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1.
Eur J Med Chem ; 276: 116666, 2024 Jul 10.
Article in English | MEDLINE | ID: mdl-39002436

ABSTRACT

Alopecia has emerged as a global concern, extending beyond the middle-aged and elderly population and increasingly affecting younger individuals. Despite its growing prevalence, the treatment options and effective drugs for alopecia remain limited due to the incomplete understanding of its underlying mechanisms. Therefore, it is urgent to explore the pathogenesis of alopecia and discover novel and safer therapeutic agents. This review provided an overview of the prevailing clinical disorders of alopecia, and the key pathways and targets involved in hair growth process. Additionally, it discusses FDA-approved drugs and clinical candidates for the treatment of alopecia, and explores small molecule compounds with anti-alopecia potential in the drug discovery phase. These endeavors are expected to provide researchers with valuable scientific insights and practical information for anti-alopecia drug discovery.

2.
Curr Drug Targets ; 2024 Jul 04.
Article in English | MEDLINE | ID: mdl-38967077

ABSTRACT

Neglected diseases are a group of infectious diseases, many of them parasitic, that mainly affect the poorest populations with limited access to health services, especially those living in remote rural areas and slums. According to the World Health Organization (WHO), neglected diseases put the lives of more than 200 million people at risk, and treatment is made difficult by the occurrence of resistance to existing medications, as well as the high level of toxicity. In this way, the potential of multitarget compounds is highlighted, defined as compounds designed to modulate multiple targets of relevance to disease, with the overall goal of enhancing efficacy and/or improving safety. Thus, the objective of our study is to evaluate existing multi-target compound approaches for neglected diseases, with an emphasis on Leishmaniasis, Chagas Disease, and Arboviruses. A literature review was performed by searching the database "Web of Sciences". In relation to the diseases covered in this work, Leishmaniasis, individually, was the one that presented the largest number of articles (11) that dealt with the topic, which can be justi-fied by the high prevalence of this disease in the world, the second most common disease was Dengue, followed by Chagas disease, Chikungunya virus, and Zika virus. Furthermore, the multi-target potential of phenolic compounds was observed in all diseases under study, with the mecha-nisms related to the nucleus and transcription being the most reported mechanisms. From this per-spective, it is worth highlighting the effectiveness of approaches related to multitarget drugs in discovering new therapeutic agents for neglected diseases.

3.
BMC Med Educ ; 24(1): 738, 2024 Jul 09.
Article in English | MEDLINE | ID: mdl-38982322

ABSTRACT

BACKGROUND: The purpose of this study was to evaluate the effectiveness and efficiency of implementing a data-driven blended online-offline (DDBOO) teaching approach in the medicinal chemistry course. METHODS: A total of 118 third-year students majoring in pharmacy were enrolled from September 2021 to January 2022. The participants were randomly assigned to either the DDBOO teaching group or the traditional lecture-based learning (LBL) group for medicinal chemistry. Pre- and post-class quizzes were administered, along with an anonymous questionnaire distributed to both groups to assess students' perceptions and experiences. RESULTS: There was no significant difference in the pre-class quiz scores between the DDBOO and LBL groups (T=-0.637, P = 0.822). However, after class, the mean quiz score of the DDBOO group was significantly higher than that of the LBL group (T = 3.742, P < 0.001). Furthermore, the scores for learning interest, learning motivation, self-learning skill, mastery of basic knowledge, teamwork skills, problem-solving ability, innovation ability, and satisfaction, as measured by the questionnaire, were significantly higher in the DDBOO group than in the traditional group (all P < 0.05). CONCLUSION: The DDBOO teaching method effectively enhances students' academic performance and satisfaction. Further research and promotion of this approach are warranted.


Subject(s)
Chemistry, Pharmaceutical , Education, Pharmacy , Educational Measurement , Students, Pharmacy , Female , Humans , Male , Young Adult , Chemistry, Pharmaceutical/education , Computer-Assisted Instruction/methods , Curriculum , Education, Distance , Education, Pharmacy/methods , Surveys and Questionnaires
4.
Molecules ; 29(13)2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38999041

ABSTRACT

Oleanolic acid (OA) is a vegetable chemical that is present naturally in a number of edible and medicinal botanicals. It has been extensively studied by medicinal chemists and scientific researchers due to its biological activity against a wide range of diseases. A significant number of researchers have synthesized a variety of analogues of OA by modifying its structure with the intention of creating more potent biological agents and improving its pharmaceutical properties. In recent years, chemical and enzymatic techniques have been employed extensively to investigate and modify the chemical structure of OA. This review presents recent advancements in medical chemistry for the structural modification of OA, with a special focus on the biotransformation, semi-synthesis and relationship between the modified structures and their biopharmaceutical properties.


Subject(s)
Oleanolic Acid , Oleanolic Acid/chemistry , Oleanolic Acid/analogs & derivatives , Oleanolic Acid/chemical synthesis , Oleanolic Acid/metabolism , Humans , Biotransformation , Structure-Activity Relationship , Molecular Structure , Animals
5.
Molecules ; 29(12)2024 Jun 20.
Article in English | MEDLINE | ID: mdl-38931004

ABSTRACT

Potassium channels have recently emerged as suitable target for the treatment of epileptic diseases. Among potassium channels, KCNT1 channels are the most widely characterized as responsible for several epileptic and developmental encephalopathies. Nevertheless, the medicinal chemistry of KCNT1 blockers is underdeveloped so far. In the present review, we describe and analyse the papers addressing the issue of KCNT1 blockers' development and identification, also evidencing the pros and the cons of the scientific approaches therein described. After a short introduction describing the epileptic diseases and the structure-function of potassium channels, we provide an extensive overview of the chemotypes described so far as KCNT1 blockers, and the scientific approaches used for their identification.


Subject(s)
Chemistry, Pharmaceutical , Epilepsy , Potassium Channel Blockers , Humans , Potassium Channel Blockers/chemistry , Potassium Channel Blockers/therapeutic use , Potassium Channel Blockers/pharmacology , Chemistry, Pharmaceutical/methods , Epilepsy/drug therapy , Epilepsy/metabolism , Structure-Activity Relationship , Animals , Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Anticonvulsants/therapeutic use , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/chemistry , Nerve Tissue Proteins/metabolism , Potassium Channels, Tandem Pore Domain/antagonists & inhibitors , Potassium Channels, Tandem Pore Domain/metabolism , Potassium Channels, Tandem Pore Domain/chemistry , Potassium Channels, Voltage-Gated/antagonists & inhibitors , Potassium Channels, Voltage-Gated/metabolism , Potassium Channels, Sodium-Activated
6.
Bioorg Med Chem ; 109: 117797, 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-38879995

ABSTRACT

This perspective underscores the rising challenge posed by emerging diseases against the backdrop of modern advancements in global public health understanding. It particularly highlights the emergence of the Oropouche virus (OROV) as a significant global threat, detailing its transmission dynamics, symptoms, and epidemiological impact, with a focus on its historical and current manifestations. It further delves into the molecular aspects of OROV, elucidating its unique characteristics, lack of structural similarity with other arboviruses, and the limited progress in medicinal chemistry research. Still, it highlights notable studies on potential antiviral agents and the challenges in drug development, emphasizing the need for innovative approaches such as structure-based drug design (SBDD) and drug repurposing. Finally, it concludes with a call to action, urging increased attention and research focus on OROV to prevent potential future pandemics fueled by viral mutations.


Subject(s)
Antiviral Agents , Orthobunyavirus , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Humans , Bunyaviridae Infections/drug therapy , Animals , Molecular Structure
7.
Biomed Chromatogr ; : e5932, 2024 Jun 23.
Article in English | MEDLINE | ID: mdl-38922712

ABSTRACT

Abnormal relaxation and contraction of intestinal smooth muscle can cause various intestinal diseases. Diarrhea is a common and important public health problem worldwide in epidemiology. Zingiber officinale Roscoe (fresh ginger) has been found to treat diarrhea, but the material basis and mechanism of action that inhibits intestinal peristalsis remain unclear. Metabolomics and serum pharmacology were used to identify differential metabolites, metabolic pathways, and pharmacodynamic substances, and were then combined with network pharmacology to explore the potential targets of ginger that inhibit intestinal peristalsis during diarrhea treatment, and the targets identified were verified using molecular docking and molecular dynamic simulation. We found that 25 active components of ginger (the six most relevant components), 35 potential key targets (three core targets), 40 differential metabolites (four key metabolites), and four major metabolic pathways were involved in the process by which ginger inhibits intestinal peristalsis during diarrhea treatment. This study reveals the complex mechanism of action and pharmacodynamic material basis of ginger in the inhibition of intestinal peristalsis, and this information helps in the development of new Chinese medicine to treat diarrhea and lays the foundation for the clinical application of ginger.

8.
ChemMedChem ; : e202400384, 2024 Jun 26.
Article in English | MEDLINE | ID: mdl-38924676

ABSTRACT

The N-benzyl piperidine (N-BP) structural motif is commonly employed in drug discovery due to its structural flexibility and three-dimensional nature. Medicinal chemists frequently utilize the N-BP motif as a versatile tool to fine-tune both efficacy and physicochemical properties in drug development. It provides crucial cation-π interactions with the target protein and also serves as a platform for optimizing stereochemical aspects of potency and toxicity. This motif is found in numerous approved drugs and clinical/preclinical candidates. This review focuses on the applications of the N-BP motif in drug discovery campaigns, emphasizing its role in imparting medicinally relevant properties. We provide an overview of approved drugs, the clinical and preclinical pipeline, and discuss its utility for specific therapeutic targets and indications, along with potential challenges.

9.
Mini Rev Med Chem ; 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38920071

ABSTRACT

Finding the most perfect drug candidates in the fields of drug discovery and medicinal chemistry will remain the main interest of drug designers. This concern necessitates organic and medicinal chemists, in most examples, to precisely design and search for drug candidates that are very analogous to the present effective drugs for solving, mainly, their proven critical pharmacological and clinical issues through slightly changing one or two atoms of the principal functional skeletons of the molecules of present therapeutics by atom swapping, removal, and/or addition procedures in organic chemical synthesis. This accurate modern chemicosimilarity tactic in drug discovery surely saves time while keeping us very close, or sometimes highly superior, to the parent pharmacophoric bioactivity (i.e., keeping considerable analogy to the parent therapeutic molecule). From this perspective and logic, the science of skeletal editing of molecules (i.e., skeletal molecular editing) arose in the era of artificial intelligence (AI) and its dramatic predictions. As a pioneer in this modern branch in pharmaceutical and therapeutic organic chemistry, in this up-to-date minireview and perspective article, an attempt was made to introduce skeletal editing and its synthetic surgeries (over molecules) to the audience (including irrelevant readers) in a simpler and more attractive way as a novel chemical technology, highlighting the previous synthetic trials (in general), demonstrating the three main techniques, and, finally, discussing the future therapeutic needs and scenarios from a medicinal chemist's viewpoint.

10.
ChemMedChem ; : e202400284, 2024 Jun 27.
Article in English | MEDLINE | ID: mdl-38932712

ABSTRACT

A conserved intracellular allosteric binding site (IABS) was recently identified at several G protein-coupled receptors (GPCRs). This target site allows the binding of allosteric modulators and enables a new mode of GPCR inhibition. Herein, we report the development of a NanoBRET-based assay platform based on the fluorescent ligand LT221 (5), to detect intracellular binding to CCR6 and CXCR1, two chemokine receptors that have been pursued as promising drug targets in inflammation and immuno-oncology. Our assay platform enables cell-free as well as cellular NanoBRET-based binding studies in a nonisotopic and straightforward manner. By combining this screening platform with a previously reported CXCR2 assay, we investigated CXCR1/CXCR2/CCR6 selectivity profiles for both known and novel squaramide analogues derived from navarixin, a known intracellular CXCR1/CXCR2 antagonist and phase II clinical candidate for the treatment of pulmonary diseases. By means of these studies we identified compound 10, a previously reported tert-butyl analogue of navarixin, as a low nanomolar intracellular CCR6 antagonist. Further, our assay platform clearly indicated intracellular binding of the CCR6 antagonist PF-07054894, currently evaluated in phase I clinical trials for the treatment of ulcerative colitis, thereby providing profound evidence for the existence and the pharmacological relevance of a druggable IABS at CCR6.

11.
Angew Chem Int Ed Engl ; : e202410954, 2024 Jun 20.
Article in English | MEDLINE | ID: mdl-38900650

ABSTRACT

The 2,2-difluoroethyl group is an important lipophilic hydrogen bond donor in medicinal chemistry, but its incorporation into small molecules is often challenging. Herein, we demonstrate electrophilic 2,2-difluoroethylation of thiol, amine and alcohol nucleophiles with a hypervalent iodine reagent, (2,2-difluoro-ethyl)(aryl)iodonium triflate, via a proposed ligand coupling mechanism. This transformation offers a complementary strategy to existing 2,2-difluoroethylation methods and allows access to a wide range of 2,2-difluoroethylated nucleophiles, including the drugs Captopril, Normorphine and Mefloquine.

12.
ChemMedChem ; : e202400063, 2024 May 22.
Article in English | MEDLINE | ID: mdl-38778500

ABSTRACT

The chemical and biological interest in this element and the molecules bearing selenium has been exponentially growing over the years. Selenium, formerly designated as a toxin, becomes a vital trace element for life that appears as selenocysteine and its dimeric form, selenocystine, in the active sites of selenoproteins, which catalyze a wide variety of reactions, including the detoxification of reactive oxygen species and modulation of redox activities. From the point of view of drug developments, organoselenium drugs are isosteres of sulfur-containing and oxygen-containing drugs with the advantage that the presence of the selenium atom confers antioxidant properties and high lipophilicity, which would increase cell membrane permeation leading to better oral bioavailability. This statement is the paramount relevance considering the big number of clinically employed compounds bearing sulfur or oxygen atoms in their structures including nucleosides and carbohydrates. Thus, in this article we have focused on the relevant features of the application of selenium in medicinal chemistry. With the increasing interest in selenium chemistry, we have attempted to highlight the most significant published data on this subject, mainly concentrating the analysis on the last years. In consequence, the recent advances of relevant pharmacological organoselenium compounds are discussed.

13.
Chemistry ; : e202401559, 2024 May 24.
Article in English | MEDLINE | ID: mdl-38787350

ABSTRACT

Porphyrin atropisomerism, which arises from restricted σ-bond rotation between the macrocycle and a sufficiently bulky substituent, was identified in 1969 by Gottwald and Ullman in 5,10,15,20-tetrakis(o-hydroxyphenyl)porphyrins. Henceforth, an entirely new field has emerged utilizing this transformative tool. This review strives to explain the consequences of atropisomerism in porphyrins, the methods which have been developed for their separation and analysis and present the diverse array of applications. Porphyrins alone possess intriguing properties and a structure which can be easily decorated and molded for a specific function. Therefore, atropisomerism serves as a transformative tool, making it possible to obtain even a specific molecular shape. Atropisomerism has been thoroughly exploited in catalysis and molecular recognition yet presents both challenges and opportunities in medicinal chemistry.

14.
Curr Pharm Teach Learn ; 16(9): 102095, 2024 May 16.
Article in English | MEDLINE | ID: mdl-38755059

ABSTRACT

INTRODUCTION: Medicinal chemistry instruction in PharmD programs at Canadian universities is considered an important foundational science. However, with few guidelines for the required content most programs have observed a decrease in hours of medicinal chemistry instruction. A Medicinal Chemistry Special Interest Group (SIG) was formed to address these issues nationally and initiated a pan-Canadian environmental scan to better understand the depth and breadth of medicinal chemistry instruction. METHODS: The SIG carried out an environmental scan to identify medicinal chemistry content, delivery and assessments in PharmD programs in Canada. RESULTS: Core medicinal chemistry concepts across the PharmD programs are in general agreement with those listed by the Accreditation Council for Pharmacy Education. Medicinal chemistry was typically taught as didactic lectures either as a standalone course or within a pharmacology course, although one program integrated some medicinal chemistry within therapeutics focused problem-based learning. There was no consistent time in program where medicinal chemistry occurred. CONCLUSIONS: The SIG found that similar medicinal chemistry content is taught across all Canadian PharmD programs, but incorporation of medicinal chemistry in therapeutics courses was minimal. Core concepts within six high-level overarching themes that guide our collective instruction were identified. The core concepts require developing high-level cognitive processes such as knowledge application and synthesis that practicing pharmacists are expected to possess for entry to practice. We the authors posit that in addition to providing a unique tool for pharmacists to employ in therapeutic decision-making, medicinal chemistry also provides early practice of important problem-solving and critical thinking skills.

15.
Eur J Med Chem ; 273: 116522, 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38801799

ABSTRACT

The growing number of scientific papers and document sources underscores the need for methods capable of evaluating the quality of publications. Researchers who are looking for relevant papers for their studies need ways to assess the scientific value of these documents. One approach involves using semantic search engines that can automatically extract important knowledge from the growing body of text. In this study, we introduce a new metric called "MAATrica," which serves as the foundation for an innovative method designed to evaluate research papers. MAATrica offers a new way to analyze and categorize text, focusing on the consistency of research documents in the life sciences, particularly in the fields of medicinal and nutraceutical chemistry. This method utilizes semantic descriptions to cover in silico experiments, as well as in vitro and in vivo essays. Created to aid in evaluation processes like peer review, MAATrica uses toolkits and semantic applications to build the proposed measure, identify scientific entities, and gather information. We have applied MAATrica to roughly 90,000 papers and present our findings here.


Subject(s)
Dietary Supplements , Dietary Supplements/analysis , Chemistry, Pharmaceutical , Humans , Semantics
16.
Bioorg Med Chem ; 106: 117749, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38744018

ABSTRACT

Aberrant RET kinase signaling is activated in numerous cancers including lung, thyroid, breast, pancreatic, and prostate. Recent approvals of selective RET inhibitors, pralsetinib and selpercatinib, has shifted the focus of RET kinase drug discovery programs towards the development of selective inhibitors. However, selective inhibitors invariably lose efficacy as the selective nature of the inhibitor places Darwinian-like pressure on the tumor to bypass treatment through the selection of novel oncogenic drivers. Further, selective inhibitors are restricted for use in tumors with specific genetic backgrounds that do not encompass diverse patient classes. Here we report the identification of a pyrimido indole RET inhibitor found to also have activity against TRK. This selective dual RET/TRK inhibitor can be utilized in tumors with both RET and TRK genetic backgrounds and can also provide blockade of NTRK-fusions that are selected for from RET inhibitor treatments. Efforts towards developing dual RET/TRK inhibitors can be beneficial in terms of encompassing more diverse patient classes while also achieving blockade against emerging resistance mechanisms.


Subject(s)
Indoles , Protein Kinase Inhibitors , Proto-Oncogene Proteins c-ret , Receptor, trkA , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Drug Discovery , Indoles/chemistry , Indoles/pharmacology , Indoles/chemical synthesis , Molecular Structure , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins c-ret/antagonists & inhibitors , Proto-Oncogene Proteins c-ret/metabolism , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrimidines/chemical synthesis , Receptor, trkA/antagonists & inhibitors , Receptor, trkA/metabolism , Structure-Activity Relationship
17.
Data Brief ; 54: 110417, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38698799

ABSTRACT

Bemis-Murcko scaffolding [1] is a powerful tool for compound clustering and subsequent analysis. Here, using ChEMBL database [2] and RDKit library [3], we have compiled the dataset of known small molecule drugs, their molecular scaffolds and associated medical indications augmented with the interactive interface. We present these data, which can be used by medicinal chemists to find most promising scaffolds for their tasks using an interactive visualization that can help to evaluate both the diversity of known drugs and pharmacological promiscuity of each particular scaffold visually. Our scripts, that are freely available, can help to carry out such scaffold-based analysis and to visualize a compound library in a similar way.

18.
Bioorg Med Chem ; 106: 117755, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38749343

ABSTRACT

Translesion synthesis (TLS) is a cellular mechanism through which actively replicating cells recruit specialized, low-fidelity DNA polymerases to damaged DNA to allow for replication past these lesions. REV1 is one of these TLS DNA polymerases that functions primarily as a scaffolding protein to organize the TLS heteroprotein complex and ensure replication occurs in the presence of DNA lesions. The C-Terminal domain of REV1 (REV1-CT) forms many protein-protein interactions (PPIs) with other TLS polymerases, making it essential for TLS function and a promising drug target for anti-cancer drug development. We utilized several lead identification strategies to identify various small molecules capable of disrupting the PPI between REV1-CT and the REV1 Interacting Regions (RIR) present in several other TLS polymerases. These lead compounds were profiled in several in vitro potency and PK assays to identify two scaffolds (1 and 6) as the most promising for further development. Both 1 and 6 synergized with cisplatin in a REV1-dependent fashion and demonstrated promising in vivo PK and toxicity profiles.


Subject(s)
Nucleotidyltransferases , Small Molecule Libraries , Nucleotidyltransferases/antagonists & inhibitors , Nucleotidyltransferases/metabolism , Humans , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Small Molecule Libraries/chemical synthesis , Animals , Structure-Activity Relationship , Protein Binding , Molecular Structure , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Dose-Response Relationship, Drug , DNA-Directed DNA Polymerase/metabolism , Mice , Translesion DNA Synthesis
20.
Chem Pharm Bull (Tokyo) ; 72(5): 422-431, 2024.
Article in English | MEDLINE | ID: mdl-38692857

ABSTRACT

Natural products are important for the development of pharmaceuticals and agrochemicals; thus, their synthesis and medicinal chemistry research is critical. Developing a total synthesis pathway for natural products confirms their structure and provides the opportunity to modify the structure in a targeted manner. A simple modification of a single oxidation step can increase the biological activity, or the complexity of the molecule can alter the property. Herein, we discuss the asymmetric total synthesis of dihydroisocoumarin-type natural products, the creation of novel antibacterial compounds through partial structural modification, and the development of antioxidants with high activity and low toxicity through dimerization strategies.


Subject(s)
Anti-Bacterial Agents , Biological Products , Drug Discovery , Biological Products/chemistry , Biological Products/chemical synthesis , Biological Products/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antioxidants/chemical synthesis , Antioxidants/chemistry , Antioxidants/pharmacology , Molecular Structure , Humans
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