Field Of Medicinal Chemistry Research Articles

Concise approach to γ-(het)aryl- and γ-alkenyl-γ-aminobutyric acids. Synthesis of vigabatrin.

γ-Aminobutyric acid (GABA) and GABA derivatives have attracted increased attention over the years in the fields of medicinal chemistry and chemical biology due to their interesting biological properties and synthetic relevance. Here, we report a short synthetic route to γ-(het)aryl- and γ-alkenyl-γ-aminobutyric acids, including the antiepileptic drug vigabatrin, from readily available donor-acceptor cyclopropanes and ammonia or methylamine. This protocol includes a facile synthesis of 2-oxopyrrolidine-3-carboxamides and their acid hydrolysis to γ-aryl- or γ-alkenyl-substituted GABAs, which can serve as perspective building blocks for the synthesis of various GABA-based N-heterocycles and bioactive compounds.

Recent Advances in the Synthesis and Applications of Phenylquinoline-4-carboxylic Acid Derivatives: A Comprehensive Review

Abstract: Phenylquinoline-4-carboxylic acid derivatives have garnered significant attention in recent years due to their diverse pharmacological and industrial applications. This comprehensive review summarizes the latest advancements in the synthesis and diverse range of applications of phenylquinoline-4-carboxylic acid derivatives. This review provides a brief overview of the significance of phenylquinoline-4-carboxylic acid derivatives in medicinal chemistry. It also explores the structural diversity achievable through modifications at various positions of the phenylquinoline-4-carboxylic acid scaffold. The pharmacological applications of phenylquinoline-4-carboxylic acid derivatives, such as anticancer, antimicrobial, anti-inflammatory, and antiviral activities, are highlighted, underscoring their potential as promising drug candidates. This comprehensive review provides a thorough overview of the recent advances in the synthesis and applications of phenylquinoline-4-carboxylic acid derivatives. The integration of synthetic methodologies, structural modifications and diverse applications makes this review a valuable resource for researchers, scientists and professionals working in the fields of medicinal chemistry.

FDA-approved drugs containing dimethylamine pharmacophore: a review of the last 50 years.

Dimethylamine (DMA) derivatives represent a promising class of compounds with significant potential in the field of medicinal chemistry. DMA derivatives exhibit a diverse range of pharmacological activities, including antimicrobial, antihistaminic, anticancer, and analgesic properties. Their unique chemical structure allows for the modulation of various biological targets, making them valuable candidates for the treatment of numerous diseases. Synthetic strategies for the preparation of DMA derivatives vary depending on the desired biological activity and target molecule. Common synthetic routes involve the modification of the DMA scaffold through functional group manipulation, scaffold hopping, or combinatorial chemistry approaches. Therapeutically, DMA derivatives have shown promise in the treatment of infectious diseases, especially bacterial infections. Additionally, by focusing on particular biochemical pathways involved in tumor growth and metastasis, DMA-based drugs have shown anticancer activity. In addition to their direct pharmacological effects, DMA derivatives can serve as valuable tools in drug delivery systems, prodrug design, and molecular imaging techniques, enhancing their utility in medicinal chemistry research. Overall, DMA derivatives represent a versatile class of compounds with immense potential in medicinal chemistry. Further research and development efforts are warranted to explore their full therapeutic capabilities and optimize their clinical utility in the treatment of various diseases. This article outlines the pharmacological properties, synthetic strategies, and therapeutic applications of DMA derivatives of FDA approved drugs, highlighting their importance in drug discovery and development.

Development of novel transition metal-catalyzed synthetic approaches for the synthesis of a dihydrobenzofuran nucleus: a review.

The synthesis of dihydrobenzofuran scaffolds bears pivotal significance in the field of medicinal chemistry and organic synthesis. These heterocyclic scaffolds hold immense prospects owing to their significant pharmaceutical applications as they are extensively employed as essential precursors for constructing complex organic frameworks. Their versatility and importance make them an interesting subject of study for researchers in the scientific community. While exploring their synthesis, researchers have unveiled various novel and efficient pathways for assembling the dihydrobenzofuran core. In the wake of extensive data being continuously reported each year, we have outlined the recent updates (post 2020) on novel methodological accomplishments employing the efficient catalytic role of several transition metals to forge dihydrobenzofuran functionalities.

Fabrication of thiosemicarbazone-based Pd(II) complexes: structural elucidations, catalytic activity towards Suzuki-Miyaura coupling reaction and antitumor activity against TNBC cells.

Currently, there are many uses of metal complexes, especially in the fields of medicinal chemistry and catalysis. Thus, fabrication of new complexes which perform as a catalyst and chemotherapeutic drug is always a beneficial addition to the literature. Herein, we report three heterocyclic thiosemicarbazone-based Pd(II) complexes [Pd(HL1)Cl] (C1), [Pd(L2)(PPh3)] (C2) and [Pd(L3)(PPh3)]Cl (C3) having coligands Cl and PPh3. Thiosemicarbazone ligands (H2L1, H2L2 and HL3) and the complexes (C1-C3) were characterized methodically using several spectroscopic techniques. Single-crystal X-ray diffraction methods reveal that the structural environment around the metal center of C2 is square planar, while for C1 and C3 it is a slighty distorted square plane. The supramolecular network of compounds was built via hydrogen bonds, C-H⋯π and π⋯π interactions. Density functional theory (DFT) study of the structure of the complexes supports experimental findings. The application of these complexes as catalysts toward Suzuki-Miyaura coupling reactions has been examined with various aryl halides and phenyl boronic acid in PEG 400 solvent. The complexes displayed good biomolecular interactions with DNA/protein, with a binding constant value of the order of 105 M-1. C3 showed greater binding efficacy toward these biomolecules than the other complexes, which might be due to the cationic nature of C3. Furthermore, antitumor activity of the complexes was studied against the human triple-negative breast cancer (TNBC) cell line MDA-MB-231. It was found that C3 was more toxic (IC50 = 10 ± 2.90 μM) toward MDA-MB-231 cells than the other complexes. A known chemotherapeutic drug, 5-fluorouracil, was included as positive control. The programmed cell death mechanism of C3 was confirmed. Additionally, complex-induced apoptosis was confirmed and occurred via a mitochondria-dependent (intrinsic) pathway.

New electrophiles targeting thiols in a reversible covalent manner.

Reversible covalent electrophiles with the advantages of both reversible and covalent interactions receive much attention in the fields of chemical biology and medicinal chemistry. Here, we report two electron-deficient olefins activated by amide and ester, amide-substituted acrylamide and methyl ester-substituted acrylamide, targeting thiols in a reversible covalent manner.

Synthesis of metal-binding amino acids.

The ability for amino acid residues to bind metals underpins the functions of metalloproteins to conduct a plethora of critical processes in living organisms as well as unnatural applications in the fields of catalysis, sensing and medicinal chemistry. The capability to access metal-binding peptides heavily relies on the ability to generate appropriate building blocks. This review outlines recently developed strategies for the synthesis of metal binding non-proteinogenic amino acids. The chemistries to access, as well as to incorporate these amino acids into peptides is presented herein.

Discovery and development of tyrosine-click (Y-click) reaction for the site-selective labelling of proteins.

With the versatile utility of bio-conjugated peptides and proteins in the fields of agriculture, food, cosmetics and pharmaceutical industry, the design of smart protocols to conjugate and modulate biomolecules becomes highly desirable. During this process, the most important consideration for biochemists is the retention of configurational integrity of the biomolecules. Moreover, this type of bioconjugation of peptide and protein becomes frivolous if the reaction is not performed with precise amino acid residues. Hence, chemo-selective, as well as site-selective reactions, that are biocompatible and possess an appropriate level of reactivity are necessary. Based on click chemistry, there are so many tyrosine (Y) conjugation strategies, such as sulfur-fluoride exchange (SuFEx), sulfur-triazole exchange (SuTEx), coupling with π-allyl palladium complexes, diazonium salts, diazodicarboxyamide-based reagents etc. Among these techniques, diazodicarboxyamide-based Y-conjugation, which is commonly known as the "tyrosine-click (Y-click) reaction", has met the expectations of synthetic and biochemists for the tyrosine-specific functionalization of biomolecules. Over the past one and a half decades, significant progress has been made in the classical organic synthesis approach, as well as its biochemical, photochemical, and electrochemical variants. Despite such progress and increasing importance, the Y-click reaction has not been reviewed to document variations in its methodology, applications, and broad utility. The present article aims to provide a summary of the approaches for the modulation of biomolecules at the hotspot of tyrosine residue by employing the Y-click reaction. The article also highlights its application for the mapping of proteins, imaging of living cells, and in the fields of analytical and medicinal chemistry.

Radical hydroboration for the synthesis of organoboron compounds.

Organoboron compounds demonstrate diverse applications in the fields of organic synthesis, materials science, and medicinal chemistry. Compared to the conventional hydroboration reaction, radical hydroboration serves as an alternative approach for the synthesis of organoborons via different mechanisms. In radical hydroboration, a boryl radical is initially generated from homolytic cleavage of a B-H or a B-B bond, which is then added to an unsaturated double bond to deliver a carbon radical. Subsequent hydrogen atom transfer or reduction of the carbon radical to form a carbanion followed by protonation gave the final product. Over the past few years, numerous efforts have been made for efficient synthesis of boryl radicals and the expansion of substrate scope of the radical hydroboration reaction. Here, we discuss the recent advancement of radical hydroboration and its associated mechanisms. Numerous radical hydroboration strategies employing N-heterocyclic carbene borane, bis(pinacolato)diboron and pinacolborane as the boron source were illustrated. Thermochemical, photochemical and electrochemical strategies for the generation of boryl radicals were also discussed in detail.

Synthesis of anti-depressant molecules via metal-catalyzed reactions: a review.

Depression is one of the most mutilating conditions in the world today. It has been difficult to make advancements toward better, more effective therapies since the introduction of antidepressant medicines in the late 1950s. One important field of medicinal chemistry is the synthesis of antidepressant molecules through metal-catalyzed procedures. The important role that different transition metals, including iron, nickel, ruthenium, and others, serve as catalysts in the synthesis of antidepressants is examined in this review. Key structural motifs included in antidepressant drugs such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and others can be synthesized in a variety of effective ways using metal-catalyzed steps. This review examines current developments in the catalytic synthesis of antidepressants and their potential application over the previous thirteen years.

Recent Progress in Environmentally-Friendly Methods for Chalcone Synthesis

Abstract: Chalcones are important scaffolds in the field of medicinal chemistry due to the presence of α,β-unsaturated ketone functionality. They are usually synthesized by reacting an aldehyde with acetophenone in the presence of acid or base using the Claisen-Schmidt condensation reaction. Numerous chalcone derivatives have been developed due to the simplicity of their synthesis, and they have intriguing biological activity that has clinical implications for a range of disorders. The review article discusses the advancements made since 2005 for the synthesis of chalcones derivatives using environmentally friendly methods such as the use of green catalysts and solvents, ultrasonic radiation, microwave energy, and methodologies involving grinding in the absence of solvents.

Identification of potential drug candidates to treat gastritis and associated oxidative stress based on some novel 2-aryl-1H-naphtho[2,3-d]imidazole: synthesis, in vitro and in silico analysis.

To identify potential scaffolds to treat gastritis and oxidative stress, 2-aryl-1H-naphtho[2,3-d]imidazole derivatives (1-15) were synthesized. The synthesis was conveniently carried out by condensing 2,3-diaminonaphthalene with variously substituted aldehydes to yield 15 new 2-aryl-1H-naphtho[2,3-d]imidazole derivatives. Structures of all synthesized compounds were elucidated using MS and NMR spectroscopic techniques. Compounds containing an imidazole moiety have continued to spark interest in the field of medicinal chemistry due to their unique properties. In continuation of this statement, to further explore the biological potential of these types of compounds, newly synthesized imidazole derivatives were evaluated for their inhibitory potential against urease and antioxidant activities. Compounds 4 and 11 were identified as the most potent urease inhibitors in the series, with IC50 values of 34.2 ± 0.72 and 42.43 ± 0.65 μM, respectively. Compounds 1, 3, 6, 11, and 15, with EC50 values in the range of 37-75 μg ml-1, showed significant antioxidant activity. Molecular docking studies of the selected synthesized compounds 3, 4, 9, and 11 were also performed to determine their binding interaction with the jack bean urease. Through docking studies, it was revealed that all the compounds that showed good inhibitory potential against urease fit well within the protein's binding pocket. Furthermore, ADME analysis was carried out to explore the drug-likeness properties of the compounds. The findings of the present work revealed that compounds 4 and 11 could be better options to treat gastritis and associated oxidative stress.

Recent advances in the synthesis and utility of thiazoline and its derivatives.

Thiazolines and their derivatives hold significant importance in the field of medicinal chemistry due to their promising potential as pharmaceutical agents. These molecular entities serve as critical scaffolds within numerous natural products, including curacin A, thiangazole, and mirabazole, and play a vital role in a wide array of physiological reactions. Their pharmacological versatility encompasses anti-HIV, neurological, anti-cancer, and antibiotic activities. Over the course of recent decades, researchers have extensively explored and developed analogs of these compounds, uncovering compelling therapeutic properties such as antioxidant, anti-tumor, anti-microbial, and anti-inflammatory effects. Consequently, thiazoline-based compounds have emerged as noteworthy targets for synthetic endeavors. In this review, we provide a comprehensive summary of recent advancements in the synthesis of thiazolines and thiazoline-based derivatives, along with an exploration of their diverse potential applications across various scientific domains.

30 Years of Kinase Inhibitors: A Historical Overview and some Brazilian Contributions

The past 30 years have been transformative in the landscape of drug discovery, and certainly one of the most ground-breaking areas was kinase research. Since its start in the mid-1990s, kinase studies have reached notable hallmarks, ranging from the development of the first inhibitor, to innovative treatment options for a range of diseases. Today, kinases remain a pivotal protein class in drug discovery. Contemporarily, the Brazilian medicinal chemistry scene has also evolved, and followed up to such trends in the global landscape of research. Notably, the creation of the Summer School of Pharmaceutical and Medicinal Chemistry (EVQFM, in portuguese) in 1995, and its subsequent 30 consecutive editions, has raised the interest and knowledge of multiple generations in Brazil. This review aims to briefly outline the history of kinase inhibitor research, some of its landmarks, and highlight some of the contributions of Brazilian researchers to this important field of medicinal chemistry.

One-pot thermo-induced radical-radical oxidative cross-coupling for symmetrical dimeric thiadiazole monosulfide formation

The production of heterocyclic sulfide is the key building block in various applications, especially in the field of medicinal chemistry. Currently, heterocyclic sulfide was synthesized via deoxygenation of sulfoxide or cross coupling between sulfur sources and halogen compounds. However, these conventional methods suffer from drawbacks such as the use of toxic solvents, harsh reaction conditions, the requirement for transition metal catalysts, inert conditions, and the generation of toxic and corrosive halide-containing waste. In this study, a milder approach using hydrogen peroxide-mediated oxidative cross-coupling of 5-alkylsulfanyl-[1,3,4]thiadiazole-2-thiol successfully produces symmetrical dimeric thiadiazole monosulfide with an isolated yield of 73‒87 %. The molecular structure of bis(2-octylsulfanyl-[1,3,4]thiadiazolyl)-5,5′-sulfide was confirmed by X-ray crystal structure analysis. Interestingly, the formation of dimeric thiadiazole monosulfide undergoes a one-pot thermo-induced pathway. Density functional theory (DFT) indicates the formation of thiadiazole monosulfide is thermodynamically favorable through the cross-coupling reaction between thiadiazole thiyl radical and thiadiazole carbon-centered radical.

Natural isothiocyanates of the genus Capparis as potential agonists of apoptosis and antitumor drugs

BACKGROUND Using gas chromatography-mass spectrometry (GC/MS) analysis, we examined the composition of volatile components present in the yellow and green fruits, seeds, and jam of the scrambling shrub Capparis cartilaginea (C. cartilaginea ). These plant samples were collected from Kibbutz Yotvata in Israel. In all the tested samples, isothiocyanates were identified. Utilizing the PASS program, we ascertained the biological activity of these isothiocyanates present in the Capparis genus. The study results highlighted that all isothiocyanates could potentially act as apoptosis agonists, making them strong candidates for antitumor drugs. This information holds significant value for the fields of medicinal chemistry, pharmacology, and practical medicine. AIM To investigate the volatile components present in the yellow and green fruits, seeds, and jam of the C. cartilaginea shrub using GC/MS analysis, to detect isothiocyanates in all the analyzed plant samples, and to assess the biological activity of these isothiocyanates utilizing the PASS program. METHODS We utilized two primary methods to analyze the volatile compounds present in the yellow and green fruits, seeds, and jams of the C. cartilaginea , native to Israel. We identified biologically active isothiocyanates in these samples. Their anticipated biological activities were determined using the PASS program, with the most dominant activities being apoptosis agonist, anticarcinogenic, and antineoplastic specifically for genitourinary cancer. RESULTS Fruits, seeds, and jams containing isothiocyanates, which exhibit antineoplastic and anticarcinogenic activities, could be suggested for cancer prevention and management. Specific isothiocyanates, with therapeutic potential in this realm, could be recommended as potent anticancer agents in practical medicine following clinical trials. CONCLUSION The discovery that isothiocyanates exhibit potent antineoplastic and anticarcinogenic activities was unexpected. Additionally, certain isothiocyanates demonstrated antifungal, antiviral (specifically against arbovirus), and antiparasitic properties.

Single Step Upgradation of Isatin to Bioactive Fused Heterocycles via Ring Expansion Reactions

AbstractIsatin, also known as indoline‐2,3‐dione, is a fused, N‐heterocyclic aromatic compound first isolated and purified in 1841. Since then, isatin and its derivatives emerged as a hot research topic for the scientific community. The number of research publications on isatin justifies their popularity. Researchers explored isatins and their derivatives as potential candidates in multidisciplinary research areas, including medicinal chemistry, synthetic organic chemistry, and polymer science. Synthetic chemists’ perspective of tailoring isatin and its family members led to more efficient synthesis strategies in which ring‐opening reactions of isatins were particularly significant due to the product's importance. Our investigation aims to group the different types of cascade ring expansion reactions of isatin to synthesise fused heterocyclic compounds such as derivatives of quinolines, quinazolinones, acridines, acridones, and few spiro heterocyclic compounds, all of which highlight an inevitable role in the field of medicinal chemistry.

4-(5-Benzyl-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-dihydrofuran-2-yl)-2-nitrobenzamide

As part of our ongoing attempt to broaden the applications of the amidoxime moiety as a potential source of new antileishmanial agents, this study focuses on the product 4-(5-Benzyl-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-dihydrofuran-2-yl)-2-nitrobenzamide. This unexpected amide was obtained in an 85% yield as the major product with a conventional amidoxime synthesis protocol (Ethanol/Na2CO3) involving the reaction of hydroxylamine and a nitrile group. The formation of this amide derivative instead of the expected amidoxime can be attributed to two complementary effects: the strong electron effect of the nitro group and the influence of ethanol, a polar protic solvent. Alternatively, the desired amidoxime derivative, 4-(5-benzyl-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-dihydrofuran-2-yl)-N′-hydroxy-2-nitrobenzimidamide, was obtained in an 80% yield by an alternative protocol (DMSO/KOtBu). This original compound, featuring a nitro group in the ortho position to the amidoxime, will be further evaluated, both in the field of medicinal chemistry and in other relevant areas, highlighting an unusual method to access amidoximes from hindered substrates.

Second All-Russian school of medical chemistry for young scientists

The second school in medicinal chemistry was held from July 3 to July 6, 2023 at St. Petersburg State University as part of the All-Russian conference with international participation “Ideas and legacy of A.E. Favorsky in organic chemistry” with the support of the St. Petersburg branch of D.I. Mendeleev Russian Chemical Society. Leading experts in the field of medicinal chemistry, young scientists and students from various institutes and universities of Russia took part in the work.

A COMPREHENSIVE REVIEW ON PHARMACOLOGICAL POTENTIALS OF CAFFEINE

Caffeine is a naturally occurring methylxanthine compound found in various plants, such as coffee beans, tea leaves, and cocoa beans. It is widely consumed worldwide in the form of beverages, dietary supplements, and medications. Caffeine exerts its pharmacological effects primarily through its interaction with adenosine receptors, resulting in widespread physiological and neurological changes. In the field of medicinal chemistry, caffeine has been extensively studied due to its diverse pharmacological actions and potential therapeutic applications. This abstract highlights the key pharmacological actions of caffeine and its relevance in medicinal chemistry research. Caffeine acts as a non-selective antagonist of adenosine receptors, particularly the A1 and A2A subtypes. By inhibiting adenosine binding, caffeine prevents the activation of these receptors, leading to increased neural activity and the release of neurotransmitters such as dopamine and glutamate. This mechanism of action underlies caffeine’s stimulant effects, including increased alertness, reduced fatigue, and improved cognitive function. Caffeine exhibits broncho dilatory effects by acting as a phosphodiesterase inhibitor, primarily targeting phosphodiesterase type 4 (PDE4). Inhibition of PDE4 prevents the breakdown of cyclic adenosine monophosphate (cAMP), leading to smooth muscle relaxation and bronchodilation. This property of caffeine has been utilized in the treatment of asthma and chronic obstructive pulmonary disease (COPD). Furthermore, caffeine possesses diuretic properties by inhibiting the reabsorption of sodium in the renal tubules. This leads to increased water excretion and urine production. The diuretic effects of caffeine have found applications in the management of fluid overload conditions, such as edema and heart failure. Additionally, caffeine has been investigated for its potential anticancer properties. Several studies have shown that caffeine can enhance the cytotoxic effects of certain chemotherapeutic agents, inhibit DNA repair mechanisms, and induce apoptosis in cancer cells. These findings have sparked interest in caffeine as an adjuvant therapy for cancer treatment, although further research is needed to establish its clinical efficacy and safety. In conclusion, caffeine exhibits a wide range of pharmacological actions, making it a versatile compound in medicinal chemistry research. Its interactions with adenosine receptors, phosphodiesterase, and renal tubules contribute to its stimulant, broncho dilatory, diuretic, and potentially anticancer effects. The understanding of caffeine’s pharmacological actions provides valuable insights for the development of novel drugs and therapeutic approaches in various fields of medicine.