Privileged Pharmacophore Research Articles

Efficient synthetic strategies for fused pyrimidine and pyridine derivatives: A review

AbstractPyrimidine and its derivatives play a paramount role in drug discovery as privileged pharmacophores with considerable chemical and biological significance and its presence in genes. This review aims to assemble a systematic evaluation of synthetic tactics of various fused pyrimidine derivatives containing nitrogen heterocycles such as pyridopyridines, pyridopyrimidines, and pyrimidopyrimidine from a pharmacological point of view and deliver an overview of methodologies presenting the chemistry of fused pyrimidine derivatives. The review details the importance of various catalysts and ring substitution using various electrophilic and nucleophilic reagents. These synthetic strategies were elaborated based on the different synthetic routes that lead to the specific type of pyrimidine and pyridine fused derivatives. The literature accumulates various developments in one‐pot condensation, the Knoevenagel–Michael addition mechanism, microwave and ultrasound irradiation, intramolecular cyclization, nano‐catalytic reactions, and so forth. Short reaction times, catalyst reusability, solvent‐free conditions, excellent yields, and stereo‐selectivity are some of the benefits of certain synthetic approaches.

Silver-catalyzed direct conversion of epoxides into cyclopropanes using N-triftosylhydrazones

Epoxides, as a prominent small ring O-heterocyclic and the privileged pharmacophores for medicinal chemistry, have recently represented an ideal substrate for the development of single-atom replacements. The previous O-to-C replacement strategy for epoxides to date typically requires high temperatures to achieve low yields and lacks substrate range and functional group tolerance, so achieving this oxygen-carbon exchange remains a formidable challenge. Here, we report a silver-catalyzed direct conversion of epoxides into trifluoromethylcyclopropanes in a single step using trifluoromethyl N-triftosylhydrazones as carbene precursors, thereby achieving oxygen-carbon exchange via a tandem deoxygenation/[2 + 1] cycloaddition. The reaction shows broad tolerance of functional groups, allowing routine cheletropic olefin synthesis in a strategy for the net oxygen-carbon exchange reaction. The utility of this method is further showcased with the late-stage diversification of epoxides derived from bioactive natural products and drugs. Mechanistic experiments and DFT calculations elucidate the reaction mechanism and the origin of the chemo- and stereoselectivity.

Medicinal chemistry-based perspective on thiophene and its derivatives: Exploring the structural insights to discover plausible druggable leads

Thiophene is a privileged pharmacophore in medicinal chemistry owing to its diversified biological attributes. The thiophene moiety has been ranked 4th in US FDA drug approval of small drug molecules,...

Design, Synthesis, and Molecular Docking Studies of Integrated Benzylidenethiazolidine‐2,4‐Dione and Thieno[2,3‐d]pyrimidine‐6‐Carboxylate Derivatives as Potent Antidiabetic agents

AbstractThe present work describes the synthesis of new series of 5‐arylidene‐thiazolidine‐2,4‐dione, thieno[2,3‐d]pyrimidine‐6‐carboxylate derivatives 9 a–o. A variety of spectroscopic techniques like IR, 13CNMR, 1HNMR and LCMS were used to establish the presence of the every synthesized scaffold. The antioxidant activity of the target compounds has been studied by three different methods indicated the significant DPPH, NO and H2O2. Further, all the derivatives were evaluated for the in vitro antidiabetic potential against human pancreatic α‐amylase (PDB ID: 5NN3) and human lysosomal acid α‐glucosidase (PDB ID: 2QV4) enzymes followed by Molecular docking studies to ascertain the binding interactions of the compounds with the enzymes. The compounds 9 b and 9 g containing methoxy groups were found to exhibit potent antidiabetic and antioxidant activity. Therefore, it was rationalized that two privileged pharmacophores i. e. aryledenethiazolidine‐2,4‐dione and thieno[2,3‐d]pyrimidine‐6‐carboxylate assimilated hybrids, may be beneficial as lead template for the advance of future anti‐diabetic agents. Thus, benzylidenethiazolidine‐2,4‐dione and thieno[2,3‐d], the two preferred pharmacophores, were rationalized. Assimilation of ‐pyrimidine‐6‐carboxylate hybrids could be advantageous as a lead template for the development of new anti‐diabetic drugs.

Multifunctional agents against Alzheimer’s disease based on oxidative stress: Polysubstituted pyrazine derivatives synthesized by multicomponent reactions

As Alzheimer’s disease (AD) is a neurodegenerative disease with a complex pathogenesis, the exploration of multi-target drugs may be an effective strategy for AD treatment. Multifunctional small molecular agents can be obtained by connecting two or more active drugs or privileged pharmacophores by multicomponent reactions (MCRs). In this paper, two series of polysubstituted pyrazine derivatives with multifunctional moieties were designed as anti-AD agents and synthesized by Passerini-3CR and Ugi-4CR. Since the oxidative stress plays an important role in the pathological process of AD, the antioxidant activities of the newly synthesized compounds were first evaluated. Subsequently, selected active compounds were further screened in a series of AD-related bioassays, including Aβ1-42 self-aggregation and deaggregation, BACE-1 inhibition, metal chelation, and protection of SH-SY5Y cells from H2O2-induced oxidative damage. Compound A3B3C1 represented the best one with multifunctional potencies. Mechanism study showed that A3B3C1 acted on Nrf2/ARE signaling pathway, thus increasing the expression of related antioxidant proteins NQO1 and HO-1 to normal cell level. Furthermore, A3B3C1 showed good in vitro human plasma and liver microsome stability, indicating a potential for further development as multifunctional anti-AD agent.

Synthesis of 3-Functionalized 4-Quinolones from Readily Available Anthranilic Acids.

We report herein an efficient synthesis of 3-functionalized 4-quinolones, a class of privileged pharmacophores found in numerous biologically and pharmaceutically active compounds. Our synthetic strategy features a telescoped two-step sequence starting from readily available anthranilic acids and functionalized methane derivatives bearing an electron-withdrawing group, such as methyl sulfones, methyl ketones, and acetonitrile. The method delivers good to excellent yields for a variety of structurally diverse substrates, showing good functional group tolerability. We believe that the disclosed method offers a highly efficient and practical entry to functionalized 4-quinolones under mild conditions that is amenable to preparative-scale synthesis.

Indole-Based Macrocyclization by Metal-Catalyzed Approaches

This review is dedicated to the different varieties of macrocycles synthesis bearing indole units in their architecture by metal-catalyzed strategies. The progress of the new macrocyclization approaches is persisted be a keen area of research. Macrocycles contain a wide variety of molecules, and among those, heteroaryl motifs are valuable constituents that provide an attractive feature to macrocyclic systems. Indole represents one of the privileged pharmacophores against a variety of targets with various biological applications. Among the nitrogen-based heterocycles, indole plays a prominent role in organic synthesis, medicinal chemistry, pharmaceuticals, natural products synthesis, agrochemicals, dye and fragrances, and drug design. These scaffolds are widely distributed in several bioactive natural products and synthetic macrocycles constructed against a specific biochemical target and the most common constituents of naturally occurring molecules. Due to its immense importance, the progress of novel approaches for the synthesis of indole-based scaffolds has increased steadily. The majority of the macrocycles synthesis proceeds through the macrolactamization and macrolactonization, as well as the C–C bond macrocyclization process described by metal-catalyzed ring-closing metathesis (RCM) and coupling reactions. Among macrocyclizations, metal-catalyzed approaches are considered one of the most powerful tools for synthetic chemists in the design of a variety of macrocycles. This review aims to give a comprehensive insight into the synthesis of varieties of macrocycles bearing indole scaffold catalyzed by various transition metals that emerged in the literature over the last two decades. We hope that this review will persuade synthetic chemists to search for novel strategies for the C–C bond macrocyclization by metal-catalyzed protocols.

Thiazolidinone-Heterocycle Frameworks: A Concise Review of Their Pharmacological Significance.

Molecular hybridization is deemed an optimistic approach in drug design and the discovery of novel biologically active molecules as it may advance their affinity and potency while concurrently decreasing associated resistance and side effects. Approximately 20 % of approved drugs were developed using this approach in the past few years. Thiazolidinone is one of the privileged pharmacophores in medicinal chemistry and is associated with various biological activities; it forms a functional unit in several FDA-approved drugs. Consequently, this pharmacophore has attracted the attention of many research groups to further explore its pharmacological relevance by coupling it with other pharmacophoric moieties. This review presents a concise account of scholarly research exploits directed at the biological activities of newly synthesized thiazolidinone-tagged molecular hybrids. Focused attention is given to the existing structural activity relationship in each compound library and the toxicity profile of potent compounds including in silico docking studies (where applicable). This work would provide a base on which new pharmaceuticals with improved potency can be modelled.

Cu2O-Decorated Marigold Hollow Alumina Microsphere Nanoparticles as a Robust and Efficient Catalyst for the Synthesis of Isoquinolones

The design of a heterogeneous catalyst involving plentifully accessible transition metal-based nanoparticles for the sustainable synthesis of valuable N-heterocycles has attracted much attention in recent years. The isoquinolone moiety is one of the privileged pharmacophores found in various natural products and drug molecules, so development of its synthetic methodology has always been in demand. Herein, we report a novel Cu2O-decorated marigold hollow alumina microsphere nanocatalytic system for the synthesis of isoquinolones using 2-bromobenzonitriles and ketones under neat condition. The prepared nanocatalyst was well characterized by scanning electron microscopy, high-resolution transmission electron microscopy, powder X-ray diffraction, energy-dispersive X-ray analysis, X-ray photoelectron spectroscopy, and Brunauer–Emmett–Teller techniques. The present method is facile and showed better green chemistry metrics such as low E-factor, high reaction mass efficiency, and high turnover number and can be reused for five cycles without any loss in its catalytic activity.

Synthetic methodology-enabled discovery of a tunable indole template for COX-1 inhibition and anti-cancer activity

Establishing structure–activity relationships (SAR) for privileged pharmacophores, such as the indole scaffold, is a key step in the early stages of drug discovery. Herein, we report the synthesis and preliminary SAR studies on substituted 6-hydroxyindole-7-carboxylates as a tunable framework for COX inhibition and anti-cancer activity. To facilitate the SAR discovery, a modular synthetic methodology was employed which enabled the synthesis of the substituted indoles. From the synthesized compounds, five displayed COX-1 inhibition activity in a colorimetric assay with their intracellular activity further confirmed by a cell-based target validation assay. Following molecular docking analyses, key interactions between the active compounds and the COX enzymes were elucidated. In addition to the identified COX inhibitors, two compounds showed selective cytotoxicity against Hep-G2, MCF-7, and LnCaP. The mechanism of cell death was investigated and found to include induction of Caspase-3 activation and cleavage, down-regulation of anti-apoptotic proteins Bcl-xL and Bcl-2, and upregulation of Bax. Finally, two representative compounds were confirmed to induce cell cycle arrest at the G1/G0 stage. In summary, the 6-hydroxyindole-7-carboxylate framework shows promising versatility as a template for the discovery of anti-inflammation or anti-cancer agents, given the evidence of its COX inhibitory and anti-cancer activities herein presented.

Novel one-pot synthesis of a library of 2-aryloxy-1,4-naphthoquinone derivatives. Determination of antifungal and antibacterial activity.

The development of new antibiotics and inexpensive antifungals is an important field of research. Based on the privileged pharmacophore of lawsone, a series of phenolic ether derivatives of 1,4-naphthoquinone were synthesized easily in one step in reasonable yields. All the new compounds were characterized and tested as potential antifungal and antibacterial agents against Candida albicans, Escherichia coli and Staphylococcus aureus. Compound 55 has significant antibacterial action (as good as or better than the controls) against E. coli and S. aureus. Against C. albicans, compounds 38, 46, 47 and 60 were the best candidates as antifungals. Using a qualitative structure–activity analysis, a correlation between molar mass and antimicrobial activity was identified, regardless of the substituent group on the phenolic moiety, except for 55 and 63, where electronic effects seem more important. An in silico evaluation of the absorption, distribution, metabolism and excretion (ADME) for 37, 50, 55 and 63 was made, indicating that the classic Lipinski's rule of five applies in all cases.

Recent Updates on the Synthesis of Bioactive Quinoxaline-Containing Sulfonamides

Quinoxaline is a privileged pharmacophore that has broad-spectrum applications in the fields of medicine, pharmacology and pharmaceutics. Similarly, the sulfonamide moiety is of considerable interest in medicinal chemistry, as it exhibits a wide range of pharmacological activities. Therefore, the therapeutic potential and biomedical applications of quinoxalines have been enhanced by incorporation of the sulfonamide group into their chemical framework. The present review surveyed the literature on the preparation, biological activities and structure-activity relationship (SAR) of quinoxaline sulfonamide derivatives due to their broad range of biomedical activities, such as diuretic, antibacterial, antifungal, neuropharmacological, antileishmanial, anti-inflammatory, anti-tumor and anticancer action. The current biological diagnostic findings in this literature review suggest that quinoxaline-linked sulfonamide hybrids are capable of being established as lead compounds; modifications on quinoxaline sulfonamide derivatives may give rise to advanced therapeutic agents against a wide variety of diseases.

Diversity-oriented functionalization of 2-pyridones and uracils

Heterocycles 2-pyridone and uracil are privileged pharmacophores. Diversity-oriented synthesis of their derivatives is in urgent need in medicinal chemistry. Herein, we report a palladium/norbornene cooperative catalysis enabled dual-functionalization of iodinated 2-pyridones and uracils. The success of this research depends on the use of two unique norbornene derivatives as the mediator. Readily available alkyl halides/tosylates and aryl bromides are utilized as ortho-alkylating and -arylating reagents, respectively. Widely accessible ipso-terminating reagents, including H/DCO2Na, boronic acid/ester, terminal alkene and alkyne are compatible with this protocol. Thus, a large number of valuable 2-pyridone derivatives, including deuterium/CD3-labeled 2-pyridones, bicyclic 2-pyridones, 2-pyridone-fenofibrate conjugate, axially chiral 2-pyridone (97% ee), as well as uracil and thymine derivatives, can be quickly prepared in a predictable manner (79 examples reported), which will be very useful in new drug discovery.

Direct Synthesis of Bicyclic Acetals via Visible Light Catalysis.

SummaryPolysubstituted bicyclic acetals are a class of privileged pharmacophores with a unique 3D structure and an adjacent pair of hydrogen bond acceptors. The key, fused acetal functionality is often assembled, via intramolecular cyclization, from linear substrates that are not readily available. Herein, we report a formal cycloaddition between cinnamyl alcohols and cyclic enol ethers under ambient photoredox catalysis conditions. Polysubstituted bicyclic acetals can be prepared in one step from readily available building blocks. Employment of sugar-derived enol ethers allows easy access to a library of scaffolds with intriguing conformation and medicinal chemistry potential.

Fused and Substituted Pyrimidine Derivatives as Profound Anti-Cancer Agents.

The rationale behind drug design is the strategic utilization of heterocyclic fragments with specific physicochemical properties to form molecular targeted agents. Among the heterocyclic molecules, pyrimidine has proved to be a privileged pharmacophore for various biological cancer targets. The anti-cancer potential of small molecules with fused and substituted pyrimidines can be enhanced through bioisosteric replacements and altering their ADME parameters. Although several small molecules are used in cancer chemotherapy, oncology therapeutics has various limitations, especially in their routes of administration and their concurrent side effects. Such pernicious effects may be overcome, via selective biological targeting. In this review, the biological targets, to inhibit cancer, have been discussed. The structural activity relationship of fused and substituted pyrimidines was studied. Eco-friendly synthetic approaches for pyrimidine derivatives have also been discussed. This review will give an insight to scientists and researchers of medicinal chemistry discipline to design small molecules having a pyrimidine scaffold with high anti-cancer potential.

Coumarin derivatives with anticancer activities: An update.

Cancer can invade or spread to almost all parts of the body. The increasing morbidity and high mortality of cancer create a great demand for the development of novel anticancer drugs. Coumarin derivatives are ubiquitous in nature and can readily interact with diverse enzymes and receptors in cancer cells via weak bond interactions; hence, coumarin is a highly privileged pharmacophore for the development of novel anticancer agents. This review will focus on the recent development of coumarin hybrids as potential anticancer agents covering articles published from 2019 to 2020.

The Pictet-Spengler Reaction Updates Its Habits.

The Pictet-Spengler reaction (P-S) is one of the most direct, efficient, and variable synthetic method for the construction of privileged pharmacophores such as tetrahydro-isoquinolines (THIQs), tetrahydro-β-carbolines (THBCs), and polyheterocyclic frameworks. In the lustro (five-year period) following its centenary birthday, the P-S reaction did not exit the stage but it came up again on limelight with new features. This review focuses on the interesting results achieved in this period (2011–2015), analyzing the versatility of this reaction. Classic P-S was reported in the total synthesis of complex alkaloids, in combination with chiral catalysts as well as for the generation of libraries of compounds in medicinal chemistry. The P-S has been used also in tandem reactions, with the sequences including ring closing metathesis, isomerization, Michael addition, and Gold- or Brønsted acid-catalyzed N-acyliminium cyclization. Moreover, the combination of P-S reaction with Ugi multicomponent reaction has been exploited for the construction of highly complex polycyclic architectures in few steps and high yields. The P-S reaction has also been successfully employed in solid-phase synthesis, affording products with different structures, including peptidomimetics, synthetic heterocycles, and natural compounds. Finally, the enzymatic version of P-S has been reported for biosynthesis, biotransformations, and bioconjugations.

Morpholine as ubiquitous pharmacophore in medicinal chemistry: Deep insight into the structure-activity relationship (SAR).

Morpholine is a versatile moiety, a privileged pharmacophore and an outstanding heterocyclic motif with wide ranges of pharmacological activities due to different mechanisms of action. The ability of morpholine to enhance the potency of the molecule through molecular interactions with the target protein (kinases) or to modulate the pharmacokinetic properties propelled medicinal chemists and researchers to synthesize morpholine ring by the efficient ways and to incorporate this moiety to develop various lead compounds with diverse therapeutic activities. The present review primarily focused on discussing the most promising synthetic leads containing morpholine ring along with structure-activity relationship (SAR) to reveal the active pharmacophores accountable for anticancer, anti-inflammatory, antiviral, anticonvulsant, antihyperlipidemic, antioxidant, antimicrobial and antileishmanial activity. This review outlines some of the recent effective chemical synthesis for morpholine ring. The review also highlighted the metabolic liability of some clinical drugs containing this nucleus and various researches on modified morpholine to enhance the metabolic stability of drugs as well. Drugs bearing morpholine ring and those under clinical trials are also mentioned with the role of morpholine and their mechanism of action. This review will provide the necessary knowledge base to the medicinal chemists in making strategic structural changes in designing morpholine derivatives.

Cascade CuH-Catalysed Conversion of Alkynes to Enantioenriched 1,1-Disubstituted Products.

Enantioenriched α-aminoboronic acids play a unique role in medicinal chemistry and have emerged as privileged pharmacophores in proteasome inhibitors. Additionally, they represent synthetically useful chiral building blocks in organic synthesis. Recently, CuH-catalyzed asymmetric alkene hydrofunctionalization has become a powerful tool to construct stereogenic carbon centers. In contrast, applying CuH cascade catalysis to achieve reductive 1,1-difunctionalization of alkynes remains an important, but largely unaddressed, synthetic challenge. Herein, we report an efficient strategy to synthesize α-aminoboronates via CuH-catalyzed hydroboration/hydroamination cascade of readily available alkynes. Notably, this transformation selectively delivers the desired 1,1-heterodifunctionalized product in favor of alternative homodifunctionalized, 1,2-heterodifunctionalized, or reductively monofunctionalized byproducts, thereby offering rapid access to these privileged scaffolds with high chemo-, regio- and enantioselectivity.

Copper‐Catalyzed Radical Cross‐Coupling of Oxime Esters and Sulfinates for Synthesis of Cyanoalkylated Sulfones

AbstractSulfones and alkylnitriles play a significant role in both organic and medicinal chemistry, as versatile synthetic building blocks and privileged pharmacophores in many natural products and bioactive compounds. Herein, a room‐temperature, copper‐catalyzed radical cross‐coupling of redox‐active cycloketone oxime esters and sulfinate salts is described for the first time. Key to the success of this process involves catalytic generation of a cyclic iminyl radical and ensuing ring‐opening C−C bond cleavage. The resultant cyanoalkyl radical is then engaged in cross‐coupling with nucleophilic sulfinate to form cyanoalkylated sulfones.