Medicinal Chemistry Research Articles

Atroposelective catalysis.

Atropisomeric compounds-stereoisomers that arise from the restricted rotation about a single bond-have attracted widespread attention in recent years due to their immense potential for applications in a variety of fields, including medicinal chemistry, catalysis and molecular nanoscience. This increased interest led to the invention of new molecular motors, the incorporation of atropisomers into drug discovery programmes and a wide range of novel atroposelective reactions, including those that simultaneously control multiple stereogenic axes. A diverse set of synthetic methodologies, which can be grouped into desymmetrizations, (dynamic) kinetic resolutions, cross-coupling reactions and de novo ring formations, is available for the catalyst-controlled stereoselective synthesis of various atropisomer classes. In this Review, we generalize the concepts for the catalyst-controlled stereoselective synthesis of atropisomers within these categories with an emphasis on recent advancements and underdeveloped atropisomeric scaffolds beyond stereogenic C(sp2)-C(sp2) axes. We also discuss more complex systems with multiple stereogenic axes or higher-order stereogenicity.

Medicinal perspective of a promising scaffold – dihydropyrimidinones: A review

AbstractDihydropyrimidinones (DHMPs) are the most important pharmacophore in Medicinal Chemistry. The synthetic approach for deriving DHMPs involves the Biginelli reaction or a combination of it with other multi‐component reactions (MCRs). The scaffold has received considerable attention due to its diverse therapeutic activity. This review delves into the exploration of the biological characteristics of DHMPs, which play a pivotal role in various therapeutic areas including “anti‐inflammatory, anti‐HIV, anticancer, antitubercular, antifungal, antibacterial, antihyperglycemic, antihypertensive, anticonvulsant, antimalarial, antioxidant,” reverse transcriptase (RT) inhibitor, antispasmodic, calcium channel blockers, antiproliferative, urease inhibitor, cyclooxygenase (COX‐2), and β‐glucuronidase inhibitor activities. The insights provided in this review have the potential to aid researchers in the formulation of novel drugs, facilitating creation of more resilient, efficient, and safer therapeutic agents with reduced toxicity and minimized adverse effects.

Discovery of novel fluorescent azaindoles with cytotoxic action in A2780 ovarian carcinoma cells.

Azaindole scaffold is a privileged structure in medicinal chemistry and some derivatives have demonstrated to be potential anticancer drugs. Herein, a set of novel azaindoles, comprising the four regioisomers, bearing a morpholine (azaindoles 3a-d) and N-methyl-N-benzylamine (azaindoles 4a-d) groups were prepared. Among these compounds, azaindoles 4 exhibited higher cytotoxicity against the ovarian cancer cell line A2780 and normal dermal fibroblasts compared to azaindoles 3. Furthermore, azaindoles 4b and 4c promoted a delay in the cell cycle of the cancer cell line, inspiring an investigation into the intracellular localization of these derivatives.

Synthesis of Sterically Hindered Dialkyl Ethers via Palladium-Catalyzed Fluoro-alkoxylation of gem-Difluoroalkenes.

Organofluorine compounds are of high value in medicinal and agricultural chemistry. Herein, we report a palladium-catalyzed fluoro-alkoxylation of gem-difluoroalkenes for the synthesis of much more challenging sterically hindered ethers. This reaction represents a direct synthesis method for α-trifluoromethyl ethers with a broad functional group tolerance and excellent regioselectivity. This system employs N-fluorobenzenesulfonimide (NFSI) as an electrophilic fluorine source and alcohols as nucleophilic donors, including but not limited to sterically hindered tert-substituted alcohols.

Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study

N-(Benzothiazole-2-yl)pyrrolamide DNA gyrase inhibitors with benzyl or phenethyl substituents attached to position 3 of the benzothiazole ring or to the carboxamide nitrogen atom were prepared and studied for their inhibition of Escherichia coli DNA gyrase by supercoiling assay. Compared to inhibitors bearing the substituents at position 4 of the benzothiazole ring, the inhibition was attenuated by moving the substituent to position 3 and further to the carboxamide nitrogen atom. A co-crystal structure of (Z)-3-benzyl-2-((4,5-dibromo-1H-pyrrole-2-carbonyl)imino)-2,3-dihydrobenzo[d]-thiazole-6-carboxylic acid (I) in complex with E. coli GyrB24 (ATPase subdomain) was solved, revealing the binding mode of this type of inhibitor to the ATP-binding pocket of the E. coli GyrB subunit. The key binding interactions were identified and their contribution to binding was rationalised by quantum theory of atoms in molecules (QTAIM) analysis. Our study shows that the benzyl or phenethyl substituents bound to the benzothiazole core interact with the lipophilic floor of the active site, which consists mainly of residues Gly101, Gly102, Lys103 and Ser108. Compounds with substituents at position 3 of the benzothiazole core were up to two orders of magnitude more effective than compounds with substituents at the carboxamide nitrogen. In addition, the 6-oxalylamino compounds were more potent inhibitors of E. coli DNA gyrase than the corresponding 6-acetamido analogues.

Rutaecarpine-inspired scaffold-hopping strategy and Ullmann cross-coupling based synthetic approach: Identification of pyridopyrimidinone-indole based novel anticancer chemotypes

Natural products as starting templates have shown historically major contribution to development of drugs. Inspired by the structure–function of an anticancer natural alkaloid Rutaecarpine, the Scaffold-hopped Acyclic Analogues of Rutaecarpine (SAAR) with ‘N’-atom switch (1°-hop) and ring-opening (2°-hop) were investigated. A new synthetic route was developed for an effective access to the analogues, i.e. 2-indolyl-pyrido[1,2-a]pyrimidinones, which involved preparation of N-Boc-N’-phthaloyltryptamine/mexamine-bromides and pyridopyrmidinon-2-yl triflate, a nickel/palladium-catalysed Ullmann cross-coupling of these bromides and triflate, deprotection of phthalimide followed by N-aroylation, and Boc-deprotection. Fourteen novel SAAR-compounds were prepared, and they showed characteristic antiproliferative activity against various cancer cells. Three most active compounds (11a, 11b, and 11c) exhibited good antiproliferative activity, IC50 7.7–15.8 µM against human breast adenocarcinoma cells (MCF-7), lung cancer cells (A549), and colon cancer cells (HCT-116). The antiproliferative property was also observed in the colony formation assay. The SAAR compound 11b was found to have superior potency than original natural product Rutaecarpine and an anticancer drug 5-FU in antiproliferative activities with relatively lower cytotoxicity towards normal breast epithelial cells (MCF10A) and significantly higher inhibitory effect on cancer cells’ migration. The compound 11b was found to possess favourable in silico physicochemical characteristics (lipophilicity-MLOGP, TPSA, and water solubility-ESOL, and others), bioavailability score, and pharmacokinetic properties (GI absorption, BBB non-permeant, P-gp, and CYP2D6). Interestingly, the compound 11b did not show any medicinal chemistry structural alert of PAINS and Brenk filter. The study represents for the first time the successful discovery of new potent anticancer chemotypes using Rutaecarpine natural alkaloid as starting template and reaffirms the significance of natural product-inspired scaffold-hopping technique in drug discovery research.

Mechanical-Force-Induced Non-spontaneous Dehalogenative Deuteration of Aromatic Iodides Enabled by Using Piezoelectric Materials as a Redox Catalyst.

The development of green and efficient deuteration methods is of great significance for various fields such as organic synthesis, analytical chemistry, and medicinal chemistry. Herein, we have developed a dehalogenative deuteration strategy using piezoelectric materials as catalysts in a solid-phase system under ball-milling conditions. This non-spontaneous reaction is induced by mechanical force. D2O can serve as both a deuterium source and an electron donor in the transformation, eliminating the need for additional stoichiometric exogenous reductants. A series of (hetero)aryl iodides can be transformed into deuterated products with high deuterium incorporation. This method not only effectively overcomes existing synthetic challenges but can also be used for deuterium labelling of drug molecules and derivatives. Bioactivity experiments with deuterated drug molecule suggest that the D-ipriflavone enhances the inhibitory effects on osteoclast differentiation of BMDMs in vitro.

Mechanical‐Force‐Induced Non‐spontaneous Dehalogenative Deuteration of Aromatic Iodides Enabled by Using Piezoelectric Materials as a Redox Catalyst

AbstractThe development of green and efficient deuteration methods is of great significance for various fields such as organic synthesis, analytical chemistry, and medicinal chemistry. Herein, we have developed a dehalogenative deuteration strategy using piezoelectric materials as catalysts in a solid‐phase system under ball‐milling conditions. This non‐spontaneous reaction is induced by mechanical force. D2O can serve as both a deuterium source and an electron donor in the transformation, eliminating the need for additional stoichiometric exogenous reductants. A series of (hetero)aryl iodides can be transformed into deuterated products with high deuterium incorporation. This method not only effectively overcomes existing synthetic challenges but can also be used for deuterium labelling of drug molecules and derivatives. Bioactivity experiments with deuterated drug molecule suggest that the D‐ipriflavone enhances the inhibitory effects on osteoclast differentiation of BMDMs in vitro.

Design and synthesis of novel β‐carboline‐bisindole hybrids as potential anticancer agents

We are reporting a short and convenient pathway for the synthesis of novel β‐carboline‐bisindole hybrid compounds from relatively cheap and commercially available chemicals such as tryptamine, dialdehydes and indoles. These newly designed compounds can also be prepared in high yields with the tolerance of many functional groups under mild conditions. Notably, these β‐carboline‐bisindole hybrid compounds exhibited some promising applications as anticancer agents against the three common cancer cell lines MCF‐7 (breast cancer), SK‐LU‐1 (lung cancer), and HepG2 (liver cancer). The two best compounds 5b and 5g inhibited the aforementioned cell lines with the same range of the reference Ellipticine at less than 2 µM. A molecular docking study to gain more information about the interactions between the synthesized molecules and the kinase domain of the EGFR was performed. Therefore, this finding can have significant impacts on the development of future research in medicinal chemistry and drug discovery.

Effect of Tether Length on endo/exo Stereoselectivity in Alkene–Arene meta‐Photocycloaddition Reactions towards the Aphidocolin/Stemodin Scaffolds

AbstractIntramolecular alkene‐arene meta‐photocycloadditions are powerful transformations that use the enhanced reactivity of photoexcited benzene rings to facilitate addition of an alkene 1,3 across donor groups and form complex three‐dimensional fused‐ring systems from readily accessible starting materials. Intramolecular examples have traditionally been restricted to three‐membered tethers, with cycloaddition resulting from exo‐conformation. However, by judicious tether design we have demonstrated that a four‐membered tether can also proceed in good yield; interestingly, via an endo exciplex (1.2 : 1) enabling access to both natural product skeletons and interesting scaffolds for medicinal chemistry research.

Glass Box and Black Box Machine Learning Approaches to Exploit Compositional Descriptors of Molecules in Drug Discovery and Aid the Medicinal Chemist.

The synthetic medicinal chemist plays a vital role in drug discovery. Today there are AI tools to guide next syntheses, but many are "Black Boxes" (BB). One learns little more than the prediction made. There are now also AI methods emphasizing visibility and "explainability" (thus explainable AI or XAI) that could help when "compositional data" are used, but they often still start from seemingly arbitrary learned weights and lack familiar probabilistic measures based on observation and counting from the outset. If probabilistic methods were used in a complementary way with BB methods and demonstrated comparable predictive power, they would provide guidelines about what groups to include and avoid in next syntheses and quantify the relationships in probabilistic terms. These points are demonstrated by blind test comparison of two main types of BB methods and a probabilistic "Glass Box" (GB) method new outside of medicine, but which appears well suited to the above. Because many probabilities can be involved, emphasis is on the predictive power of its simplest explanatory models. There are usually more inactive compounds by orders of magnitude, often a problem for machine learning methods. However, the approaches used here appear to work well for such "real world data".

A survey of isatin hybrids and their biological properties.

The emergence of diverse infections worldwide, which is a serious global threat to human existence, necessitates the urgent development of novel therapeutic candidates that can combat these diseases with efficacy. Molecular hybridization has been established as an efficient technique in designing bioactive molecules capable of fighting infections. Isatin, a core nucleus of an array of compounds with diverse biological properties can be modified at different positions leading to the creation of novel drug targets, is an active area of medicinal chemistry. This review containing published articles from 2005 to 2022 highlights isatin hybrids which have been synthesized and reported in the literature alongside a discussion on their biological properties. The enriched structure-activity relationship studies discussed provides insights for the rational design of novel isatin hybrids with tailored biological properties as effective therapeutic candidates inspired by nature.

Thiophenyl Derivatives of Nicotinamide Are Metabolized by the NAD Salvage Pathway into Unnatural NAD Derivatives That Inhibit IMPDH and Are Toxic to Peripheral Nerve Cancers.

N-Pyridinylthiophene carboxamide (compound 21) displays activity against peripheral nerve sheath cancer cells and mouse xenografts by an unknown mechanism. Through medicinal chemistry, we identified a more active derivative, compound 9, and found that only analogues with structures similar to nicotinamide retained activity. Genetic screens using compound 9 found that both NAMPT and NMNAT1, enzymes in the NAD salvage pathway, are necessary for activity. Compound 9 is metabolized by NAMPT and NMNAT1 into an adenine dinucleotide (AD) derivative in a cell-free system, cultured cells, and mice, and inhibition of this metabolism blocked compound activity. AD analogues derived from compound 9 inhibit IMPDH in vitro and cause cell death by inhibiting IMPDH in cells. These findings nominate these compounds as preclinical candidates for the development of tumor-activated IMPDH inhibitors to treat neuronal cancers.

Silver-Catalyzed (Z)-β-Fluoro-vinyl Iodonium Salts from Alkynes: Efficient and Selective Syntheses of Z-Monofluoroalkenes.

Monofluoroalkenes are stable and lipophilic amide bioisosteres used in medicinal chemistry. However, efficient and stereoselective methods for synthesizing Z-monofluoroalkenes are underdeveloped. We envisage (Z)-β-fluoro-vinyl iodonium salts (Z-FVIs) as coupling partners for the diverse and stereoselective synthesis of Z-monofluoroalkenes. Disclosed herein is the development and application of a silver(I)-catalyzed process for accessing a broad scope of (Z)-FVIs with exclusive Z-stereoselectivity and regioselectivity from alkynes in a single step. Experimental and computational studies provide insight into the mechanism of the catalytic cycle and the role of the silver(I) catalyst, and the reactivity of (Z)-FVIs is explored through several stereospecific derivatizations.

Low-migration, deep photocuring thiobarbituric acid-based one-component visible photoinitiators for high-efficiency photopolymerization

The practical applications of thiobarbiturates in medicinal chemistry exemplifies their exceptional biosafety, which is crucial for developing high-efficiency photopolymerization and low-migration photoinitiators (PIs). In this study, five novel D-π-A visible PIs (ANs) were designed and synthesized via using aniline derivatives as the electron donor (D) and thiobarbituric acid as electron acceptor (A). EPR and steady-state photolysis display that the conjugated structure can be destroyed by intramolecular electron/proton transfer, leading to photobleaching. Real-time infrared (FT-IR) analyses have confirmed effective polymerization of 1,6-hexanediol diacrylate (HDDA) initiated by ANs and ANs/N-methyldiethanolamine (MDEA) under illumination. The experimental molar extinction coefficient (ε) aligns with the oscillator strength (f) calculated via DFT, while the high ε and f of AN-5 facilitate electron transfer and free radical generation, resulting in improved initiation efficiency. The conversion rate of independent initiating polymerization exhibits an impressive 78 %. Moreover, colorless polymer columns initiated by AN-5 and AN-5/MDEA display curing depths of 45 mm and 50 mm, along with photobleaching rates reaching up to 98.7 % and 100 %, respectively. Especially, AN-5 exhibits the mere 0.2 % extraction rate from polymerization films under illumination (60 min). These results indicated the great potential of thiobarbituric acid-based ANs in deep-curing materials, food packaging.

Enhanced Sampling in Molecular Dynamics Simulations: How Many MD Snapshots can be Needed to Reproduce the Biological Behavior?

Since its early days in the 19th century, medicinal chemistry has concentrated its efforts on the treatment of diseases, using tools from areas such as chemistry, pharmacology, and molecular biology. The understanding of biological mechanisms and signaling pathways is crucial information for the development of potential agents for the treatment of diseases mainly because they are such complex processes. Given the limitations that the experimental approach presents, computational chemistry is a valuable alternative for the study of these systems and their behavior. Thus, classical molecular dynamics, based on Newton's laws, is considered a technique of great accuracy, when appropriated force fields are used, and provides satisfactory contributions to the scientific community. However, as many configurations are generated in a large MD simulation, methods such as Statistical Inefficiency and Optimal Wavelet Signal Compression Algorithm are great tools that can reduce the number of subsequent QM calculations. Accordingly, this review aims to briefly discuss the importance and relevance of medicinal chemistry allied to computational chemistry as well as to present a case study where, through a molecular dynamics simulation of AMPK protein (50 ns) and explicit solvent (TIP3P model), a minimum number of snapshots necessary to describe the oscillation profile of the protein behavior was proposed. For this purpose, the RMSD calculation, together with the sophisticated OWSCA method was used to propose the minimum number of snapshots.

Characterization of novel compounds that directly bind to and inactivate the HPV E6 protein for treatment of HPV-associated cervical and oropharyngeal cancers.

e15122 Background: The human papillomavirus (HPV) E6 protein is necessary for viral genome replication and is always expressed in HPV-induced malignancies. We performed in silico screening of chemical libraries for molecules that bind to a pocket on the cancer associated HPV-16 E6 protein. We focused on the protein-protein interaction of E6 with one of its cellular binding partners, the ubiquitin ligase E6AP. In a trimolecular complex with E6, E6AP ubiquitinates p53, leading to its destruction by the proteasome. We designed, synthesized, and characterized >300 compounds that 1) bind to the E6AP interaction surface of the HPV-16 E6 protein; 2) are armed with a ‘warhead’ to make an irreversible bond with a specific cysteine in this HPV-16 E6 binding pocket; 3) and restore levels of p53 and selectively decrease viability of HPV-16 expressing tumor derived cells. Methods: E6 inhibitor optimization was guided by in silico docking strategies, co-crystallization, and medicinal chemistry, followed by biochemical and cellular assays to iteratively design and synthesize molecules with increased E6 inhibitory activities. Results: We used whole protein mass spectrometry to interrogate covalent bonding to E6, showing irreversible binding to the cysteine in the targeted E6 binding pocket without the other 13 cysteines in E6, with Ki in the range of seconds. Biolayer interferometry and fluorescence polarimetry measured blockade of E6 with E6AP, with IC50 in the range of 400-600 nM. To establish in cell inactivation of E6, human cervical cancer derived SiHa cells that express HPV-16 E6 were incubated with compounds, showing dose dependent increase of p53 levels up to 8-fold after 24 hrs, an effect that was not observed in the HPV-16- cell line RPE-1 expressing wild-type p53. Viability of two cervical (SiHa, CaSki) and two oropharyngeal HPV-16+ cancer cell lines (UM-SC-47, UM-SCC-104) was reduced with an IC50 of ~2-3 µM, with an IC50>30µM in RPE-1 cells and telomerase immortalized human keratinocytes. These in vitro and cell-based experiments revealed dependence on the cysteine residue in the E6AP binding pocket of E6. For in vivo proof-of-concept studies, we developed mouse xenograft models, performed by engrafting SiHa, UM-SC-47 and UM-SCC-104 cancer derived cells subcutaneously into the flank of immunodeficient mice. Lead compounds were administered by intraperitoneal injection and demonstrated nearly complete inhibition (> 70% tumor reduction) in HPV-16 tumor growth compared to vehicle. Anti-tumor activity was not observed with the HPV-negative tumor cell line C33A. Conclusions: HPV-16 is identified in about 50% of all cervical cancers and the majority of head and neck malignancies. Inactivation of the HPV E6 protein represents the opportunity for a novel molecular targeted approach for medical treatment of HPV-16 expressing cancers of the cervix and oropharynx.

Gold-catalyzed Reactions of Substituted 1,5-diynes: Recent Advances and their Chemistry

Abstract: Diynes are identified as exceptionally potent and superior substrates in gold-catalyzed organic transformations. Gold (I) and gold (III) complexes exhibit unique activity towards diynes, encouraging the nucleophilic addition of different functional groups both inter and intra- molecularly. In this review, particularly, we focused on recent advances in gold-catalyzed reactions of 1,5-diynes along with their mechanistic aspects. These reactions are interesting for constructing molecular complexity, medicinal chemistry, and material science.

Advances in Synthesis of Indazole Variants: A Comprehensive Review of Transition Metal, Acid/Base and Green Chemistry-based Catalytic Approaches

Background:: Indazole is a heterocyclic motif widely used in medicinal chemistry due to its positive photophysical properties. The development of new methods for synthesizing the indazole scaffold is of great importance in drug discovery. Methods:: This study presents a detailed review of current advances in indazole synthesis, focusing on catalyst-based and green chemistry approaches. The analysis is classified based on acid-base and transition-metal catalysts and green chemistry methods. Catalyst-based advances have given a new impetus to the synthesis of this effective pharmacophore. Results:: The extensive literature on indazole synthesis demonstrates the notable progress achieved through catalyst-based approaches. These methods have enabled researchers to create a wide range of indazole derivatives and analogs, facilitating their application in pharmaceutical products and organic molecules. The use of acid-base and transition-metal catalysts has been particularly effective in enhancing the efficiency and selectivity of indazole synthesis. Conclusion:: Indazoles and their variants are widely used in pharmaceutical products and organic molecules. The recent literature indicates that catalyst-based approaches have resulted in significant advancements in indazole synthesis. This review may be useful for researchers in medicinal chemistry, content chemistry, and agrochemistry.

Recent advances in isatin-based chemosensors: A comprehensive review.

A comprehensive review presents an illuminating exploration of the vast potential of isatin, an easily accessible organic compound. This review is a valuable resource, offering a concise yet comprehensive account of the recent breakthroughs in isatin applications in medicinal chemistry, fluorescence sensing, and organic synthesis. Moreover, it dives into the exciting advancements in isatin-based chemosensors, demonstrating their remarkable ability to detect and recognize diverse cations and anions with exceptional precision. Researchers and scientists in the fields of sensing and organic chemistry will find this review indispensable for sparking innovation and developing cutting-edge technologies with significant real-world impact.