124821429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Black Cumin Seed (Nigella sativa) in Inflammatory Disorders: Therapeutic Potential and Promising Molecular Mechanisms","authors":"Hager K. Rashwan, Shahenda Mahgoub, Nermeen Z Abuelezz, Hatem K. Amin","doi":"10.3390/ddc2020027","DOIUrl":"https://doi.org/10.3390/ddc2020027","url":null,"abstract":"Inflammation is an essential defense mechanism against harmful stimuli. However, uncontrolled inflammatory mechanisms culminate in disturbed responses that contribute to multiple serious diseases. Besides common synthetic drugs, there is a growing interest in optimizing the use of natural products as therapeutic or protective supplements against inflammatory disorders. Black cumin seed (BCS), or Nigella sativa (Family Ranunculaceae), is widely used as a health-supportive herb in the Middle East, Far East and West Asia. BCS is a rich source of phytochemicals, and studies have reported its promising effects against a variety of metabolic, proliferative, respiratory, and neurological disorders associated with disrupted inflammatory pathways. This review presents an updated comprehensive assessment of BCS’s effects against various inflammatory disorders and highlights the role of BCS’s bioactive constituents in inflammation and oxidative stress pathways. Moreover, it outlines the future possibilities for enhancing therapeutic activity through efficient pharmaceutical formulations. Thorough analysis of international research studies published between the years 1998 and 2023 reveals the promising anti-inflammatory potential of BCS’s bioactive constituents through modulating inflammation and crucial oxidative stress players in inflammatory disorders. Thus, the bioactive constituents of BCS can be further boosted by updated technologies such as nano-incorporation for the improved management of inflammatory diseases.","PeriodicalId":131152,"journal":{"name":"Drugs and Drug Candidates","volume":"32 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127295048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antimicrobial Nanoformulations Based on Schinus areira Essential Oil","authors":"A. Cutró, Anike P V Ferreyra Maillard, Pablo R. Dalmasso, S. Rodriguez, A. Hollmann","doi":"10.3390/ddc2020026","DOIUrl":"https://doi.org/10.3390/ddc2020026","url":null,"abstract":"The goal of this research was to create an antibacterial formulation from Scinus areira essential oil (EO) that could spread in water. To achieve this, we developed liposomal formulations of DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine) or DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) that encapsulated the EO. In addition, we utilized the EO as a reducing and stabilizing agent to synthesize silver nanoparticles (AgNPs). The nanoformulations were characterized by determining their size and zeta potential. In the case of liposomal formulations, chemical composition, and encapsulation efficiency were also determined. Furthermore, antimicrobial activity studies against Gram-positive and Gram-negative model bacteria were carried out for both kinds of formulations. The results obtained showed the successful encapsulation of the S. areira EO in multilamellar liposomes of phosphatidylcholine with high efficiency. DPPC liposomes have proven to be a better encapsulation system, retaining more monoterpenes from the EO and therefore presenting antimicrobial activity against S. aureus with an minimal inhibitory concentration (MIC) value of 3 mg/mL of EO. On the other hand, it was also possible to obtain AgNPs by using S. areira EO, which showed antimicrobial activity against S. aureus and E. coli at low concentrations of EO, with MIC values of 6.68 µg/mL and 3.4 µg/mL of silver, respectively. The data obtained will contribute to enhancing the biotechnological value of natural products derived from native plant species in Argentina. This will be achieved through the generation of novel formulations with antibacterial activity and potential bioavailability.","PeriodicalId":131152,"journal":{"name":"Drugs and Drug Candidates","volume":"58 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130356352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The (–)-Borneol Effect on Addiction/Abstinence by Morphine in Mice","authors":"Maurício P. M. Amaral, Melquisedeque da Rocha Viana, Altamiro Teixeira Osório, Luciano da Silva Lopes, F. P. M. D. Amaral, M. Lucarini, A. Durazzo, D. Arcanjo, R. C. M. Oliveira","doi":"10.3390/ddc2020025","DOIUrl":"https://doi.org/10.3390/ddc2020025","url":null,"abstract":"Opioids such as morphine are the first choice in acute and chronic pain treatment. However, they lead to addiction. Several studies have searched (i) to find a molecule that can replace morphine use or (ii) to reduce its adverse effects. This work aimed to evaluate whether (–)-Borneol [(–)-BOR], a bicyclic monoterpene, in doses of 25, 50, and 100 mg/kg (i.p.), has an antiaddictive effect on morphine (5 mg/kg, i.p.) and reduces its withdrawal symptoms precipitated by naloxone (8 mg/kg, i.p.) in Swiss mice. Furthermore, the (–)-BOR genotoxic potential was also investigated by the comet assay. The antiaddictive effect of (–)-BOR was evaluated by the conditioned preference place (CPP). The CPP was induced by morphine administration during the conditioning phase. The effects of (–)-BOR on the rewarding characteristics of morphine were tested in mice with the administration of (–)-BOR, naloxone, or vehicle (NaCl 0.9%), 30 min before morphine. This work also investigated the (–)-BOR effect on morphine withdrawal symptoms precipitated by naloxone. Morphine withdrawal symptoms were induced by administering morphine twice daily for 5 days, precipitated by naloxone administration on the sixth day. The effect of (–)-BOR on reducing morphine withdrawal symptoms was evaluated in mice that received (–)-BOR before daily morphine administration. Finally, the comet assay was performed to assess the DNA damage degree caused by the (–)-BOR (100 mg/kg, i.p.) administration. The comet assay was performed on peripheral blood taken from the tail of each animal. Cyclophosphamide (50 mg/kg, i.p.) was used to induce DNA damage. After starting the protocol, analyses were performed for 4 h (acute effect) and 24 h (repair effect). The (–)-BOR (100 mg/kg, i.p.) significantly attenuated (*** p < 0.001) the acquisition of morphine-induced CPP and reduced only the jumping behavior in the morphine withdrawal model. The best-studied dose was 100 mg/kg, being evaluated, then, in the comet assay. (–)-BOR at 100 mg/kg did not show the genotoxic effect when compared with the cyclophosphamide group (CYCLO, 50 mg/kg, i.p.) after 4 h or 24 h, a period that corresponded to the repair time of DNA fragmentation. The study showed that (–)-BOR attenuated the acquisition of CPP by morphine and made opioid withdrawal milder. In the comet assay, although (–)-BOR caused DNA damage, this damage was significantly less than the damage by CYCLO, at either 4 h or 24 h after the treatments.","PeriodicalId":131152,"journal":{"name":"Drugs and Drug Candidates","volume":"48 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127226162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Vitro Evaluation of Arylsulfonamide Derivatives against Trypanosoma cruzi","authors":"P. Júnior, S. Murta/, J. G. Taylor","doi":"10.3390/ddc2020024","DOIUrl":"https://doi.org/10.3390/ddc2020024","url":null,"abstract":"Chagas disease is caused by the parasite protozoan Trypanosoma cruzi (T. cruzi) and affects millions of people in over 21 countries in around the world. The main forms of treatment of this disease, benznidazole and nifurtimox, present low cure rates in the chronic phase and often have serious side effects. Herein, we describe the evaluation of the trypanocidal activity of arylsulfonamides. The arylsulfonamides were evaluated in vitro against the amastigote and trypomastigote forms of the parasite. An enantiomerically pure example of arylsulfonamide was also tested. The initial results suggest that the arylsulfonamides evaluated act as DNA binding agents. A moderate activity was monitored against the intracellular forms of T. cruzi, with the best compound exhibiting an IC50 value at 22 μM and a selectivity index of 120. However, the level of activity was not favorable for progressing towards in vivo studies for Chagas disease.","PeriodicalId":131152,"journal":{"name":"Drugs and Drug Candidates","volume":"11 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134391438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selinexor and Other Selective Inhibitors of Nuclear Export (SINEs)—A Novel Approach to Target Hematologic Malignancies and Solid Tumors","authors":"Kajetan Karaszewski, W. Jędrzejczak","doi":"10.3390/ddc2020023","DOIUrl":"https://doi.org/10.3390/ddc2020023","url":null,"abstract":"Exportin 1 (XPO1) is a crucial molecule of nucleocytoplasmic transport. Among others, it exports molecules important for oncogenesis from the nucleus to the cytoplasm. The expression of XPO1 is increased in numerous malignancies, which contributes to the abnormal localization of tumor suppressor proteins in the cytoplasm and subsequent cell cycle dysregulation. Selective inhibitors of nuclear export (SINEs) are novel anticancer agents that target XPO1, arrest tumor suppressor proteins in the nucleus, and induce apoptosis in cancer cells. Selinexor, a first-in-class SINE, has already been approved for the treatment of relapsed/refractory multiple myeloma and relapsed/refractory diffuse large B cell lymphoma not otherwise specified. It has also been proven effective in relapsed/refractory and previously untreated acute myeloid leukemia patients. In addition, numerous studies have yielded promising results in other malignancies of the hematopoietic system and solid tumors. However, future clinical use of selinexor and other SINEs may be hampered by their significant toxicity.","PeriodicalId":131152,"journal":{"name":"Drugs and Drug Candidates","volume":"104 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124743231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of the N501Y Mutation on Ligands Complexed with SARS-CoV-2 RBD: Insights on Potential Drug Candidates for COVID-19","authors":"Camila Fonseca Amorim da Silva, Samanta Omae Camalhonte, Michell de Oliveira Almeida, S. C. Araujo, M. Sannomiya, J. Lago, K. M. Honório","doi":"10.3390/ddc2020022","DOIUrl":"https://doi.org/10.3390/ddc2020022","url":null,"abstract":"Bioactive compounds against SARS-CoV-2 targets could be potential treatments for COVID-19. Inhibitors of the receptor-binding domain (RBD) on the viral spike protein can block its binding to the human angiotensin-converting enzyme type II (ACE2) receptor. This study presents ligands based on natural products and synthetic compounds, targeting multiple N501/Y501 RBDs, besides RBD-ACE2, over different regions. The selected compounds were evaluated by docking using consensus scoring, pharmacokinetics/toxicological analyses, and molecular dynamics. Additionally, N501/Y501 RBD-ACE2 interaction properties and RBD–ligand complexes were compared. We identified that coenzyme Q10, 1-stearoyl-2-arachidonoylglycerol, and palmitone showed the greatest RBD interactions. Targeting specific residues (in particular, tyrosine) in the C-, N-terminal, and central RBD sites promoted more stable protein–ligand interactions than in the N-terminal region only. Our results indicate that the molecules had more energetically favorable interactions with residues from distinct RBD regions rather than only interacting with residues in the N-terminal site. Moreover, the compounds might better interact with mutated N501Y than N501 RBDs. These hits can be optimized to leads and investigated through QSAR models and biological assays to comprehend mechanisms better. Altogether, such strategies may anticipate antiviral strategies if or when future variants and other CoVs arise.","PeriodicalId":131152,"journal":{"name":"Drugs and Drug Candidates","volume":"9 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121544503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}