Recent advances in transition metal-catalyzed reactions of chloroquinoxalines: Applications in bioorganic chemistry.

The importance of the quinoxaline framework is exemplified by its presence in the well-known drugs such as varenicline, brimonidine, quinacillin, etc. In the past few years, preparation of a variety of organic compounds containing the quinoxaline framework has been reported by several research groups. The chloroquinoxalines were successfully used as substrates in many of these synthetic approaches due to their easy availability along with the reactivity especially towards a diverse range of metal and transition metal-catalyzed transformations including Sonogashira, Suzuki, Heck type of cross-coupling reactions. The transition metals e.g., Pd, Cu, Fe and Nb catalysts played a key role in these transformations for the construction of various CX (e.g., CC, CN, CO, CS, CP, CSe, etc) bonds. These approaches can be classified based on the catalyst employed, type of the reaction performed and nature of CX bond formation during the reaction. Several of these resultant quinoxaline derivatives have shown diverse biological activities which include apoptosis inducing activities, SIRT1 inhibition, inhibition of luciferace enzyme, antibacterial and antifungal activities, cytotoxicity towards cancer cells, inhibition of PDE4 (phosphodiesterase 4), potential uses against COVID-19, etc. Notably, a review article covering the literature based on transition metal-catalyzed reactions of chloroquinoxalines at the same time summarizing the relevant biological activities of resultant products is rather uncommon. Therefore, an attempt is made in the current review article to summarize (i) the recent advances noted in the transition metal-catalyzed reactions of chloroquinoxalines (ii) with the relevant mechanistic discussions (iii) along with the in vitro, and in silico biological studies (wherever reported) (iv) including Structure-Activity Relationship (SAR) within the particular series of the products reported between 2010 and 2022.

Recent Advances in Macrocyclic Drugs and Microwave-Assisted and/or Solid-Supported Synthesis of Macrocycles.

Macrocycles represent attractive candidates in organic synthesis and drug discovery. Since 2014, nineteen macrocyclic drugs, including three radiopharmaceuticals, have been approved by FDA for the treatment of bacterial and viral infections, cancer, obesity, immunosuppression, etc. As such, new synthetic methodologies and high throughput chemistry (e.g., microwave-assisted and/or solid-phase synthesis) to access various macrocycle entities have attracted great interest in this chemical space. This article serves as an update on our previous review related to macrocyclic drugs and new synthetic strategies toward macrocycles (Molecules, 2013, 18, 6230). In this work, I first reviewed recent FDA-approved macrocyclic drugs since 2014, followed by new advances in macrocycle synthesis using high throughput chemistry, including microwave-assisted and/or solid-supported macrocyclization strategies. Examples and highlights of macrocyclization include macrolactonization and macrolactamization, transition-metal catalyzed olefin ring-closure metathesis, intramolecular C-C and C-heteroatom cross-coupling, copper- or ruthenium-catalyzed azide-alkyne cycloaddition, intramolecular SNAr or SN2 nucleophilic substitution, condensation reaction, and multi-component reaction-mediated macrocyclization, and covering the literature since 2010.

The emergence of the C-H functionalization strategy in medicinal chemistry and drug discovery.

Owing to the market competitiveness and urgent societal need, an optimum speed of drug discovery is an important criterion for successful implementation. Despite the rapid ascent of artificial intelligence and computational and bioanalytical techniques to accelerate drug discovery in big pharma, organic synthesis of privileged scaffolds predicted in silico for in vitro and in vivo studies is still considered as the rate-limiting step. C-H activation is the latest technology added into an organic chemist's toolbox for the rapid construction and late-stage modification of functional molecules to achieve the desired chemical and physical properties. Particularly, elimination of prefunctionalization steps, exceptional functional group tolerance, complexity-to-diversity oriented synthesis, and late-stage functionalization of privileged medicinal scaffolds expand the chemical space. It has immense potential for the rapid synthesis of a library of molecules, structural modification to achieve the required pharmacological properties such as absorption, distribution, metabolism, excretion, toxicology (ADMET) and attachment of chemical reporters for proteome profiling, metabolite synthesis, etc. for preclinical studies. Although heterocycle synthesis, late-stage drug modification, 18F labelling, methylation, etc. via C-H functionalization have been reviewed from the synthetic standpoint, a general overview of these protocols from medicinal and drug discovery aspects has not been reviewed. In this feature article, we will discuss the recent trends of C-H activation methodologies such as synthesis of medicinal scaffolds through C-H activation/annulation cascade; C-H arylation for sp2-sp2 and sp2-sp3 cross-coupling; C-H borylation/silylation to introduce a functional linchpin for further manipulation; C-H amination for N-heterocycles and hydrogen bond acceptors; C-H fluorination/fluoroalkylation to tune polarity and lipophilicity; C-H methylation: methyl magic in drug discovery; peptide modification and macrocyclization for therapeutics and biologics; fluorescent labelling and radiolabelling for bioimaging; bioconjugation for chemical biology studies; drug-metabolite synthesis for biodistribution and excretion studies; late-stage diversification of drug-molecules to increase efficacy and safety; cutting-edge DNA encoded library synthesis and improved synthesis of drug molecules via C-H activation in medicinal chemistry and drug discovery.

Orodispersible films: Conception to quality by design.

Orodispersible films (ODFs) are ultra-thin, stamp-sized, elegant, portable and patient-centric pharmaceutical dosage forms that do not need water to be ingested. They are particularly useful for paediatric and geriatric patient populations with special needs such as dysphagia, Parkinson's disease, and oral cancer. Accordingly, they hold tremendous potential in gaining patient compliance, convenience and pharmacotherapy. In the present review, conception and evolution of ODFs as a product and its technology are discussed. The review continues by providing overview about the potential of ODFs as carriers for delivering drugs, herbal extracts, probiotics and vaccines. Besides, strategies employed in drug cargo loading, taste masking of bitter drugs and enhancing drug stability are discussed. Finally, the review concludes by providing a brief overview about quality by design (QbD) principles in development of ODFs.

Synthesis of Non-canonical Amino Acids and Peptide Containing Them for Establishment of the Template for Drug Discovery.

Non-canonical amino acid derivatives are an attractive scaffold for novel drug candidates. Among the methods used to prepare this motif, the asymmetric Mannich-type reaction of α-imino carboxylic acid derivatives is a preeminent strategy because a wide variety of non-canonical amino acids can be accessed by changing only the nucleophile. Preparing the common substrate is difficult, however, which makes this method problematic. We developed a convenient method for synthesizing common substrates using MnO2-mediated oxidation of stable precursors. Peptides bearing non-canonical amino acids are another attractive synthetic target. We propose a new approach for synthesizing non-canonical amino acid-containing peptides by directly applying various organic reactions to peptidic substrates. Using hydrophobic anchor-supported peptides, we directly applied ring-closing metathesis and asymmetric Friedel-Crafts reactions to peptidic substrates. We also developed a novel recyclable organocatalyst according to the nature of the hydrophobic anchor tagged compound.

Collective synthesis of acetylenic pharmaceuticals via enantioselective Nickel/Lewis acid-catalyzed propargylic alkylation.

Chiral acetylenic derivatives are found in many bioactive compounds and are versatile functional groups in organic chemistry. Here, we describe an enantioselective nickel/Lewis acid-catalyzed asymmetric propargylic substitution reaction from simple achiral materials under mild condition. The introduction of a Lewis acid cocatalyst is crucial to the efficiency of the transformation. Notably, we investigate this asymmetric propargylic substitution reaction for the development of a range of structurally diverse natural products. The power of this strategy is highlighted by the collective synthesis of seven biologically active compounds: (-)-Thiohexital, (+)-Thiopental, (+)-Pentobarbital, (-)-AMG 837, (+)-Phenoxanol, (+)-Citralis, and (-)-Citralis Nitrile.

Efficient and Short Method for Conjugation of 1-Nitro-9-Aminoacridine to Important Peptidyl Fragments by a Solid Support Synthesis.

The efficient and short techniques for conjugation of 9-aminoacridine with different peptidyl fragments are necessary for the development of active pharmaceutical ingredients (API). They need to be adopted to generate a new branch of acridine conjugates, enhancing their bioavailability for the examination in biological systems. The branch of developing acridine conjugates, built via different linkers and synthesized in this study, are expected as potential effective chemotherapeutics with dual mechanism of action. Recently, the methodology based on a solid-phase technique has been successfully demonstrated in preparing a number of promising compounds. However, the reaction conditions for amide bond formation between 1-nitro-9-aminoacridine and peptidyl fragments need to be optimized. In this study, the optimization of amide bond formation was demonstrated with the use of the solid-phase synthesis to build a new promising group of 1-nitro-9-aminoacridines conjugated to lactoferrin fragments via especially carboxy linker length.

Pyrazolyl-Ureas as Interesting Scaffold in Medicinal Chemistry.

The pyrazole nucleus has long been known as a privileged scaffold in the synthesis of biologically active compounds. Within the numerous pyrazole derivatives developed as potential drugs, this review is focused on molecules characterized by a urea function directly linked to the pyrazole nucleus in a different position. In the last 20 years, the interest of numerous researchers has been especially attracted by pyrazolyl-ureas showing a wide spectrum of biological activities, ranging from the antipathogenic activities (bacteria, plasmodium, toxoplasma, and others) to the anticarcinogenic activities. In particular, in the anticancer field, pyrazolyl-ureas have been shown to interact at the intracellular level on many pathways, in particular on different kinases such as Src, p38-MAPK, TrKa, and others. In addition, some of them evidenced an antiangiogenic potential that deserves to be explored. This review therefore summarizes all these biological data (from 2000 to date), including patented compounds.

Preparation of cyclohexene isotopologues and stereoisotopomers from benzene.

The hydrogen isotopes deuterium (D) and tritium (T) have become essential tools in chemistry, biology and medicine1. Beyond their widespread use in spectroscopy, mass spectrometry and mechanistic and pharmacokinetic studies, there has been considerable interest in incorporating deuterium into drug molecules1. Deutetrabenazine, a deuterated drug that is promising for the treatment of Huntington's disease2, was recently approved by the United States' Food and Drug Administration. The deuterium kinetic isotope effect, which compares the rate of a chemical reaction for a compound with that for its deuterated counterpart, can be substantial1,3,4. The strategic replacement of hydrogen with deuterium can affect both the rate of metabolism and the distribution of metabolites for a compound5, improving the efficacy and safety of a drug. The pharmacokinetics of a deuterated compound depends on the location(s) of deuterium. Although methods are available for deuterium incorporation at both early and late stages of the synthesis of a drug6,7, these processes are often unselective and the stereoisotopic purity can be difficult to measure7,8. Here we describe the preparation of stereoselectively deuterated building blocks for pharmaceutical research. As a proof of concept, we demonstrate a four-step conversion of benzene to cyclohexene with varying degrees of deuterium incorporation, via binding to a tungsten complex. Using different combinations of deuterated and proteated acid and hydride reagents, the deuterated positions on the cyclohexene ring can be controlled precisely. In total, 52 unique stereoisotopomers of cyclohexene are available, in the form of ten different isotopologues. This concept can be extended to prepare discrete stereoisotopomers of functionalized cyclohexenes. Such systematic methods for the preparation of pharmacologically active compounds as discrete stereoisotopomers could improve the pharmacological and toxicological properties of drugs and provide mechanistic information related to their distribution and metabolism in the body.

Visible-Light-Mediated Dearomatisation of Indoles and Pyrroles to Pharmaceuticals and Pesticides.

Dearomatisation of indole derivatives to the corresponding isatin derivatives has been achieved with the aid of visible light and oxygen. It should be noted that isatin derivatives are highly important for the synthesis of pharmaceuticals and bioactive compounds. Notably, this chemistry works excellently with N-protected and protection-free indoles. Additionally, this methodology can also be applied to dearomatise pyrrole derivatives to generate cyclic imides in a single step. Later this methodology was applied for the synthesis of four pharmaceuticals and a pesticide called dianthalexin B. Detailed mechanistic studies revealed the actual role of oxygen and photocatalyst.

Reductive Amination in the Synthesis of Pharmaceuticals.

Reductive amination plays a paramount role in pharmaceutical and medicinal chemistry owing to its synthetic merits and the ubiquitous presence of amines among biologically active compounds. It is one of the key approaches to C-N bond construction due to its operational easiness and a wide toolbox of protocols. Recent studies show that at least a quarter of C-N bond-forming reactions in the pharmaceutical industry are performed via reductive amination. This Review concisely compiles information on 71 medical substances that are synthesized by reductive amination. Compounds are grouped according to the principle of action, which includes drugs affecting the central nervous system, drugs affecting the cardiovascular system, anticancer drugs, antibiotics, antiviral and antifungal medicines, drugs affecting the urinary system, drugs affecting the respiratory system, antidiabetic medications, drugs affecting the gastrointestinal tract, and drugs regulating metabolic processes. A general synthetic scheme is provided for each compound, and the description is focused on reductive amination steps. The green chemistry metric of reaction mass efficiency was calculated for all reactions.

Examining barbiturate scaffold for the synthesis of new agents with biological interest.

Aim: Barbiturates have a long history of being used as drugs presenting wide varieties of biological activities (antimicrobial, anti-urease and antioxidant). Reactive oxygen species are associated with inflammation implicated in cancer, atherosclerosis and autoimmune diseases. Multitarget agents represent a powerful approach to the therapy of complicated inflammatory diseases. Results: A novel series of barbiturates has been synthesized and evaluated in several in vitro assays. Compound 16b (lipoxygenases inhibitor, 55.0 µM) was found to be a cyclooxygenase-2 inhibitor (27.5 µM). Compound 8b was profiled as a drug-like candidate. Conclusion: The barbiturate core represents a new scaffold for lipoxygenases inhibition, and the undertaken derivatives show promise as multiple-target agents to combat inflammatory diseases.

An Albumin Sandwich Enhances in Vivo Circulation and Stability of Metabolically Labile Peptides.

The effectiveness of numerous molecular drugs is hampered by their poor pharmacokinetics. Different from previous approaches with limited effectiveness, most recently, emerging high-affinity albumin binding moieties (ABMs) for in vivo hitchhiking of endogenous albumin opens up an avenue to chaperone small molecules for long-acting therapeutics. Although several FDA-approved fatty acids have shown prolonged residence and therapeutic effect, an easily synthesized, water-soluble, and high-efficiency ABM with versatile drug loading ability is urgently needed to improve the therapeutic efficacy of short-lived constructs. We herein identified an ideal bivalent Evans blue derivative, denoted as N(tEB)2, as a smart ABM-delivery platform to chaperone short-lived molecules, through both computational modeling screening and efficient synthetic schemes. The optimal N(tEB)2 could reversibly link two molecules of albumin through its two binding heads with a preferable spacer, resulting in significantly extended circulation half-life of a preloaded cargo and water-soluble. Notably, this in situ dimerization of albumin was able to sandwich peptide therapeutics to protect them from proteolysis. As an application, we conjugated N(tEB)2 with exendin-4 for long-acting glucose control in a diabetic mouse model, and it was superior to both previously tested NtEB-exendin-4 (Abextide) and the newly FDA-approved semaglutide, which has been arguably the best commercial weekly formula so far. Hence, this novel albumin binder has excellent clinical potential for next-generation biomimetic drug delivery systems.

Synthetic Approaches to the New Drugs Approved During 2017.

New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition while serving as leads for designing future new drugs. This annual review describes the most likely process-scale synthetic approaches to 31 new chemical entities approved for the first time globally in 2017.

Characterising covalent warhead reactivity.

Many drugs currently used are covalent inhibitors and irreversibly inhibit their targets. Most of these were discovered through serendipity. Covalent inhibitions can have many advantages from a pharmacokinetic perspective. However, until recently most organisations have shied away from covalent compound design due to fears of non-specific inhibition of off-target proteins leading to toxicity risks. However, there has been a renewed interest in covalent modifiers as potential drugs, as it possible to get highly selective compounds. It is therefore important to know how reactive a warhead is and to be able to select the least reactive warhead possible to avoid toxicity. A robust NMR based assay was developed and used to measure the reactivity of a variety of covalent warheads against serine and cysteine - the two most common targets for covalent drugs. A selection of these warheads also had their reactivity measured against threonine, tyrosine, lysine, histidine and arginine to better understand our ability to target non-traditional residues. The reactivity was also measured at various pHs to assess what effect the environment in the active site would have on these reactions. The reactivity of a covalent modifier was found to be very dependent on the amino acid residue.

Colistin Sulfate Chiral Stationary Phase for the Enantioselective Separation of Pharmaceuticals Using Organic Polymer Monolithic Capillary Chromatography.

A new functionalized polymer monolithic capillary with a macrocyclic antibiotic, namely colistin sulfate, as chiral selector was prepared via the copolymerization of binary monomer mixtures consisting of glycidyl methacrylate (GMA) and ethylene glycol dimethacrylate (EGDMA) in porogenic solvents namely 1-propanol and 1,4-butanediol, in the presence of azobisiso-butyronitrile (AIBN) as initiator and colistin sulfate. The prepared capillaries were investigated for the enantioselective nano-LC separation of a group of racemic pharmaceuticals, namely, α- and ß-blockers, anti-inflammatory drugs, antifungal drugs, norepinephrine-dopamine reuptake inhibitors, catecholamines, sedative hypnotics, antihistaminics, anticancer drugs, and antiarrhythmic drugs. Acceptable separation was achieved for many drugs using reversed phase chromatographic conditions with no separation achieved under normal phase conditions. Colistin sulfate appears to be useful addition to the available macrocyclic antibiotic chiral phases used in liquid chromatography.

Established and In-trial GPCR Families in Clinical Trials: A Review for Target Selection.

The largest family of drug targets in clinical trials constitute of GPCRs (G-protein coupled receptors) which accounts for about 34% of FDA (Food and Drug Administration) approved drugs acting on 108 unique GPCRs. Factors such as readily identifiable conserved motif in structures, 127 orphan GPCRs despite various de-orphaning techniques, directed functional antibodies for validation as drug targets, etc. has widened their therapeutic windows. The availability of 44 crystal structures of unique receptors, unexplored non-olfactory GPCRs (encoded by 50% of the human genome) and 205 ligand receptor complexes now present a strong foundation for structure-based drug discovery and design. The growing impact of polypharmacology for complex diseases like schizophrenia, cancer etc. warrants the need for novel targets and considering the undiscriminating and selectivity of GPCRs, they can fulfill this purpose. Again, natural genetic variations within the human genome sometimes delude the therapeutic expectations of some drugs, resulting in medication response differences and ADRs (adverse drug reactions). Around ~30 billion US dollars are dumped annually for poor accounting of ADRs in the US alone. To curb such undesirable reactions, the knowledge of established and currently in clinical trials GPCRs families can offer huge understanding towards the drug designing prospects including "off-target" effects reducing economical resource and time. The druggability of GPCR protein families and critical roles played by them in complex diseases are explained. Class A, class B1, class C and class F are generally established family and GPCRs in phase I (19%), phase II(29%), phase III(52%) studies are also reviewed. From the phase I studies, frizzled receptors accounted for the highest in trial targets, neuropeptides in phase II and melanocortin in phase III studies. Also, the bioapplications for nanoparticles along with future prospects for both nanomedicine and GPCR drug industry are discussed. Further, the use of computational techniques and methods employed for different target validations are also reviewed along with their future potential for the GPCR based drug discovery.

Iron-Catalyzed Cross-Couplings in the Synthesis of Pharmaceuticals: In Pursuit of Sustainability.

The scarcity of precious metals has led to the development of sustainable strategies for metal-catalyzed cross-coupling reactions. The establishment of new catalytic methods using iron is attractive owing to the low cost, abundance, ready availability, and very low toxicity of iron. In the last few years, sustainable methods for iron-catalyzed cross-couplings have entered the critical area of pharmaceutical research. Most notably, iron is one of the very few metals that have been successfully field-tested as highly effective base-metal catalysts in practical, kilogram-scale industrial cross-couplings. In this Minireview, we critically discuss the strategic benefits of using iron catalysts as green and sustainable alternatives to precious metals in cross-coupling applications for the synthesis of pharmaceuticals. The Minireview provides an essential introduction to the fundamental aspects of practical iron catalysis, highlights areas for improvement, and identifies new fields to be explored.

Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions.

Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.