Compounds For Drug Discovery Research Articles

Autofluorescent antimalarials by hybridization of artemisinin and coumarin: in vitro/in vivo studies and live-cell imaging.

Malaria is one of our planet's most widespread and deadliest diseases, and there is an ever-consistent need for new and improved pharmaceuticals. Natural products have been an essential source of hit and lead compounds for drug discovery. Antimalarial drug artemisinin (ART), a highly effective natural product, is an enantiopure sesquiterpene lactone and occurs in Artemisia annua L. The development of improved antimalarial drugs, which are highly potent and at the same time inherently fluorescent is particularly favorable and highly desirable since they can be used for live-cell imaging, avoiding the requirement of the drug's linkage to an external fluorescent label. Herein, we present the first antimalarial autofluorescent artemisinin-coumarin hybrids with high fluorescence quantum yields of up to 0.94 and exhibiting excellent activity in vitro against CQ-resistant and multidrug-resistant P. falciparum strains (IC50 (Dd2) down to 0.5 nM; IC50 (K1) down to 0.3 nM) compared to reference drugs CQ (IC50 (Dd2) 165.3 nM; IC50 (K1) 302.8 nM) and artemisinin (IC50 (Dd2) 11.3 nM; IC50 (K1) 5.4 nM). Furthermore, a clear correlation between in vitro potency and in vivo efficacy of antimalarial autofluorescent hybrids was demonstrated. Moreover, deliberately designed autofluorescent artemisinin-coumarin hybrids, were not only able to overcome drug resistance, they were also of high value in investigating their mode of action via time-dependent imaging resolution in living P. falciparum-infected red blood cells.

Anti-ovarian cancer potential, in silico studies, and anti-Alzheimer's disease effects of some natural compounds as cholinesterase inhibitors.

Ovarian cancer ranks seventh in the most common malignant tumors in females and seriously threatens women's reproductive health. Natural sources may lead to basic research on potential bioactive components as lead compounds in drug discovery and, ultimately, therapeutic treatments for ovarian cancer and other diseases. Alzheimer's disease (AD) and ovarian cancer are complex diseases of aging that impose an enormous public health burden worldwide. Additionally, people with AD have low levels of acetylcholine in their brains. Enzymes called cholinesterases break down acetylcholine in the brain. If their action is inhibited, more acetylcholine is available for communication among brain cells. In this study, pregnanolone, diethylstilbestrol (DES), flavokawain C, and methyl 3,4,5-trihydroxybenzoate molecules obtained excellent-to-good inhibitory against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes with IC50 values ranging between 77.18±8.62 to 461.35±28.54μM for AChE and 23.86±4.07 to 306.62±32.46μM for BuChE. The calculations revealed the probable interactions and their characteristics at an atomic level. Indeed, the docking scores of DES, flavokawain C, pregnanolone, and methyl 3,4,5-trihydroxybenzoate for AChE are -6.685, -6.247, -6.672, and -5.183(kcal/mol), respectively. This value for the compounds against BuChE is -6.042, -8.851, -5.655, and -5.898(kcal/mol), respectively. Additionally, these compounds significantly decreased ovarian cancer cell viability. Additionally, 100μM dose of all molecules caused good reductions in ovarian cancer cell viability.

Protoglobin‐Catalyzed Formation of cis‐Trifluoromethyl‐Substituted Cyclopropanes by Carbene Transfer

AbstractTrifluoromethyl‐substituted cyclopropanes (CF3‐CPAs) constitute an important class of compounds for drug discovery. While several methods have been developed for synthesis of trans‐CF3‐CPAs, stereoselective production of corresponding cis‐diastereomers remains a formidable challenge. We report a biocatalyst for diastereo‐ and enantio‐selective synthesis of cis‐CF3‐CPAs with activity on a variety of alkenes. We found that an engineered protoglobin from Aeropyrnum pernix (ApePgb) can catalyze this unusual reaction at preparative scale with low‐to‐excellent yield (6–55 %) and enantioselectivity (17–99 % ee), depending on the substrate. Computational studies revealed that the steric environment in the active site of the protoglobin forced iron‐carbenoid and substrates to adopt a pro‐cis near‐attack conformation. This work demonstrates the capability of enzyme catalysts to tackle challenging chemistry problems and provides a powerful means to expand the structural diversity of CF3‐CPAs for drug discovery.

Protoglobin-Catalyzed Formation of cis-Trifluoromethyl-Substituted Cyclopropanes by Carbene Transfer.

Trifluoromethyl-substituted cyclopropanes (CF3 -CPAs) constitute an important class of compounds for drug discovery. While several methods have been developed for synthesis of trans-CF3 -CPAs, stereoselective production of corresponding cis-diastereomers remains a formidable challenge. We report a biocatalyst for diastereo- and enantio-selective synthesis of cis-CF3 -CPAs with activity on a variety of alkenes. We found that an engineered protoglobin from Aeropyrnum pernix (ApePgb) can catalyze this unusual reaction at preparative scale with low-to-excellent yield (6-55 %) and enantioselectivity (17-99 % ee), depending on the substrate. Computational studies revealed that the steric environment in the active site of the protoglobin forced iron-carbenoid and substrates to adopt a pro-cis near-attack conformation. This work demonstrates the capability of enzyme catalysts to tackle challenging chemistry problems and provides a powerful means to expand the structural diversity of CF3 -CPAs for drug discovery.

Terpenoids and other secondary metabolites produced by the Eutypella fungi and their bioactivities

The fungi Eutypella could metabolize a myriad of natural products with unique structures and diverse bioactivities, which were deemed as key sources for lead compounds in drug discovery. Since the first research on the genus Eutypella in 2009, a myriad of secondary metabolites including terpenoids, alkaloids, and polyketides have been discovered in this genus, and most of them exhibited significant pharmacological activities. However, there are no systematic reviews that reported about the structures and bioactivities of Eutypella up to now. In this review, a total of 153 secondary metabolites and 42 references have been systematically summarized, and we found that the terpenoids (68.09%) and alkaloids (19.15%) were the new main components of this fungi, and the primary antiproliferative activity (64.89%) was mainly derived from the terpenoids and alkaloids. Thus, this review about the chemical diversity and biological activities of the metabolites from the fungus Eutypella provided a new perspective for the development of new drugs for pharmacologists.

Evaluation of target-specific natural compounds for drug discovery against Leishmaniasis.

Leishmaniasis is a parasitic disease with no effective vaccine still now. Globally, it has affected millions of people, precisely in the undeveloped and developing countries. The control strategy for leishmaniasis depends only on chemotherapeutic methods that are associated with several side effects. Therefore, to overcome these negative impacts natural products are the best alternative for developing effective herbal-based drugs, which can act as one of the safest and effective alternative options to treat this particular disease. Leishmania, the causative agent of this disease possesses unique enzymes and metabolic pathways that are different from its mammalian host. Moreover, these unique enzymes, along with the signaling molecules and metabolic pathways that are crucial for its survival, serve as a suitable drug target for the evaluation of specific natural inhibitors to overcome leishmaniasis. Hence, in this review, we have discussed various specific targets of Leishmania, along with their natural inhibitors which can play a significant role in anti-leishmanial drug discovery.

Visible-Light Photoredox-Catalyzed Decarboxylation of α-Oxo Carboxylic Acids to C1-Deuterated Aldehydes and Aldehydes.

The synthesis of high-value-added C1-deuterated aldehydes would improve the availability of deuterated lead compounds for deuterium-labeled drug discovery. Herein, we develop a metal-free synthesis of C1-deuterated aldehydes with D2O from α-oxo carboxylic acids at ambient temperature. Via visible-light photoredox-catalyzed decarboxylation, stoichiometric reductants and oxidants were avoided. Various functional groups were tolerated and resulted in C1-deuterium aldehydes in up to 92% yield and 91-97% D incorporation under mild conditions. This method is also applied to the synthesis of various aldehydes. Primary mechanistic studies indicate that the catalytic pathway occurs via a reductive quenching pathway followed by hydrogen atom transfer.

Naturally Occurring O-Heterocycles as Anticancer Agents.

Cancer is a leading cause of death worldwide. Proper efficient drugs are required to treat this deadly disease. Natural products have long been a vital source of anticancer agents and they have generated various "lead compounds" suitable for drug developments. With the recent advancement of chemical synthesis and bioevaluation techniques, these lead compounds of natural origins have been utilized for the production of useful anticancer drugs. Among the naturally occurring bioactive compounds, various O-heterocycles have been evaluated as remarkable cancer therapeutic agents. These compounds generally possess unique structures and novel mechanisms of action. In the present review article, some selected O-heterocycles as promoting anticancer agents have been discussed in brief. Various natural sources and chemistry, as well as bioactivities of these compounds, have been described. The development of improved analogues of these compounds through synthetic modifications and efficient bioevaluation, along with proper studies on structure-activity relationship and mechanism of actions, has been mentioned. The article has demonstrated the recent relevance of naturally occurring O-heterocyclic compounds in the current anticancer drug discovery and development scenario.

Mass Spectroscopy as an Analytical Tool to Harness the Production of Secondary Plant Metabolites: The Way Forward for Drug Discovery.

The molecular map of diverse biological molecules linked with structure, function, signaling, and regulation within a cell can be elucidated using an analytically demanding omic approach. The latest trend of using "metabolomics" technologies has explained the natural phenomenon of opening a new avenue to understand and enhance bioactive compounds' production. Examination of sequenced plant genomes has revealed that a considerable portion of these encodes genes of secondary metabolism. In addition to genetic and molecular tools developed in the current era, the ever-increasing knowledge about plant metabolism's biochemistry has initiated an approach for wisely designed, more productive genetic engineering of plant secondary metabolism for improved defense systems and enhanced biosynthesis of beneficial metabolites. Secondary plant metabolites are natural products synthesized by plants that are not directly involved with their average growth and development but play a vital role in plant defense mechanisms. Plant secondary metabolites are classified into four major classes: terpenoids, phenolic compounds, alkaloids, and sulfur-containing compounds. More than 200,000 secondary metabolites are synthesized by plants having a unique and complex structure. Secondary plant metabolites are well characterized and quantified by omics approaches and therefore used by humans in different sectors such as agriculture, pharmaceuticals, chemical industries, and biofuel. The aim is to establish metabolomics as a comprehensive and dynamic model of diverse biological molecules for biomarkers and drug discovery. In this chapter, we aim to illustrate the role of metabolomic technology, precisely liquid chromatography-mass spectrometry, capillary electrophoresis mass spectrometry, gas chromatography-mass spectrometry, and nuclear magnetic resonance spectroscopy, specifically as a research tool in the production and identification of novel bioactive compounds for drug discovery and to obtain a unified insight of secondary metabolism in plants.

Halometabolites isolated from the marine-derived fungi with potent pharmacological activities.

Halometabolites, usually produced in marine environment, are an important group of natural halogenated compounds with rich biological functionality and drugability and thus play a crucial role in pharmaceutical and/or agricultural applications. In the exploration of novel halometabolites from marine microorganisms, the growing number of halogenated compounds makes it necessary to fully present these metabolites with diverse structures and considerable bioactivities. This review particularly focuses on the chemodiversity and bioactivities of halometabolites from marine-derived fungi. As a result, a total of 145 naturally halogenated compounds, including 118 chlorinated, 23 brominated, and four iodinated compounds, were isolated from 17 genera of marine-derived fungi. Interestingly, many of halometabolites, especially for the brominated and iodinated compounds, are generated by the substitution of bromide and iodide ions for the chloride ion in cultivation process. In addition, these compounds possess diverse structural types, which are classified into polyketides (62.7%), phenols (16.6%), alkaloids (14.5%), and terpenoids (6.2%). Their cytotoxic, antibacterial, and anti-inflammatory activities indicate the high potential of these halogenated compounds as lead compounds for drug discovery.

Effects of Green Tea (-)-Epigallocatechin-3-Gallate (EGCG) on Cardiac Function - A Review of the Therapeutic Mechanism and Potentials.

Heart disease, the leading cause of death worldwide, refers to various illnesses that affect heart structure and function. Specific abnormalities affecting cardiac muscle contractility and remodeling and common factors including oxidative stress, inflammation, and apoptosis underlie the pathogenesis of heart diseases. Epidemiology studies have associated green tea consumption with lower morbidity and mortality from cardiovascular diseases, including heart and blood vessel dysfunction. Among the various compounds found in green tea, catechins are believed to play a significant role in producing benefits to cardiovascular health. Comprehensive literature reviews have been published to summarize the tea catechins' antioxidative, anti-inflammatory, and anti-apoptosis effects in various diseases, such as cardiovascular diseases, cancers, and metabolic diseases. However, recent studies on tea catechins, especially the most abundant (-)-Epigallocatechin-3-Gallate (EGCG), revealed their capabilities in regulating cardiac muscle contraction by directly altering myofilament Ca2+ sensitivity on force development and Ca2+ ion handling in cardiomyocytes under both physiological and pathological conditions. In vitro and in vivo data also demonstrated that green tea extract or EGCG protected or rescued cardiac function, independent of their well-known effects against oxidative stress and inflammation. This mini-review will focus on the specific effects of tea catechins on heart muscle contractility at the molecular and cellular level, revisit their effects on oxidative stress and inflammation in various heart diseases, and discuss EGCG's potential as one of the lead compounds for new drug discovery for heart diseases.

Therapeutic approaches of nutraceuticals in the prevention of Alzheimer's disease.

Alzheimer's disease (AD) is a neurological illness that causes memory loss over time. Currently, available pharmaceutical medicines and products are limited, and they have side effects at a higher price. Researchers and scientists have observed significant effects of nutraceuticals. Various preclinical and clinical studies were investigated for the Anti-Alzheimer's activity of nutraceuticals. The increasing ability of the pathogenesis of AD has led to the analysis of novel therapeutic targets, including the pathophysiological mechanisms and distinct cascades. So, current improvement will show the most adequate and prominent nutraceuticals and suggested concise mechanisms involving autophagy regulation, anti-inflammatory, antioxidant, mitochondrial homeostasis, and others. The effects of nutraceuticals cannot be ignored; it is important to investigate high-quality clinical trials. Given the potential of nutraceuticals to battle AD as multi-targeted therapies, it's vital to evaluate them as viable lead compounds for drug discovery and development. To the best of the authors 'knowledge, modification of blood-brain barrier permeability, bioavailability, and aspects of randomized clinical trials should be considered in prospective investigations. PRACTICAL APPLICATIONS: Advancements in molecular diagnostic and fundamentals have implemented particular usefulness for drug evaluation. An excess of experimental knowledge occurs regarding the effect of nutraceuticals on AD. There are various preclinical and clinical studies that have been done on nutraceuticals. In addition, various substitute inhibit and enhance some pathophysiological levels associated with AD. Nutraceuticals are easily available and have fewer side effects with cost-effective advantages. However, further investigations and clinical trials are required to encourage its effect on disease.

Pipeline Impact of Radiolabeled Compounds in Drug Discovery and Development.

The long-lived radionuclides tritium and carbon-14 have been used for many years in pharmaceutical research and development for making key efficacy and toxicological decisions. Early discovery utilizes radiolabels for compound selection through radioligand binding assays and autoradiography. In preclinical safety evaluation, the use of labeled compounds for adsorption, distribution, metabolism, and excretion studies is often preferred for the added detection sensitivity. As the drug substance proceeds to the clinic, human metabolism studies are reliant on the use of labeled materials to fulfill required regulatory applications.

Antiviral plant-derived natural products to combat RNA viruses: Targets throughout the viral life cycle.

There is a need for new effective antivirals, particularly in response to the development of antiviral drug resistance and emerging RNA viruses such as SARS‐CoV‐2. Plants are a significant source of structurally diverse bioactive compounds for drug discovery suggesting that plant‐derived natural products could be developed as antiviral agents. This article reviews the antiviral activity of plant‐derived natural products against RNA viruses, with a focus on compounds targeting specific stages of the viral life cycle. A range of plant extracts and compounds have been identified with antiviral activity, often against multiple virus families suggesting they may be useful as broad‐spectrum antiviral agents. The antiviral mechanism of action of many of these phytochemicals is not fully understood and there are limited studies and clinical trials demonstrating their efficacy and toxicity in vivo. Further research is needed to evaluate the therapeutic potential of plant‐derived natural products as antiviral agents.

Aspiletrein A Induces Apoptosis Cell Death via Increasing Reactive Oxygen Species Generation and AMPK Activation in Non-Small-Cell Lung Cancer Cells.

Lung cancer remains a leading cause of death in cancer patients, and deregulation of apoptosis is a serious concern in clinical practice, even though therapeutic intervention has been greatly improved. Plants are a versatile source of biologically active compounds for anticancer drug discovery, and aspiletrein A (AA) is a steroidal saponin isolated from Aspidistra letreae that has a potent cytotoxic effect on various cancer cell lines. In this study, we investigated and determined the underlying molecular mechanism by which AA induces apoptosis. AA strongly induced apoptosis in NSCLC cells by mediating ROS generation and thereby activating AMP-activated protein kinase (AMPK) signaling. Consequently, downstream signaling and levels of phosphorylated mTOR and Bcl-2 were significantly decreased. Pretreatment with either an antioxidant, N-acetylcysteine, or an AMPK inhibitor, compound C, could reverse the apoptosis-inducing effect and counteract the effect of AA on the AMPK signaling pathway. Decreased levels of Bcl-2 were due to AA-mediating Bcl-2 degradation via a ROS/AMPK/mTOR axis-dependent proteasomal mechanism. Consistently, the apoptotic-inducing effect of AA was also observed in patient-derived malignant lung cancer cells, and it suppressed an in vitro 3D-tumorigenesis. This study identified the underlying mechanism of AA on lung cancer apoptosis, thereby facilitating potential research and development of this compound for further clinical implications.

Computational prediction of potential drug-like compounds from Cannabis sativa leaf extracts targeted towards Alzheimer therapy

• Phytochemicals isolated from Cannabis sativa can improve behavioral symptoms associated with neurological diseases including AD. • Morphinan-6-one demonstrated inhibitory actions against AChE and DDC, suggesting that it might have dual functions in AD. • Morphinan-6-one is hypothesized to be a modulatory molecule for acetylcholinesterase. This study was aimed at evaluating the inhibitory effects of the phytochemicals from the Cannabis sativa (Cannabis) leaf extracts against Alzheimer’s disease (AD) protein targets. Twelve compounds derived from the Cannabis sativa leaf extracts were evaluated as potential inhibitors of acetylcholinesterase (AChE), dopa decarboxylase (DDC), serotonin receptor 2C (HTR2C) and monoamine oxidase (MAO). Ligand-based and receptor-ligand complex were used to derive the pharmacophore hypothesis. In silico study through molecular docking simulation method was adopted to analyze the inhibitory activity of the compounds in question. Molecular dynamic simulation (MDs) was performed to assess the stability of the top-ranked phytochemicals. The binding energies of these compounds to the four targets were investigated by the Molecular Mechanics for the Generalized Born Model and Solvent Accessibility method (MM-GBSA). The binding-free energy suggests that cannabinol, cannabichromene, linoelaidic acid and morphinan-6-one can be utilized as lead compounds in drug discovery and development of AD to inhibit activity of AChE, DCC gene, MAO and HTR2C. The MDs indicated that AChE-Cannabinol, DCC-Cannabicoumaronone, MAO-Linoelaidic acid, and HTR2C-morphinan-6-one were stable over the entire course of 100 ns suggesting their role in the regulation of the diseases in which their respective receptors are implicated.

Novel 1,3-Thiazole Analogues with Potent Activity against Breast Cancer: A Design, Synthesis, In Vitro, and In Silico Study.

Breast cancer is the most common cancer in women, responsible for over half a million deaths in 2020. Almost 75% of FDA-approved drugs are mainly nitrogen- and sulfur-containing heterocyclic compounds, implying the importance of such compounds in drug discovery. Among heterocycles, thiazole-based heterocyclic compounds have demonstrated a broad range of pharmacological activities. In the present study, a novel set of 1,3-thiazole derivatives was designed and synthesized based on the coupling of acetophenone derivatives, and phenacyl bromide was substituted as a key reaction step. The activity of synthesized compounds was screened against the proliferation of two breast cancer cell lines (MCF-7 and MDA-MB-231). Almost all compounds exhibited a considerable antiproliferative activity toward the breast cancer cells as compared to staurosporine, with no significant cytotoxicity toward the epithelial cells. Among the synthesized compounds, compound 4 exhibited the most potent antiproliferative activity, with an IC50 of 5.73 and 12.15 µM toward MCF-7 and MDA-MB-231 cells, respectively, compared to staurosporine (IC50 = 6.77 and 7.03 µM, respectively). Exploring the mechanistic insights responsible for the antiproliferative activity of compound 4 revealed that compound 4 possesses a significant inhibitory activity toward the vascular endothelial growth factor receptor-2 (VEGFR-2) with (IC50 = 0.093 µM) compared to Sorafenib (IC50 = 0.059 µM). Further, compound 4 showed the ability to induce programmed cell death by triggering apoptosis and necrosis in MCF-7 cells and to induce cell cycle arrest on MCF-7 cells at the G1 stage while decreasing the cellular population in the G2/M phase. Finally, detailed in silico molecular docking studies affirmed that this class of compounds possesses a considerable binding affinity toward VEGFR2 proteins. Overall, these results indicate that compound 4 could be a promising lead compound for developing potent anti-breast cancer compounds.

A Comprehensive Review of Andrographis paniculata (Burm. f.) Nees and Its Constituents as Potential Lead Compounds for COVID-19 Drug Discovery.

The COVID-19 pandemic has intensively disrupted global health, economics, and well-being. Andrographis paniculata (Burm. f.) Nees has been used as a complementary treatment for COVID-19 in several Asian countries. This review aimed to summarize the information available regarding A. paniculata and its constituents, to provide critical points relating to its pharmacological properties, safety, and efficacy, revealing its potential to serve as a source of lead compounds for COVID-19 drug discovery. A. paniculata and its active compounds possess favorable antiviral, anti-inflammatory, immunomodulatory, and antipyretic activities that could be beneficial for COVID-19 treatment. Interestingly, recent in silico and in vitro studies have revealed that the active ingredients in A. paniculata showed promising activities against 3CLpro and its virus-specific target protein, human hACE2 protein; they also inhibit infectious virion production. Moreover, existing publications regarding randomized controlled trials demonstrated that the use of A. paniculata alone or in combination was superior to the placebo in reducing the severity of upper respiratory tract infection (URTI) manifestations, especially as part of early treatment, without serious side effects. Taken together, its chemical and biological properties, especially its antiviral activities against SARS-CoV-2, clinical trials on URTI, and the safety of A. paniculata, as discussed in this review, support the argument that A. paniculata is a promising natural source for drug discovery regarding COVID-19 post-infectious treatment, rather than prophylaxis.

Microbial Natural Products with Antiviral Activities, Including Anti-SARS-CoV-2: A Review.

The SARS-CoV-2 virus, which caused the COVID-19 infection, was discovered two and a half years ago. It caused a global pandemic, resulting in millions of deaths and substantial damage to the worldwide economy. Currently, only a few vaccines and antiviral drugs are available to combat SARS-CoV-2. However, there has been an increase in virus-related research, including exploring new drugs and their repurposing. Since discovering penicillin, natural products, particularly those derived from microbes, have been viewed as an abundant source of lead compounds for drug discovery. These compounds treat bacterial, fungal, parasitic, and viral infections. This review incorporates evidence from the available research publications on isolated and identified natural products derived from microbes with anti-hepatitis, anti-herpes simplex, anti-HIV, anti-influenza, anti-respiratory syncytial virus, and anti-SARS-CoV-2 properties. About 131 compounds with in vitro antiviral activity and 1 compound with both in vitro and in vivo activity have been isolated from microorganisms, and the mechanism of action for some of these compounds has been described. Recent reports have shown that natural products produced by the microbes, such as aurasperone A, neochinulin A and B, and aspulvinone D, M, and R, have potent in vitro anti-SARS-CoV-2 activity, targeting the main protease (Mpro). In the near and distant future, these molecules could be used to develop antiviral drugs for treating infections and preventing the spread of disease.

On-DNA Hydroalkylation to Introduce Diverse Bicyclo[1.1.1]pentanes and Abundant Alkyls via Halogen Atom Transfer.

DNA-encoded libraries have proven their tremendous value in the identification of new lead compounds for drug discovery. To access libraries in new chemical space, many methods have emerged to transpose traditional mol-scale reactivity to nmol-scale, on-DNA chemistry. However, procedures to access libraries with a greater fraction of C(sp3) content are still limited, and the need to "escape from flatland" more readily on-DNA remains. Herein, we report a Giese addition to install highly functionalized bicyclo[1.1.1]pentanes (BCPs) using tricyclo[1.1.1.01,3]pentane (TCP) as a radical linchpin, as well as other diverse alkyl groups, on-DNA from the corresponding organohalides as non-stabilized radical precursors. Telescoped procedures allow extension of the substrate pool by at least an order of magnitude to ubiquitous alcohols and carboxylic acids, allowing us to "upcycle" these abundant feedstocks to afford non-traditional libraries with different physicochemical properties for the small-molecule products (i.e., non-peptide libraries with acids). This approach is amenable to library production, as a DNA damage assessment revealed good PCR amplifiability and only 6% mutated sequences for a full-length DNA tag.