Medicinal Chemistry Community Research Articles

Deciphering the enigmas of non-nucleoside reverse transcriptase inhibitors (NNRTIs): A medicinal chemistry expedition towards combating HIV drug resistance.

The pivotal involvement of reverse transcriptase activity in the pathogenesis of the progressive HIV virus has stimulated gradual advancements in drug discovery initiatives spanning three decades. Consequently, nonnucleoside reverse transcriptase inhibitors (NNRTIs) have emerged as a preeminent category of therapeutic agents for HIV management. Academic institutions and pharmaceutical companies have developed numerous NNRTIs, an essential component of antiretroviral therapy. Six NNRTIs have received Food and Drug Administration approval and are widely used in clinical practice, significantly improving the quality of HIV patients. However, the rapid emergence of drug resistance has limited the effectiveness of these medications, underscoring the necessity for perpetual research and development of novel therapeutic alternatives. To supplement the existing literatures on NNRTIs, a comprehensive review has been compiled to synthesize this extensive dataset into a comprehensible format for the medicinal chemistry community. In this review, a thorough investigation and meticulous analysis were conducted on the progressions achieved in NNRTIs within the past 8 years (2016-2023), and the experiences and insights gained in the development of inhibitors with varying chemical structures were also summarized. The provision of a crucial point of reference for the development of wide-ranging anti-HIV medications is anticipated.

Catalytic Asymmetric Construction of Chiral Polysubstituted 3-Azabicyclo[3.1.1]heptanes by Copper-Catalyzed Stereoselective Formal [4π+2σ] Cycloaddition.

The direct construction of bioisosteric compounds enriched in Csp3 content represents an attractive and dependable approach to imbuing biologically active molecules with enhanced three-dimensional characteristics, finding wide utility across the synthetic and medicinal chemistry community. Despite recent advancements in the synthesis of (aza)-bicyclo[3.1.1]heptanes (BCHeps and aza-BCHeps), which serve as meta-substituted (aza)-arene bioisosteres, the enantioselective assembly of chiral 3-aza-BCHeps remains a coveted goal yet to be achieved. Here, we disclose an unprecedented copper-catalyzed asymmetric formal [4π+2σ] cycloaddition of bicyclo[1.1.0]butanes (BCBs) and azomethine ylides, furnishing a diverse array of enantioenriched 3-aza-BCHeps with exceptional levels of diastereo- and enantioselectivites (51 examples, all >20:1 dr, mostly 97-99% ee). Both mono- and disubstituted BCBs are well compatible with this protocol, offering an enticing route for the efficient synthesis of challenging tetrasubstituted bicyclic products bearing two quaternary centers. The synthetic significance of this methodology is further demonstrated by the successful preparation of several piperidine drug analogues.

New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives.

In recent years, synthetic lethality has been recognized as a solid paradigm for anticancer therapies. The discovery of a growing number of synthetic lethal targets has led to a significant expansion in the use of synthetic lethality, far beyond poly(ADP-ribose) polymerase inhibitors used to treat BRCA1/2-defective tumors. In particular, molecular targets within DNA damage response have provided a source of inhibitors that have rapidly reached clinical trials. This Perspective focuses on the most recent progress in synthetic lethal targets and their inhibitors, within and beyond the DNA damage response, describing their design and associated therapeutic strategies. We will conclude by discussing the current challenges and new opportunities for this promising field of research, to stimulate discussion in the medicinal chemistry community, allowing the investigation of synthetic lethality to reach its full potential.

Asymmetric Carbene Transfer: Enhancing Chemical Diversity for Drug Discovery.

The quest to explore chemical space is vital for identifying novel disease targets, impacting both the effectiveness and safety profile of therapeutic agents. The tangible chemical space, currently estimated at a conservative 108 synthesized compounds, pales in comparison to the theoretically conceivable diversity of 1060 molecules. To bridge this vast gap, organic chemists are spearheading innovative methodologies that promise to broaden this limited chemical diversity. A beacon of this progressive wave is Asymmetric Carbene Transfer (ACT), a burgeoning strategy that significantly boosts molecular diversity with efficient bond-formation and precise chiral control. This review focuses on the capabilities of ACT in creating pharmaceutically significant molecules, encompassing an array of natural products and bioactive compounds. Through the lens of ACT, we discern its substantial influence on drug discovery, paving the way for novel therapeutic avenues by expanding the boundaries of molecular diversity. This review will shed light on prospective methodological developments of ACT and articulate their conceivable contributions to the medicinal chemistry arena.

Gas Delivery Relevant to Human Health using Porous Materials.

Gases are essential for various applications relevant to human health, including in medicine, biomedical imaging, and pharmaceutical synthesis. However, gases are significantly more challenging to safely handle than liquids and solids. Herein, we review the use of porous materials, such as metal-organic frameworks (MOFs), zeolites, and silicas, to adsorb medicinally relevant gases and facilitate their handling as solids. Specific topics include the use of MOFs and zeolites to deliver H2S for therapeutic applications, 129Xe for magnetic resonance imaging, O2 for the treatment of cancer and hypoxia, and various gases for use in organic synthesis. This Perspective aims to bring together the organic, inorganic, medicinal, and materials chemistry communities to inspire the design of next-generation porous materials for the storage and delivery of medicinally relevant gases.

Reaction Paradigms that Leverage Cycloaddition and Ring Strain to Construction Bicyclic Aryl Bioisosteres from Bicyclo[1.1.0]butanes

AbstractWithin a medicinal chemist's toolbox, one of the most effective strategies to improve the overall properties of a biologically active compound is bioisosteric replacement. Ever since the first example of replacing benzene with a bicyclo[1.1.1]pentane (BCP) group was published in the late 1990s,[1] the medicinal chemistry community has continually been expanding the scope of such phenyl bioisosteric replacements. Recent interest from academia has focused on novel synthetic strategies to access C(sp3)‐rich bicyclic hydrocarbons with expanded ring sizes. Herein, we summarize some of these transformations and reveal that most rely on strain releasing cycloadditions with bicyclo[1.1.0]butane (BCB) and bicyclo[2.1.0]pentane (housane). We have organized this review based on the mechanism of such strain release strategies, namely, carbene cycloadditions, energy transfer photocatalyzed cycloadditions, electron transfer catalyzed cycloadditions, and polar cycloadditions.

C−F bond activation enables synthesis of aryl difluoromethyl bicyclopentanes as benzophenone-type bioisosteres

Bioisosteric design has become an essential approach in the development of drug molecules. Recent advancements in synthetic methodologies have enabled the rapid adoption of this strategy into drug discovery programs. Consequently, conceptionally innovative practices would be appreciated by the medicinal chemistry community. Here we report an expeditous synthetic method for synthesizing aryl difluoromethyl bicyclopentane (ADB) as a bioisostere of the benzophenone core. This approach involves the merger of light-driven C−F bond activation and strain-release chemistry under the catalysis of a newly designed N-anionic-based organic photocatalyst. This defluorinative coupling methodology enables the direct conversion of a wide variety of commercially available trifluoromethylaromatic C−F bonds (more than 70 examples) into the corresponding difluoromethyl bicyclo[1.1.1]pentanes (BCP) arenes/difluoromethyl BCP boronates in a single step. The strategy can also be applied to [3.1.1]and [4.1.1]propellane systems, providing access to analogues with different geometries. Moreover, we have successfully used this protocol to rapidly prepare ADB-substituted analogues of the bioactive molecule Adiporon. Biological testing has shown that the ADB scaffold has the potential to enhance the pharmacological properties of benzophenone-type drug candidates.

Discovery and Optimization of WDR5 Inhibitors via Cascade Deoxyribonucleic Acid-Encoded Library Selection Approach.

The DNA-encoded library (DEL) is a powerful hit generation tool for chemical biology and drug discovery; however, the optimization of DEL hits remained a daunting challenge for the medicinal chemistry community. In this study, hit compounds targeting the WIN binding domain of WDR5 were discovered by the initial three-cycle linear DEL selection, and their potency was further enhanced by a cascade DEL selection from the focused DEL designed based on the original first run DEL hits. As expected, these new compounds from the second run of focused DEL were more potent WDR5 inhibitors in the protein binding assay confirmed by the off-DNA synthesis. Interestingly, selected inhibitors exhibited good antiproliferative activity in two human acute leukemia cell lines. Taken together, this new cascade DEL selection strategy may have tremendous potential for finding high-affinity leads against WDR5 and provide opportunities to explore and optimize inhibitors for other targets.

Podophyllotoxin: Recent Advances in the Development of Hybridization Strategies to Enhance Its Antitumoral Profile.

Podophyllotoxin is a naturally occurring cyclolignan isolated from rhizomes of Podophyllum sp. In the clinic, it is used mainly as an antiviral; however, its antitumor activity is even more interesting. While podophyllotoxin possesses severe side effects that limit its development as an anticancer agent, nevertheless, it has become a good lead compound for the synthesis of derivatives with fewer side effects and better selectivity. Several examples, such as etoposide, highlight the potential of this natural product for chemomodulation in the search for new antitumor agents. This review focuses on the recent chemical modifications (2017-mid-2023) of the podophyllotoxin skeleton performed mainly at the C-ring (but also at the lactone D-ring and at the trimethoxyphenyl E-ring) together with their biological properties. Special emphasis is placed on hybrids or conjugates with other natural products (either primary or secondary metabolites) and other molecules (heterocycles, benzoheterocycles, synthetic drugs, and other moieties) that contribute to improved podophyllotoxin bioactivity. In fact, hybridization has been a good strategy to design podophyllotoxin derivatives with enhanced bioactivity. The way in which the two components are joined (directly or through spacers) was also considered for the organization of this review. This comprehensive perspective is presented with the aim of guiding the medicinal chemistry community in the design of new podophyllotoxin-based drugs with improved anticancer properties.

Explainable artificial intelligence: A taxonomy and guidelines for its application to drug discovery

AbstractArtificial intelligence (AI) is having a growing impact in many areas related to drug discovery. However, it is still critical for their adoption by the medicinal chemistry community to achieve models that, in addition to achieving high performance in their predictions, can be trusty explained to the end users in terms of their knowledge and background. Therefore, the investigation and development of explainable artificial intelligence (XAI) methods have become a key topic to address this challenge. For this reason, a comprehensive literature review about explanation methodologies for AI based models, focused in the field of drug discovery, is provided. In particular, an intuitive overview about each family of XAI approaches, such as those based on feature attribution, graph topologies, or counterfactual reasoning, oriented to a wide audience without a strong background in the AI discipline is introduced. As the main contribution, we propose a new taxonomy of the current XAI methods, which take into account specific issues related with the typical representations and computational problems study in the design of molecules. Additionally, we also present the main visualization strategies designed for supporting XAI approaches in the chemical domain. We conclude with key ideas about each method category, thoroughly providing insightful analysis about the guidelines and potential benefits of their adoption in medical chemistry.This article is categorized under: Data Science > Artificial Intelligence/Machine Learning

The Hitchhiker's Guide to Deep Learning Driven Generative Chemistry.

This microperspective covers the most recent research outcomes of artificial intelligence (AI) generated molecular structures from the point of view of the medicinal chemist. The main focus is on studies that include synthesis and experimental in vitro validation in biochemical assays of the generated molecular structures, where we analyze the reported structures' relevance in modern medicinal chemistry and their novelty. The authors believe that this review would be appreciated by medicinal chemistry and AI-driven drug design (AIDD) communities and can be adopted as a comprehensive approach for qualifying different research outcomes in AIDD.

Non-steroidal CYP17A1 Inhibitors: Discovery and Assessment.

CYP17A1 is an enzyme that plays a major role in steroidogenesis and is critically involved in the biosynthesis of steroid hormones. Therefore, it remains an attractive target in several serious hormone-dependent cancer diseases, such as prostate cancer and breast cancer. The medicinal chemistry community has been committed to the discovery and development of CYP17A1 inhibitors for many years, particularly for the treatment of castration-resistant prostate cancer. The current Perspective reflects upon the discovery and evaluation of non-steroidal CYP17A1 inhibitors from a medicinal chemistry angle. Emphasis is placed on the structural aspects of the target, key learnings from the presented chemotypes, and design guidelines for future inhibitors.

Multicomponent Reaction-Assisted Drug Discovery: A Time- and Cost-Effective Green Approach Speeding Up Identification and Optimization of Anticancer Drugs.

Multicomponent reactions (MCRs) have emerged as a powerful strategy in synthetic organic chemistry due to their widespread applications in drug discovery and development. MCRs are flexible transformations in which three or more substrates react to form structurally complex products with high atomic efficiency. They are being increasingly appreciated as a highly exploratory and evolutionary tool by the medicinal chemistry community, opening the door to more sustainable, cost-effective and rapid synthesis of biologically active molecules. In recent years, MCR-based synthetic strategies have found extensive application in the field of drug discovery, and several anticancer drugs have been synthesized through MCRs. In this review, we present an overview of representative and recent literature examples documenting different approaches and applications of MCRs in the development of new anticancer drugs.

Discovery of Linvencorvir (RG7907), a Hepatitis B Virus Core Protein Allosteric Modulator, for the Treatment of Chronic HBV Infection.

Described herein is the first-time disclosure of Linvencorvir (RG7907), a clinical compound and a hepatitis B virus (HBV) core protein allosteric modulator, for the treatment of chronic HBV infection. Built upon the core structure of hetero aryl dihydropyrimidine, RG7907 was rationally designed by combining all the drug-like features of low CYP3A4 induction, potent anti-HBV activity, high metabolic stability, low hERG liability, and favorable animal pharmacokinetic (PK) profiles. In particular, the chemistry strategy to mitigate CYP3A4 induction through introducing a large, rigid, and polar substituent at the position that has less interaction with the therapeutic biological target (HBV core proteins herein) is of general interest to the medicinal chemistry community. RG7907 demonstrated favorable animal PK, pharmacodynamics, and safety profiles with sufficient safety margins supporting its clinical development in healthy volunteers and HBV-infected patients.

Sugars in Multicomponent Reactions: A Toolbox for Diversity-Oriented Synthesis

AbstractMulticomponent reactions (MCRs) cover strategically employed chemical transformations that incorporate three or more reactants in one pot leading to a functionalized final product. Thus, it is an ideal tool to achieve high levels of complexity, diversity, yields of desired products, atom economy, and reduced reaction times. Sugars belong to the class of naturally occurring compounds with fascinating applications in the field of drug discovery due to the presence of various hydroxy groups and well-defined stereochemistry. However, their potential in MCRs has been realized only recently. This account describes recent advances in the synthesis of sugar-derived heterocycles synthesized by MCRs. We hope to encourage the synthetic and medicinal chemistry community to apply this powerful MCR chemistry to generate novel glycoconjugate challenges.1 Introduction2 Synthesis of Various Functionalized Sugar Compounds2.1 Passerini and Ugi Multicomponent Reactions2.2 Petasis Reaction2.3 Hantzsch Reaction2.4 Domino Ferrier–Povarov Reaction2.5 Marckwald Reaction2.6 Groebke–Blackburn–Bienaymé (GBB) Reaction2.7 Prins–Ritter Reaction2.8 Debus–Radziszewski Imidazole Synthesis Reaction2.9 Mannich Reaction2.10 A3-Coupling Reaction2.11 [3+2]-Cycloaddition Reactions2.12 Miscellaneous Reactions3 Conclusion

Screening the Pathogen Box to Discover and Characterize New Cruzain and TbrCatL Inhibitors

Chagas disease and Human African Trypanosomiasis, caused by Trypanosoma cruzi and T. brucei, respectively, pose relevant health challenges throughout the world, placing 65 to 70 million people at risk each. Given the limited efficacy and severe side effects associated with current chemotherapy, new drugs are urgently needed for both diseases. Here, we report the screening of the Pathogen Box collection against cruzain and TbrCatL, validated targets for Chagas disease and Human African Trypanosomiasis, respectively. Enzymatic assays were applied to screen 400 compounds, validate hits, determine IC50 values and, when possible, mechanisms of inhibition. In this case, 12 initial hits were obtained and ten were prioritized for follow-up. IC50 values were obtained for six of them (hit rate = 1.5%) and ranged from 0.46 ± 0.03 to 27 ± 3 µM. MMV687246 was found to be a mixed inhibitor of cruzain (Ki = 57 ± 6 µM) while MMV688179 was found to be a competitive inhibitor of cruzain with a nanomolar potency (Ki = 165 ± 63 nM). A putative binding mode for MMV688179 was obtained by docking. The six hits discovered against cruzain and TbrCatL are of great interest for further optimization by the medicinal chemistry community.

Asymmetric Organocatalysis: A Survival Guide to Medicinal Chemists.

Majority of drugs act by interacting with chiral counterparts, e.g., proteins, and we are, unfortunately, well-aware of how chirality can negatively impact the outcome of a therapeutic regime. The number of chiral, non-racemic drugs on the market is increasing, and it is becoming ever more important to prepare these compounds in a safe, economic, and environmentally sustainable fashion. Asymmetric organocatalysis has a long history, but it began its renaissance era only during the first years of the millennium. Since then, this field has reached an extraordinary level, as confirmed by the awarding of the 2021 Chemistry Nobel Prize. In the present review, we wish to highlight the application of organocatalysis in the synthesis of enantio-enriched molecules that may be of interest to the pharmaceutical industry and the medicinal chemistry community. We aim to discuss the different activation modes observed for organocatalysts, examining, for each of them, the generally accepted mechanisms and the most important and developed reactions, that may be useful to medicinal chemists. For each of these types of organocatalytic activations, select examples from academic and industrial applications will be disclosed during the synthesis of drugs and natural products.

Antiproliferative Activity Predictor: A New Reliable In Silico Tool for Drug Response Prediction against NCI60 Panel.

In vitro antiproliferative assays still represent one of the most important tools in the anticancer drug discovery field, especially to gain insights into the mechanisms of action of anticancer small molecules. The NCI-DTP (National Cancer Institute Developmental Therapeutics Program) undoubtedly represents the most famous project aimed at rapidly testing thousands of compounds against multiple tumor cell lines (NCI60). The large amount of biological data stored in the National Cancer Institute (NCI) database and many other databases has led researchers in the fields of computational biology and medicinal chemistry to develop tools to predict the anticancer properties of new agents in advance. In this work, based on the available antiproliferative data collected by the NCI and the manipulation of molecular descriptors, we propose the new in silico Antiproliferative Activity Predictor (AAP) tool to calculate the GI50 values of input structures against the NCI60 panel. This ligand-based protocol, validated by both internal and external sets of structures, has proven to be highly reliable and robust. The obtained GI50 values of a test set of 99 structures present an error of less than ±1 unit. The AAP is more powerful for GI50 calculation in the range of 4-6, showing that the results strictly correlate with the experimental data. The encouraging results were further supported by the examination of an in-house database of curcumin analogues that have already been studied as antiproliferative agents. The AAP tool identified several potentially active compounds, and a subsequent evaluation of a set of molecules selected by the NCI for the one-dose/five-dose antiproliferative assays confirmed the great potential of our protocol for the development of new anticancer small molecules. The integration of the AAP tool in the free web service DRUDIT provides an interesting device for the discovery and/or optimization of anticancer drugs to the medicinal chemistry community. The training set will be updated with new NCI-tested compounds to cover more chemical spaces, activities, and cell lines. Currently, the same protocol is being developed for predicting the TGI (total growth inhibition) and LC50 (median lethal concentration) parameters to estimate toxicity profiles of small molecules.

Synthesis, Molecular Docking, and Neuroprotective Effect of 2-Methylcinnamic Acid Amide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)—An Induced Parkinson’s Disease Model

Parkinson’s disease (PD) has emerged as the second most common form of human neurodegenerative disorders. However, due to the severe side effects of the current antiparkinsonian drugs, the design of novel and safe compounds is a hot topic amongst the medicinal chemistry community. Herein, a convenient peptide method, TBTU (O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate), was used for the synthesis of the amide (E)-N-(2-methylcinnamoyl)-amantadine (CA(2-Me)-Am; 3)) derived from amantadine and 2-methylcinnamic acid. The obtained hybrid was studied for its antiparkinsonian activity in an experimental model of PD induced by MPTP. Mice (C57BL/6,male, 8 weeks old) were divided into four groups as follows: (1) the control, treated with normal saline (i.p.) for 12 consecutive days; (2) MPTP (30 mg/kg/day, i.p.), applied daily for 5 consecutive days; (3) MPTP + CA(2-Me)-Am, applied for 12 consecutive days, 5 days simultaneously with MPTP and 7 days after MPTP; (4) CA(2-Me)-Am +oleanoic acid (OA), applied daily for 12 consecutive days. Neurobehavioral parameters in all experimental groups of mice were evaluated by rotarod test and passive avoidance test. Our experimental data showed that CA(2-Me)-Am in parkinsonian mice significantly restored memory performance, while neuromuscular coordination approached the control level, indicating the ameliorating effects of the new compound. In conclusion, the newly synthesized hybrid might be a promising agent for treating motor disturbances and cognitive impairment in experimental PD.

1,2,3-Triazole Linked Chalcone-Morpholine Hybrids: Synthesis, In Vitro Antibacterial Evaluation and In Silico ADMET Predictions

Emerging multi-drug resistance (MDR) bacteria are alarming the medicinal chemistry community to establish a new class of antimicrobials with high selectivity, less toxicity, and a new mode of action. Therefore, a new series of chalcone-morpholine hybrids (6a–p) were synthesized using copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition to link the above two pharmacophores with the 1,2,3-triazole ring. Antibacterial potentials of all the synthesized compounds were studied against two Gram-positive (Bacillus subtilis and Staphylococcus aureus), and three Gram-negative (Escherichia coli, Pseudomonas putida, and Klebsiella pneumonia) bacterial strains. Among the tested series of compounds, 6a, 6c, and 6m against all the bacterial strains, 6e against both the Gram-positive bacteria, and 6h against all the Gram-negative bacteria were found to exhibit broad-spectrum activity compared with the standard Ampicillin. Furthermore, in silico ADME profiles were also predicted to set effective lead candidates for effective antibacterial agents.