Scaffolds For Drug Discovery Research Articles

Catalytic Asymmetric [4+1] Spiroannulation of α-Bromo-β-Naphthols with Azoalkenes by an Electrophilic Dearomatization/S RN 1-Debromination Approach

Catalytic Asymmetric [4+1] Spiroannulation of α-Bromo-β-Naphthols with Azoalkenes by an Electrophilic Dearomatization/S _RN 1-Debromination Approach

Metabolic Profiling of Vasorelaxant Extract from Malvaviscus arboreus by LC/QTOF-MS.

We aimed to develop a standardized methodology to determine the metabolic profile of organic extracts from Malvaviscus arboreus Cav. (Malvaceae), a Mexican plant used in traditional medicine for the treatment of hypertension and other illnesses. Also, we determined the vasorelaxant activity of these extracts by ex vivo rat thoracic aorta assay. Organic extracts of stems and leaves were prepared by a comprehensive maceration process. The vasorelaxant activity was determined by measuring the relaxant capability of the extract to decrease a contraction induced by noradrenaline (0.1 μM). The hexane extract induced a significant vasorelaxant effect in a concentration- and endothelium-dependent manner. Secondary metabolites, such as polyunsaturated fatty acids, terpenes and one flavonoid, were annotated by liquid chromatography/quadrupole time-of-flight mass spectrometry (LC/QTOF-MS) in positive ion mode. This exploratory study allowed us to identify bioactive secondary metabolites from Malvaviscus arboreus, as well as identify potentially-new vasorelaxant molecules and scaffolds for drug discovery.

Stereospecific N-acylation of indoles and corresponding microwave mediated synthesis of pyrazinoindoles using hexafluoroisopropanol

Abstract We envisioned a facile construction of diversified pyrazinoindoles by using 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) as the solvent and catalyst, hence eliminating metal catalyzed routes for its development. The process is facilitated by HFIP that has emerged as a powerful tool for development of novel fused heterocycles. This cascade approach blends the asymmetric N-acylation with consecutive intramolecular cyclisation via Pictet-Spengler reaction as an efficient tool forming overall two stereogenic centers. Our approach deals with incorporation of l -amino acid on substituted indoles to provide the chiral N-acylated indole precursor followed by cyclisation to access pyrazinoindole derivatives in high enantiomeric excess up to >99% in good to excellent yields, which have great potential as molecular scaffolds in drug discovery. We have also described the mechanistic course of the reaction based on density functional theory.

Curcumin as Scaffold for Drug Discovery against Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) are one of major public health problems and their impact is continuously growing. Curcumin has been proposed for the treatment of several of these pathologies, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) due to the ability of this molecule to reduce inflammation and aggregation of involved proteins. Nevertheless, the poor metabolic stability and bioavailability of curcumin reduce the possibilities of its practical use. For these reasons, many curcumin derivatives were synthetized in order to overcome some limitations. In this review will be highlighted recent results on modification of curcumin scaffold in the search of new effective therapeutic agents against NDs, with particular emphasis on AD.

The Importance of Rhodanine Scaffold in Medicinal Chemistry: A Comprehensive Overview.

After the clinical use of epalrestat that contains a rhodanine ring, in type II diabetes mellitus and diabetic complications, rhodanin-based compounds have become an important class of heterocyclic in the field of medicinal chemistry. Various modifications to the rhodanine ring have led to a broad spectrum of biological activity of these compounds. Synthesis of rhodanine derivatives, depended on advenced throughput scanning hits, frequently causes potent and selective modulators of targeted enzymes or receptors, which apply their pharmacological activities through different mechanisms of action. Rhodanine-based compounds will likely stay a privileged scaffold in drug discovery because of different probability of chemical modifications of the rhodanine ring. We have, therefore reviewed their biological activities and structure activity relationship.

Alpha-Glucosidase and Alpha-Amylase Inhibitory Activities, Molecular Docking, and Antioxidant Capacities of Salvia aurita Constituents.

Diabetes mellitus (DM) is one of the most dangerous metabolic diseases with a high rate of mortality worldwide. It is well known that insulin resistance and deficiency in insulin production from pancreatic β-cells are the main characteristics of DM. Due to the detrimental side effects of the current treatment, there is a considerable need to develop new effective antidiabetic drugs, especially alpha-glucosidase and alpha-amylase inhibitors with lesser adverse effects. These inhibitors are known to be directly involved in the delay of carbohydrate digestion, resulting in a reduction of glucose absorption rate and, consequently, reducing the postprandial rise of plasma glucose, which can reduce the risk of long-term diabetes complications. Furthermore, natural products are well-known sources for the discovery of new bioactive compounds that can serve as scaffolds for drug discovery, including that of new antidiabetic drugs. The phytochemical investigation of Salvia aurita collected from Hogobach Pass, Eastern Cape Province, South Africa (SA), yielded four known abietane diterpenes namely carnosol (1), rosmanol (2), 7-methoxyrosmanol (3), 12-methoxycarnosic acid (4), and one flavonoid named 4,7-dimethylapigenin (5). Structural characterization of these isolated compounds was conducted using 1 and 2D NMR, in comparison with reported spectroscopic data. These compounds are reported for the first time from S. aurita. The biological evaluation of the isolated compound against alpha-glucosidase exhibited strong inhibitory activities for 3 and 2 with the half maximal inhibitory concentration (IC50) values of 4.2 ± 0.7 and 16.4 ± 1.1 µg/mL respectively, while 4 and 1 demonstrated strong alpha-amylase inhibitory activity amongst the isolated compounds with IC50 values of 16.2 ± 0.3 and 19.8 ± 1.4 µg/mL. Molecular docking analysis confirms the strong inhibitory activity of 3 against alpha-glucosidase. Additionally, excellent antioxidant capacities were displayed by 2, 1, and 3, respectively, with oxygen radical absorbance capacity (ORAC) (25.79 ± 0.01; 23.96 ± 0.01; 23.94 ± 0.02) mM Trolox equivalent (TE)/g; 1 and 2 as ferric-ion reducing antioxidant power (FRAP) (3.92 ± 0.002; 1.52 ± 0.002) mM ascorbic acid equivalent (AAE)/g; 5 and 2 as Trolox equivalent absorbance capacity (TEAC) (3.19 ± 0.003; 2.06 ± 0.003) mM TE/g. The methanolic extract of S. aurita is a rich source of abietane diterpenes with excellent antioxidant and antidiabetic activities that can be useful to modulate oxidative stress and might possibly be excellent candidates for the management of diabetes. This is the first scientific report on the phytochemical isolation and biological evaluation of the alpha-glucosidase and alpha-amylase inhibitory activities of Salvia aurita.

Asymmetric Spirocyclization Enabled by Iridium and Brønsted Acid-Catalyzed Formal Reductive Cycloaddition

A catalytic, enantioselective spirocyclization of formanilides or formylindolines and enamides has been developed herein. The reaction proceeds through a sequential iridium-catalyzed hydrosilylatio...

Recent Applications of Benzimidazole as a Privileged Scaffold in Drug Discovery.

Benzimidazole is an aromatic bicyclic heterocycle that is regarded as a valuable privileged scaffold in medicinal chemistry. Many marketed drugs and natural products containing benzimidazole scaffolds exert great influence in fighting various diseases, such as hypertension, peptic ulcers, parasitic infections, and cancer. In this review, we introduce the pharmacological applications of some marketed drugs and lead compounds with a focus on anticancer agents, reporting the corresponding data to show the biological activities at their targets. The publications in this review encompass those from 2014 to 2019.

Levoglucosenone and Its Pseudoenantiomer iso-Levoglucosenone as Scaffolds for Drug Discovery and Development.

The bioderived platform molecule levoglucosenone (LGO, 1) and its readily prepared pseudoenantiomer (iso-LGO, 2) have each been subjected to α-iodination reactions with the product halides then being engaged in palladium-catalyzed Ullmann cross-coupling reactions with various bromonitropyridines. The corresponding α-pyridinylated derivatives such as 11 and 24, respectively, are produced as a result. Biological screening of such products reveals that certain of them display potent and selective antimicrobial and/or cytotoxic properties. In contrast, the azaindoles obtained by reductive cyclization of compounds such as 11 and 12 are essentially inactive in these respects. Preliminary mode-of-action studies are reported.

Steroidal Pyrazolines As a Promising Scaffold in Drug Discovery

Steroidal pyrazolines constitute an interesting and promising scaffold for drug discovery as they display diverse chemical reactivity and a wide range of biological activities. Literature reports indicate potent anticancer potential of steroidal pyrazolines along with broad-spectrum antimicrobial activities. Strong neuroprotective effects with steroids possessing pyrazoline moiety have also been observed. Among all the therapeutically active steroidal pyrazolines, D-ring-substituted derivatives are highly potent and the least toxic. The current and futuristic research approaches in this area are focused towards the exploration of this promising scaffold to develop molecules with widespread pharmacological activities. This review article mainly covers the synthetic and pharmacological aspects of steroidal pyrazolines, which will assist the medicinal chemists working in this area in their scientific endeavors.

Methods for generating and screening libraries of genetically encoded cyclic peptides in drug discovery.

Drug discovery has traditionally focused on using libraries of small molecules to identify therapeutic drugs, but new modalities, especially libraries of genetically encoded cyclic peptides, are increasingly used for this purpose. Several technologies now exist for the production of libraries of cyclic peptides, including phage display, mRNA display and split-intein circular ligation of peptides and proteins. These different approaches are each compatible with particular methods of screening libraries, such as functional or affinity-based screening, and screening in vitro or in cells. These techniques allow the rapid preparation of libraries of hundreds of millions of molecules without the need for chemical synthesis, and have therefore lowered the entry barrier to generating and screening for inhibitors of a given target. This ease of use combined with the inherent advantages of the cyclic-peptide scaffold has yielded inhibitors of targets that have proved difficult to drug with small molecules. Multiple reports demonstrate that cyclic peptides act as privileged scaffolds in drug discovery, particularly against 'undruggable' targets such as protein-protein interactions. Although substantial challenges remain in the clinical translation ofhits from screens of cyclic-peptide libraries, progress continues to be made in this area, with an increasing number of cyclic peptides entering clinical trials. Here, we detail the various platforms for producing and screening libraries of genetically encoded cyclic peptides and discuss and evaluate the advantages and disadvantages of each approach when deployed for drug discovery.

3',4'-Dihydro-2'H-spiro[indoline-3,1'-isoquinolin]-2-ones as potential anti-cancer agents: synthesis and preliminary screening.

Both tetrahydroisoquinolines (THIQs) and oxindoles (OXs) display a broad range of biological activities including anti-cancer activity, and are therefore recognized as two privileged scaffolds in drug discovery. In the present study, 24 3′,4′-dihydro-2′H-spiro[indoline-3,1′-isoquinolin]-2-ones, designed as molecular hybrids of THIQ and OX, were synthesized and screened in vitro against 59 cell lines in the NCI-60 screen. Twenty compounds displayed weak to moderate inhibition of cell proliferation; among them, three compounds displayed at least 50% inhibition of cell proliferation. The compounds appeared to target primarily renal cell cancer lines; however, leukaemia, melanoma, non-small cell lung cancer, prostate, ovarian and even breast cancer cell lines were also affected. Therefore, this class of spirooxindoles may provide useful leads in the search for new anti-cancer agents.

Flavones as a Privileged Scaffold in Drug Discovery: Current Developments.

Flavones are one of the main subclasses of flavonoids with diverse pharmacological properties. They have been reported to possess antimalarial, antimicrobial, anti-tuberculosis, anti-allergic, antioxidant, anti-inflammatory activities, among others. The present review summarizes the recent information on the pharmacological properties of naturally occurring and synthetic flavones. Scientific publications referring to natural and synthetic flavones in relation to their biological activities were hand-searched in databases such as SciFinder, PubMed (National Library of Medicine), Science Direct, Wiley, ACS, SciELO, Springer, among others. As per the literature, seventy-five natural flavones were predicted as active compounds with reference to their IC50 (<20 µg/mL) in in vitro studies. Also, synthetic flavones were found active against several diseases. As per the literature, flavones are important sources for the potential treatment of multifactorial diseases. However, efforts toward the development of flavone-based therapeutic agents are still needed. The appearance of new catalysts and chemical transformations is expected to provide avenues for the synthesis of unexplored flavones, leading to the discovery of flavones with new properties and biological activities.

Pyrrolo[2,1-a]isoquinoline scaffold in drug discovery: advances in synthesis and medicinal chemistry.

Pyrrolo[2,1-a]isoquinoline (PIq) is a nitrogen heterocyclic scaffold of diverse alkaloids endowed with several biological activities, including antiretroviral and antitumor activities. Several 5,6-dihydro-PIq (DHPIq) alkaloids, belonging to the lamellarins' family, have proved to be cytotoxic to tumor cells, as well as reversers of multidrug resistance. In this review, we provide an overview of the main achievements over the last decade in the synthetic approaches to access libraries of PIq compounds along with a survey, as comprehensive as possible, of bioactivity, mechanism of action, pharmacophore and structure-activity relationships of synthetic analogs of DHPIq-based alkaloids. The focus is mainly on the potential exploitation of the (DH)PIq scaffold in design and development of novel antitumor drugs.

Design, crystal structures and sustainable synthesis of family of antipyrine derivatives: Abolish to bacterial and parasitic infection

This work explores the facile synthesis of a series of antipyrine acetylinic framework (3a-3h). The newly synthesized compounds are recognized by IR, NMR (1H, 13C), X-ray diffraction. This collection played indispensable role in the development of biologically active agents. Our goal is to enable adoption of green chemistry within the pharmaceutical industry for the benefit of society, industry and the environment. This work articulates a new possible scaffold for drug discovery against protozoal pathogens (Entamoeba histolytica and Giardia lamblia) and bacterial strain (Staphylococcus aureus, Vibrio cholera, E. coli, Bacillus subtillus). The purpose of the present undertaking is to put low price anti parasitic drug using green technology. It is envisaged that the alliance of anti pyrine derivative and acetylene framework into a single scaffold boosts the effectiveness of anti bacterial as well as anti-parasitic treatment and may be vital for meeting future challenges in medicinal world.

Novel Isatin-based activator of p53 transcriptional functions in tumor cells.

Bioinorganic medicinal chemistry remains a hot field for research aimed at developing novel anti-cancer treatments. Discovery of metal complexes as potent antitumor chemotherapeutics such as cisplatin led to a significant shift of focus toward organometallic/ bioinorganic compounds containing transition metals and their chelates as novel scaffolds for drug discovery. In that way, transition metal complexes coordinated to essential biological scaffolds represent a highly promising class of compounds for design of novel target-specific therapeutics. Here, we report novel data on p53 activating Isatin-based Cu(II) complex exhibiting cytotoxic properties towards HCT116 and MCF7 tumor cell lines, as confirmed by cell viability assay and flow cytometry analysis of apoptosis. Furthermore, putative p53-mediated mechanism of action of this compound is supported by quantitative analysis of TP53, MDM2 and PUMA genes expression, as well as luciferase-based p53 pathway activation assay. Multiplex immunoassay analysis of inflammatory markers revealed potential modulation of several cytokines and chemokines.

Leveraging Atropisomerism to Obtain a Selective Inhibitor of RET Kinase with Secondary Activities toward EGFR Mutants.

Unstable atropisomerism is innate in many common scaffolds in drug discovery, commonly existing as freely rotating aryl-aryl bonds. Such compounds can access the majority of dihedral conformations around the bond axis; however, most small molecules bind their target within a narrow range of these available conformations. The remaining accessible conformations can interact with other proteins leading to compound promiscuity. Herein, we leverage atropisomerism to restrict the accessible low-energy dihedral conformations available to a promiscuous kinase inhibitor and achieve highly selective and potent inhibitors of the oncogenic target rearranged during transfection (RET) kinase. We then evaluate our lead inhibitor against kinases that were predicted to bind compounds in a similar conformational window to RET, discovering a potent inhibitor of drug-resistant epidermal growth factor receptor (EGFR) mutants including L858R/T790M/C797S EGFR. Leveraging atropisomerism to restrict accessible conformational space should be a generally applicable strategy due to the prevalence of unstable atropisomerism in drug discovery.

Carbazole Derivatives as Antiviral Agents: An Overview.

Viruses represent the most common cause of infectious diseases worldwide and those with rapid propagation and high infection rates cause human and animal pandemics. These fast-spreading diseases are generally treated with antiviral drugs but, often, drug resistance occurs because of the ability of the pathogens to mutate rapidly and become less susceptible to the treatments. Even though new antivirals have been approved, e.g., in HIV (human immunodeficiency virus) and HCV (hepatitis C virus) therapeutic areas, the need to dispose of new pharmaceutical tools for the management of infections that still have no treatment is of growing interest. In these areas, carbazole represents an important privileged scaffold in drug discovery. Many compounds with a carbazolic core have been developed and some of them have shown antiviral activity. This review provides an overview on some already known carbazole derivatives, pointing the attention on the running progresses in identifying new molecules with carbazolic structure, that have shown interesting and encouraging in vitro and in vivo properties. These drugs may be exploited as valid alternatives in antiviral therapy.

A Perspective on Thiazolidinone Scaffold Development as a New Therapeutic Strategy for Toxoplasmosis

Toxoplasma gondii is one of the most successful parasites due to its ability to infect a wide variety of warm-blooded animals. It is estimated that one-third of the world's population is latently infected. The generic therapy for toxoplasmosis has been a combination of antifolates such as pyrimethamine or trimethoprim with either sulfadiazine or antibiotics such as clindamycin with a combination with leucovorin to prevent hematologic toxicity. This therapy shows limitations such as drug intolerance, low bioavailability or drug resistance by the parasite. There is a need for the development of new molecules with the capacity to block any stage of the parasite's life cycle in humans or in a different type of hosts. Heterocyclic compounds are promissory drugs due to its reported biological activity; for this reason, thiazolidinone and its derivatives are presented as a new alternative not only for its inhibitory activity against the parasite but also for its high selectivity-level with high therapeutic index. Thiazolidinones are an important scaffold known to be associated with anticancer, antibacterial, antifungal, antiviral, antioxidant, and antidiabetic activities. The molecule possesses an imidazole ring that has been described as an antiprotozoal agent with antiparasitic properties and less toxicity. Thiazolidinone derivatives have been reportedly as building blocks in organic chemistry and as scaffolds for drug discovery. Here we present a perspective of how structural modifications of the thiazolidinone core could generate new compounds with high anti-parasitic effect and less toxic results.

Solid‐Phase Synthesis of Tetramic Acid via Resin‐Bound Enol Ethers as a Privileged Scaffold in Drug Discovery

AbstractThis paper reports the practical synthesis of a tetramic acid scaffold on solid phase using simple, commercially available building blocks under mild conditions. Acyclic precursors were assembled on solid phase in four steps, and cyclization was achieved by Wittig olefination. The target compounds contained three points of diversification and allowed for further modifications while still being attached to the resin. Solid‐phase synthesis represents a method of choice, particularly for parallel synthesis, because the intermediates can be isolated simply and quickly by washing the resin beads, which typically takes only minutes.magnified image