Natural Product-like Scaffolds Research Articles

Controlled Aerobic Oxidative Dimerization of Hydroxystilbenoids by Chromium Catalysis.

Aerobic oxidative dimerization of hydroxystilbenoids is described. A Cr-salen complex catalyzed the dimerization of hydroxystilbenoids in 1,1,1,3,3,3-hexafluoroisopropanol to form compounds comprising a natural product-like scaffold (quadrangularin) or its precursor depending on the aromatic substituents. The addition of a catalytic amount of scandium triflate [Sc(OTf)3] to the reaction system altered the reaction outcome to give a different natural product-like compound, a pallidol-type dimer.

Design, synthesis, biological evaluation and in silico studies of N-(pyridin-2-yl)-benzamides derivatives as quorum sensing inhibitors

The emergence of bacterial resistance against chemical treatment is a big threat to the efficacy of bacterial infection treatment. One of the major reasons for resistance to antimicrobial agents is growth of microorganisms in biofilm. An alternative treatment by developing novel anti-biofilm agents had led to the concept of quorum sensing (QS) inhibition, which primarily targets QS signaling system by disrupting cell-cell communication. Therefore, this study focuses to develop novel antimicrobial agents which work by QS inhibition and act as anti-biofilm agents against Bacillus Subtilis and Pseudomonas Aeruginosa. In this work, a natural product-like scaffolds from Asinex library were screened and N-pyridin-2-yl-benzamide moiety was chosen to design and synthesize. Synthesized compounds were evaluated for potential anti-biofilm activity for the aforesaid microorganisms and also checked for cell viability assay, where two potent compounds 3a and 3c showed their static biofilm activity to ∼59% and ∼58% at 100 μM, respectively against Bacillus subtilis. These synthesized compounds were investigated for physicochemical parameters and binding mode prediction through molecular modelling tools. The interactions and stability of these compounds showed better affinity towards TasA and LasR proteins from Bacillus subtilis and Pseudomonas aeruginosa, respectively. Furthermore, molecular dynamic simulation for 100 ns was executed in order to appreciate the stability of the protein and ligand complex. The overall results promised that N-pyridin-2-yl-benzamide derivatives can be discovered as a lead in developing potent anti-quorum sensing agents against various bacteria.

Considerations for Achieving Maximized DNA Recovery in Solid-Phase DNA-Encoded Library Synthesis.

DNA-encoded library (DEL) technology enables rapid, economical synthesis, and exploration of novel chemical space. Reaction development for DEL synthesis has recently accelerated in pace with a specific emphasis on ensuring that the reaction does not compromise the integrity of the encoding DNA. However, the factors that contribute to a reaction's "DNA compatibility" remain relatively unknown. We investigated several solid-phase reactions and encoding conditions and determined their impact on DNA compatibility. Conditions that minimized the accessibility of reactive groups on the DNA encoding tag (switching solvent, low temperature, double-stranded encoding tag) significantly improved compatibility. We showcased this approach in the multistep synthesis of an acyldepsipeptide (ADEP1) fragment, which preserved 73% of DNA for a >100-fold improvement over canonical conditions. These results are particularly encouraging in the context of multistep reaction sequences to access natural product-like scaffolds and more broadly underscore the importance of reconciling the biophysical properties and reactivity of DNA with chemistry development to yield high-quality libraries of those scaffolds.

Late-Stage Conversion of a Metabolically Labile Aryl Methyl Ether-Containing Natural Product to Fluoroalkyl Analogues.

We report the conversion of aryl methyl ethers and phenols into six fluoroalkyl analogues through late-stage functionalization of a natural product-derived FDA-approved therapeutic. This series of short synthetic sequences exploits a combination of both modern and traditional methods and demonstrates that some recently reported methods do not always work as well as desired on a natural product-like scaffold. Nonetheless, reaction optimization can deliver sufficient quantities of each target analogue for medicinal chemistry purposes. In some cases, classical reactions and synthetic sequences still outcompete modern organofluorine transformations, which should encourage the continued search for improved reactions. Overall, the project provides a valuable synthetic roadmap for medicinal chemists to access a range of fluorinated therapeutic candidates with distinct physicochemical properties relative to the original O-based analogue.

Comparative subtractive proteomics based ranking for antibiotic targets against the dirtiest superbug: Acinetobacter baumannii

Multidrug-resistant Acinetobacter baumannii is indeed to be the most successful nosocomial pathogen responsible for myriad infections in modern health care system. Computational methodologies based on genomics and proteomics proved to be powerful tools for providing substantial information about different aspects of A. baumannii biology that made it possible to design new approaches for treating multi, extensive and total drug resistant isolates of A. baumannii. In this current approach, 35 completely annotated proteomes of A. bauamnnii were filtered through a comprehensive subtractive proteomics pipeline for broad-spectrum drug candidates. In total, 10 proteins (KdsA, KdsB, LpxA, LpxC, LpxD, GpsE, PhoB, UvrY, KdpE and OmpR) could serve as ideal candidates for designing novel antibiotics. The work was extended with KdsA enzyme for structure information, prediction of intrinsic disorders, active site details, and structure based virtual screening of library containing natural product-like scaffolds. Most of the enzyme structure has fixed three-dimensional conformation. The selection of inhibitor for KdsA enzyme was based on druglikeness, pharmacokinetics and docking scores. Compound-4636 (5-((3-chloro-5-methyl-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)methoxy)-2-(((1-hydroxy-4-methylpentan-2-yl)amino)methyl)phenol) was revealed as the most potent inhibitor against A. baumannii KdsA enzyme having Gold fitness score of 77.68 and Autodock binding energy of −6.2 kcal/mol. The inhibitor completely follows Lipinski rule of five, Ghose rule, and Egan rule. Molecular dynamics simulation for KdsA and KdsA-4636 complex was performed for 100 ns to unveil what conformational changes the enzyme underwent in the absence and presence of the inhibitor, respectively. The average root means square deviation (RMSD) for both systems was found 3.5 Å, which signifies stable structure of the enzyme in both bounded and unbounded states. Absolute binding energy using Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) reflected high affinity and vigorous interactions of the inhibitor with enzyme active residues. Findings of the current study could open up new avenues for experimentalists to design new potent antibiotics by targeting the targets screened in this study.

Complex Polycycles from Simple Propargyl Alcohols through Ruthenium-Catalyzed Cascade Reactions and One-Pot Procedures

Multiple bond-forming cascade transformations and one-pot procedures are valuable tools in organic synthesis and drug discovery. These atom-economical processes provide rapid access to natural product-like scaffolds from simple precursors. Herein, we report on ruthenium-catalyzed one-pot conversions of simple 1-alkenyl propargyl alcohols with cyclic 3-ketolactones and dienophiles. Thereby, structurally diverse fused polycycles and functionalized bicyclic structures are accessible from a common precursor with high selectivity. Some of the new drug-like molecules exhibit cytotoxic activity against KB cells.

Access to Fused Tricyclic γ-Butyrolactones, A Natural Product-like Scaffold.

Serendipitous findings of an acid mediated skeletal rearrangement of bicyclo-β-ketoester having cyclopropyl ring to access fused tricyclic γ-butyrolactones has been described. This novel transformation has been optimized to 30 mol% p-toluenesulfonic acid (p-TSA) in toluene using Dean-Stark apparatus, where the aldol condensation, cyclopropyl ring opening followed by cyclization took place in a single-pot operation. The resulting tricyclic compounds are interesting chemotype with natural product resemblance and may find useful applications in the future.

Natural product analogues: towards a blueprint for analogue-focused synthesis.

For the first time a general overview of approaches to the synthesis of natural product analogues is presented. This reflects a process of evolution of natural product synthesis which has accelerated in the years since the implementation of diversity-oriented synthesis, which has emerged in parallel with collective synthesis, diverted total synthesis and the preparation of truncated natural products optimised for biological activity. A method involving computational assessment for the validation of core-modified natural product analogues is discussed.

A biosynthesis-inspired approach to over twenty diverse natural product-like scaffolds.

A synthetic approach to diverse scaffolds was developed that was inspired by diterpene biosynthesis. Initial scaffolds, generated using Diels-Alder reactions of furyl-functionalised amines, were transformed into alternative scaffolds using cleavage, ring expansion, annulation and rearrangement reactions. In total, 25 diverse scaffolds were prepared that were shown to have high natural product-likeness.

Construction of Enantiopure Taxoid and Natural Product-like Scaffolds Using a C-C Bond Cleavage/Arylation Reaction.

An approach to construct enantiopure complex natural product-like frameworks, including the first reported synthesis of a C17 oxygenated taxoid scaffold, is presented. A palladium-catalyzed C-C activation/cross-coupling is utilized to access these structures in a short sequence from (+)-carvone; the scope of this reaction is explored.

Protonation-Triggered Carbon-Chain Elongation in Geranyl Pyrophosphate Synthase (GPPS)

Geranyl pyrophosphate synthase (GPPS) is responsible for the formation of geranyl pyrophosphate (GPP), a key intermediate which has the potential to derive numerous functionally and structurally diverse groups of terpenoid natural products via the head-to-tail assembly of two isoprenoid building blocks (dimethylallyl diphosphate, DMAPP; isopentenyl diphosphate, IPP) in the initial step of carbon-chain elongation during isoprenoid biosynthesis. Elucidating the detailed catalytic mechanism in GPPS is of significant interests as it will stimulate the development of new technology in generating novel natural productlike scaffolds. It has been known that the catalytic reaction involves three sequential steps, namely “ionization–condensation–elimination”, but the exact catalytic mechanism has remained controversial since the 1970s. By employing Born–Oppenheimer density functional quantum mechanics (B3LYP/6-31(+)G*)/molecular mechanics dynamics simulations, here we suggest that GPPS adopts a protonation-induced catalytic mechanism, in which there are two key points different from previously hypothesized mechanisms. The first point is the protonation of DMAPP which is essential in the initial “ionization” process but was not considered in previous mechanisms. The second point is the stereoselectivity of proton transfer (HS) from IPP to H76 residue in the final “elimination” step as identified in our simulations, in contrast to the proton transfer from IPP (HR) to DMAPP in previous hypotheses. Moreover, the free energy barrier of the whole assembly reaction is predicted to be 18.8 ± 0.6 kcal/mol, in agreement with the experimental value of 18.0 kcal/mol. Furthermore, the catalytic roles of the two Mg2+ ions at the bottom of the active site are also discussed, and key residues (K44, R47, R94, R95, K180, K235, and E73 around DMAPP and IPP) responsible for the stabilization of transition states, intermediates, and/or product are clarified. These findings can assist site-directed mutagenesis experiments in protein engineering as well as inhibitor designs.

ChemInform Abstract: Bioinspired Direct Access to Benzofuroindolines by Oxidative [3 + 2] Annulation of Phenols and Indoles.

The straightforward entry to benzofuroindoline containing natural product-like scaffolds has been achieved by a challenging [3 + 2] oxidative coupling between phenols and indoles. The reaction proceeds by NIS-oxidation of the indole followed by the trapping of the resulting electrophilic intermediate by phenol.

Cyclopentitol as a scaffold for a natural product-like compound library for drug discovery

A concise and efficient synthesis of cyclopentitols as a scaffold for a two-dimensional compound library for drug discovery is described. Starting from d-mannose, the key steps are Wittig olefination and ring-closing metathesis (RCM) followed by a [3,3]-sigmatropic Overmann rearrangement to form an sp3-rich, natural product-like scaffold from which a focused compound library with different functionalities is prepared.

Mechanism of Assembling Isoprenoid Building Blocks 1. Elucidation of the Structural Motifs for Substrate Binding in Geranyl Pyrophosphate Synthase.

Terpenes (isoprenoids) represent the most functionally and structurally diverse group of natural products. Terpenes are assembled from two building blocks, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP or DPP), by prenyltransferases (PTSs). Geranyl pyrophosphate synthase (GPPS) is the enzyme that assembles DPP and IPP in the first step of chain elongation during isoprenoid biosynthesis. The mechanism by which GPPS assembles the terpene precursor remains unknown; elucidating this mechanism will help in development of new technology to generate novel natural product-like scaffolds. With classic and QM/MM MD simulations, an "open-closed" conformation change of the catalytic pocket was observed in the GPPS active site at its large subunit (LSU), and a critical salt bridge between Asp91(in loop 1) and Lys239(in loop 2) was identified. The salt bridge is responsible for opening or closing the catalytic pocket. Meanwhile, the small subunit (SSU) regulates the size and shape of the hydrophobic pocket to flexibly host substrates with different shapes and sizes (DPP/GPP/FPP, C5/C10/C15). Further QM/MM MD simulations were carried out to explore the binding modes for the different substrates catalyzed by GPPS. Our simulations suggest that the key residues (Asp91, Lys239, and Gln156) are good candidates for site-directed mutagenesis and may help in protein engineering.

Bioinspired direct access to benzofuroindolines by oxidative [3 + 2] annulation of phenols and indoles.

The straightforward entry to benzofuroindoline containing natural product-like scaffolds has been achieved by a challenging [3 + 2] oxidative coupling between phenols and indoles. The reaction proceeds by NIS-oxidation of the indole followed by the trapping of the resulting electrophilic intermediate by phenol.

Diazoacetoacetate enones for the synthesis of diverse natural product-like scaffolds.

Diazoacetoacetate enones are a new class of Michael acceptors that enable the efficient construction of natural product-like scaffolds. Through their Michael addition reactions, including those with silyl enol ethers, indoles, pyrroles, and amines, δ-functionalized diazoacetoacetates are formed in high yield and with overall operational efficiency. Subsequent catalytic dinitrogen extrusion reactions provide access to a diverse series of natural product-like carbo- and heterocyclic ring systems in only three steps from commercial materials.

Diverted organic synthesis (DOS): accessing a new, natural product inspired, neurotrophically active scaffold through an intramolecular Pauson–Khand reaction

Drawing inspiration from the impressive neurotrophic activity exhibited by the natural product paecilomycine A, we have designed a new natural product-like scaffold employing an intramolecular Pauson-Khand reaction. Several compounds based on the new designer scaffold exhibited promising neurotrophic activity and are worthy of further biological evaluation. Our findings also highlight the importance of a DOS strategy in creating useful therapeutical leads.

Enantioselective synthesis of C-linked spiroacetal-triazoles as privileged natural product-like scaffolds

The enantioselective synthesis of novel C-linked spiroacetal-triazoles 10 is reported. The key step involves reaction of acetylenic spiroacetal 11 with several azides by the Copper-Catalysed Azide-Alkyne Cycloaddition (CuAAC). The biologically privileged spiroacetal scaffold 11 was prepared from silyl-protected Weinreb amide 19 using several reliable Grignard additions and a highly diastereoselective enzymatic kinetic resolution.

Synthesis of natural-product-like scaffolds in unprecedented efficiency via a 12-fold branching pathway

Tying the knot! The marriage of two-directional synthesis and tandem reactions allows access to twelve skeletally diverse scaffolds in just fifteen reactions. Two-directional synthesis yields a symmetrical linear “rope-like” keto-dienoate which is then subjected to twelve separate tandem reactions to “tie the rope in knots” thus creating twelve diverse natural product-like scaffolds containing useful functionality for further elaboration.

The chemist as astronaut: Searching for biologically useful space in the chemical universe

Chemical space whether defined by small molecules or large proteins is larger than can be usefully explored. One of the challenges of drug discovery is thus the definition of the overlap between chemical space, biologically useful space and pharmacological space and how this may be employed in the discovery of new small molecule drugs. Despite the decrease in drug discovery productivity in recent years there is no shortage of targets for small molecule intervention, including stroke, pain, neurodegenerative diseases, inflammation and bacterial and viral infections. Only an extremely small fraction of available chemical space has thus far been explored and it is likely that prior synthetic constraints and bias to existing frameworks and scaffolds have contributed to this. Several approaches are being employed to explore more fruitful paths to discovery. These include recognition that existing therapeutic entities already occupy validated pharmacological space and thus are good leads, the use of molecular fragments that permits a broader exploration of chemical space, and the role of templates that permit fragments to combine to generate active species. Finally, a new focus on natural product-like scaffolds from both synthetic methodologies and the genetic reengineering of biosynthetic pathways is likely to prove valuable. However the exploration of chemical space will alone not solve the current deficit in drug discovery productivity. It is necessary to recognize that cellular environments are not the dilute homogeneous solutions of many screening systems and that a more integrated systems approach will serve to maximize any success of chemical space exploration.