Interest In Medicinal Chemistry Research Articles

An Artificial Intelligence–Supported Medicinal Chemistry Project: An Example for Incorporating Artificial Intelligence Within the Pharmacy Curriculum

ObjectiveThis study aims to integrate and use AI to teach core concepts in a medicinal chemistry course and to increase the familiarity of pharmacy students with AI in pharmacy practice and drug development. Artificial intelligence (AI) is a multidisciplinary science that aims to build software tools that mimic human intelligence. AI is revolutionizing pharmaceutical research and patient care. Hence, it is important to include AI in pharmacy education to prepare a competent workforce of pharmacists with skills in this area. MethodsAI principles were introduced in a required medicinal chemistry course for first-year pharmacy students. An AI software, KNIME, was used to examine structure-activity relationships for 5 drugs. Students completed a data sheet that required comprehension of molecular structures and drug-protein interactions. These data were then used to make predictions for molecules with novel substituents using AI. The familiarity of students with AI was surveyed before and after this activity. ResultsThere was an increase in the number of students indicating familiarity with use of AI in pharmacy (before vs after: 25.3% vs 74.5%). The introduction of AI stimulated interest in the course content (> 60% of students indicated increased interest in medicinal chemistry) without compromising the learning outcomes. Almost 70% of students agreed that more AI should be taught in the PharmD curriculum. ConclusionThis is a successful and transferable example of integrating AI in pharmacy education without changing the main learning objectives of a course. This approach is likely to stimulate student interest in AI applications in pharmacy.

Asymmetric α-Fluoroalkyl-α-Amino Acids: Recent Advances in Their Synthesis and Applications.

Due to the specific properties provided by fluorine atoms to biomolecules, amino acids with fluorinated side chains are of great interest for medicinal chemistry and chemical biology. Among them, α-fluoroalkyl-α-amino acids constitute a unique class of compounds. In this review, we outline the strategies adopted for their syntheses in enantiopure or enantioenriched forms and their incorporation into peptides. We then describe the consequences of the introduction of fluorine atoms in these compounds for the modulation of their hydrophobicity and the control of their conformation. Emerging applications are presented in the areas of enzyme inhibition, medicinal chemistry, hydrolytic stability of peptides, antimicrobial peptides, PET, and 19F NMR probes.

An Insight into Fluorinated Imines and Hydrazones as Antibacterial Agents.

Fluorinated imines (Schiff bases) and fluorinated hydrazones are of particular interest in medicinal chemistry due to their potential usefulness in treating opportunistic strains of bacteria that are resistant to commonly used antibacterial agents. The present review paper is focused on these fluorinated molecules revealing strong, moderate or weak in vitro antibacterial activities, which have been reported in the scientific papers during the last fifteen years. Fluorinated building blocks and reaction conditions used for the synthesis of imines and hydrazones are mentioned. The structural modifications, which have an influence on the antibacterial activity in all the reported classes of fluorinated small molecules, are highlighted, focusing mainly on the importance of specific substitutions. Advanced research techniques and innovations for the synthesis, design and development of fluorinated imines and hydrazones are also summarized.

Library Synthesis of Cyclobutanol Derivatives by Hyperbaric [2+2] Cycloaddition Reactions

AbstractCyclobutanes are attracting a growing interest in medicinal chemistry because of their unique structure and potentially advantageous pharmacological properties. Specifically, 1,3‐disubstituted cyclobutanes have been explored as conformationally restricted propyl isosteres in drug development. In this study, a concise two‐diversification‐point library of 3‐amino‐3‐[(arenesulfonyl)methyl]cyclobutanols was synthesized through a hyperbaric [2+2] cycloaddition reaction between sulfonyl allenes and benzyl vinyl ether as the key step. Three different sulfonyl allenes were used for synthesizing the core structures that were further derivatized by the addition of up to seven amines. The amino groups were incorporated in a moderate to excellent diastereoselectivity through conjugate addition to the four‐membered‐ring scaffolds. Overall, this synthesis process demonstrates the potential for further chemical expansion and fragment growth in drug development.

Trifluoromethyl Rhodium-Carbynoid in [2+1+2] Cycloadditions.

Trifluoromethyl cationic carbyne (CF3 C+ :) possessing dual carbene-carbocation behavior emulated as trifluoromethyl metal-carbynoid (CF3 C+ =M) has not been explored yet, and its reaction characteristics are unknown. Herein, a novel α-diazotrifluoroethyl sulfonium salt was prepared and used in Rh-catalyzed three-component [2+1+2] cycloadditions for the first time with commercially available N-fused heteroarenes and nitriles, yielding a series of imidazo[1,5-a] N-heterocycles that are of interest in medicinal chemistry, in which the insertion of trifluoromethyl Rh-carbynoid (CF3 C+ =Rh) into C=N bonds of N-fused heteroarenes was involved. This strategy demonstrates synthetic applications in late-stage modification of pharmaceuticals, construction of CD3 -containing N-heterocycles, gram-scale experiments, and synthesis of phosphodiesterase 10A inhibitor analog. These highly valuable and modifiable imidazo[1,5-a] N-heterocycles exhibit good antitumor activity in vitro, thus demonstrating their potential applications in medicinal chemistry.

Eugenol derivatives containing 1,2,3-triazole-chalcone hybrids for shikimate kinase inhibition

Eugenol, a primary component of clove oil, is a compound of considerable interest in medicinal chemistry due to its demonstrated potential as an effective agent in various therapeutic applications. In this study, a series of eugenol derivatives were designed and synthesized based on the hybridization of eugenol with 1,2,3-triazole and chalcone moieties. Compound 5j and 5k were denoted as lead structures against Mycobacterium tuberculosis Shikimate Kinase (MtSK). Moreover, the docking studies indicated that both the eugenol and triazole fragments in compound 5j and 5k played a pivotal role in the inhibition activity of MtSK, owing to their binding interactions with Arg58, Pro118, and Arg136 residues. Furthermore, in silico drug-likeness prediction analysis suggested that the majority of the synthesized compounds exhibit good oral bioavailability based on their molecular properties and Lipinski’s Rule of Five predictions.

Trifluoromethyl Rhodium‐Carbynoid in [2+1+2] Cycloadditions

AbstractTrifluoromethyl cationic carbyne (CF3C+:) possessing dual carbene‐carbocation behavior emulated as trifluoromethyl metal‐carbynoid (CF3C+=M) has not been explored yet, and its reaction characteristics are unknown. Herein, a novel α‐diazotrifluoroethyl sulfonium salt was prepared and used in Rh‐catalyzed three‐component [2+1+2] cycloadditions for the first time with commercially available N‐fused heteroarenes and nitriles, yielding a series of imidazo[1,5‐a] N‐heterocycles that are of interest in medicinal chemistry, in which the insertion of trifluoromethyl Rh‐carbynoid (CF3C+=Rh) into C=N bonds of N‐fused heteroarenes was involved. This strategy demonstrates synthetic applications in late‐stage modification of pharmaceuticals, construction of CD3‐containing N‐heterocycles, gram‐scale experiments, and synthesis of phosphodiesterase 10A inhibitor analog. These highly valuable and modifiable imidazo[1,5‐a] N‐heterocycles exhibit good antitumor activity in vitro, thus demonstrating their potential applications in medicinal chemistry.

Catalyst-Controlled Intermolecular Homobenzylic C(sp3)-H Amination for the Synthesis of β-Arylethylamines.

The combination of a tailored sulfamate with a C4-symmetrical rhodium(II) tetracarboxylate allows to uncover a selective intermolecular amination of unactivated homobenzylic C(sp3)-H bonds. The reaction has a broad scope (>30 examples) and proceeds with a high level of regioselectivity with homobenzylic/benzylic ratio of up to 35:1, thereby providing a direct access to β-arylethylamines that are of utmost interest in medicinal chemistry. Computational investigations evidenced a concerted mechanism, involving an asynchronous transition state. Based on a combined activation strain model and energy decomposition analysis, the regioselectivity of the reaction was found to rely mainly on the degree of orbital interaction between the [Rh2]-nitrene and the C-H bond. The latter is facilitated at the homobenzylic position due to the establishment of specific noncovalent interactions within the catalytic pocket.

Unlocking the Pharmacological Potential of Benzimidazole Derivatives: A Pathway to Drug Development.

Heterocyclic molecules have garnered a massive interest in medicinal chemistry. They are heterocyclic compounds that have gained significance due to their diverse variety of pharmacological activities. Benzimidazole is a heterocyclic compound consisting of benzene and imidazole rings. The ease of synthesis and the structural versatility of benzimidazole make it a promising scaffold for drug development. Many biological actions of benzimidazole derivatives have been well documented, including antibacterial, antiviral, anticancer, anti-inflammatory, antitubercular, and anthelmintic properties. The mechanism of action of benzimidazole derivatives varies with their chemical structure and target enzyme. This review has explored numerous methods for producing benzimidazole derivatives as well as a broad range of pharmacological activities. SAR investigations are also discussed in this review as they provide crucial details regarding the essential structural qualities that benzimidazole derivatives must have in order to be biologically active, which could aid in the rational design of new drug candidates. Benzimidazole scaffold is an exclusive structure in drug design and discovery. Many new pharmaceutical drugs containing benzimidazole are anticipated to be available within the next ten years as a result of the extensive therapeutic applications of benzimidazole and its derivatives. This review inspired many researchers to develop more biologically active compounds bearing benzimidazole, expanding the scope of finding a remedy for other diseases. From this study, we concluded that 2-substituted benzimidazole was considered more extensively by researchers.

Structure and biological property studies of the fluorinated sulfonic esters derived from 2-hydroxy-4-(hydroxy/methoxy)acetophenone as inhibitors of biochemical targets linked to type 2 diabetes mellitus

Small molecule multi-target drugs substituted with fluorine atom/s or fluorine-containing group/s continue to attract considerable interest in medicinal chemistry due to their advantages in the treatment of multifactorial diseases. In this study, fluorine-containing alkyl and benzenesulfonyl chloride building blocks were reacted with 2,4-dihydroxyacetophenone 1a or 2-hydroxy-4-methoxyacetophenone 1b to afford the corresponding sulfonic ester derivatives 2a–f and 2g–j, respectively. Detailed crystallographic characterization was performed on a representative compound from each series. The compounds were evaluated through enzymatic assays in vitro for potential to inhibit biochemical targets linked to type 2 diabetes mellitus. Compound 1a and its 4-(4-fluorophenyl)sulfonyl derivative 2d exhibited strong and significant inhibitory effect in vitro against α-glucosidase (IC50 = 0.97 ± 0.02 μM and 0.81 ± 0.07 μM, respectively) and α-amylase (IC50 = 6.89 ± 0.04 μM and 4.87 ± 0.02 μM, respectively) compared to acarbose (IC50 = 8.60 ± 0.20 μM and 1.96 ± 0.03 μM, respectively). The presence of a 4-fluorophenylsulfonyl moiety resulted in moderate inhibitory activity for 2d (IC50 = 27.05 ± 0.01 μM) against protein tyrosine phosphatase 1 beta (PTP1B) compared to the PTP1B inhibitor, suramin (IC50 = 4.63 ± 0.003 μM). The test compounds exhibited strong to moderate nitric oxide radical scavenging activity in vitro against ascorbic acid (IC50 = 5.53 ± 0.03 μM) with IC50 values in the range 0.05–19.30 μM. Compounds 1a and 2d did not inhibit superoxide dismutase (SOD) activity. Molecular docking revealed the involvement of hydrophobic, hydrophilic and electrostatic interactions with amino acid residues in the active site of the test enzymes.

The Ritter reaction of N‐(hydroxymethyl)saccharin with nitriles

AbstractThe development of the Ritter reaction of N‐(hydroxymethyl)saccharin with nitriles for the synthesis of N‐[(saccharinyl)methyl]amides is reported. The success of this reaction relies on an operationally simple procedure and on the use of inexpensive reagents. The present method enables access to a variety of saccharin scaffolds of potential interest in medicinal chemistry in moderate to high yields. Furthermore, the scalability of this reaction was demonstrated by a multigram‐scale transformation, without any loss of efficiency.

An Active Group with Potential Anti-seizure Activity: A Review on 1,2,4- Triazoles

Background: Epilepsy is one of the most common neurological disorders. Many individuals continue to have seizures despite medical and surgical treatments, suggesting that the discovery of novel anti-seizure drugs is vital. Triazole compounds are widely used as pharmaceuticals and have gained significant interest in medicinal chemistry. In this article, the development of triazoles, especially 1,2,4- triazole, in the field of anti-seizure therapeutics is reviewed. Methods: The relevant literature was investigated, classified, and analysed. This article attempts to systematically review the research of triazole derivatives in the design and development of anti-seizure agents during the past two decades through extensive literature research, which was based on the information accessible in PubMed, Science Direct, Google Scholar and other databases. Results: Research results demonstrate that triazoles occupy a distinct niche in heterocyclic chemistry and represent a key motif in medicinal chemistry because of their ability to exhibit an array of properties and bioactivities. Therefore, 1,2,4-triazole appears to be an important pharmacophore, especially in the field of anti-seizure therapeutics, where its promising potential value has been explored. Conclusion: This review presents a summary of the research related to 1,2,4-triazole, which acts as a potential anti-seizure pharmacophore that could be further developed. Compounds with 1,2,4-triazole or related structures had previously shown reasonable anti-seizure activity and safety. After thorough research of this structure, it is believed that 1,2,4-triazole-containing compounds will be further developed as anti-seizure drugs for clinical use.

Nanosized metal or silicon oxides and L‐proline or 4‐hydroxy‐L‐proline in stereoselective synthesis of a dihydropyrimidinethione podand

The stereoselective Biginelli reaction involving a CH‐active podand, thiourea, and benzaldehyde using nanosized metal oxides (NiO, Fe3O4, CuO, Al2O3, SiO2, and TiO2‐SiO2), Brönsted acid, and commercially available chiral inductors (L‐proline or 4‐hydroxy‐L‐proline) was studied. The target dihydropyrimidinethione‐containing podand was obtained with an enantiomeric excess of 70% and a moderate yield under mild conditions in the presence of nanooxide NiO and 4‐hydroxy‐L‐proline. The adsorption of initial reactants and chiral inductor on the surface of nickel nanooxide was studied by IR spectroscopy. The activating and coordinating effect of the nanosized metal oxide on the initial reagents leading to an increasing the chemoselectivity and stereoselectivity of the Biginelli reaction was shown. On the basis of experimental data, one of the probable reaction mechanisms was proposed. This work further expanded the use of nanosized metal oxides in asymmetric catalysis and presented a new method for obtaining a valuable optically active podand with a 3,4‐dihydropyrimidine‐2‐(1H)‐thione moiety. Thus, the obtained results can be of interest for medicinal chemistry in the asymmetric one‐step synthesis of other enantiomerically pure compounds.

Synthesis of New Polyheterocyclic Pyrrolo[3,4-b]pyridin-5-ones via an Ugi-Zhu/Cascade/Click Strategy.

A diversity-oriented synthesis (DOS) of two new polyheterocyclic compounds was performed via an Ugi-Zhu/cascade (N-acylation/aza Diels-Alder cycloaddition/decarboxylation/dehydration)/click strategy, both step-by-step to optimize all involved experimental stages, and in one pot manner to evaluate the scope and sustainability of this polyheterocyclic-focused synthetic strategy. In both ways, the yields were excellent, considering the high number of bonds formed with release of only one carbon dioxide and two molecules of water. The Ugi-Zhu reaction was carried out using the 4-formylbenzonitrile as orthogonal reagent, where the formyl group was first transformed into the pyrrolo[3,4-b]pyridin-5-one core, and then the remaining nitrile group was further converted into two different nitrogen-containing polyheterocycles, both via click-type cycloadditions. The first one used sodium azide to obtain the corresponding 5-substituted-1H-tetrazolyl-pyrrolo[3,4-b]pyridin-5-one, and the second one with dicyandiamide to synthesize the 2,4-diamino-1,3,5-triazine-pyrrolo[3,4-b]pyridin-5-one. Both synthesized compounds may be used for further in vitro and in silico studies because they contain more than two heterocyclic moieties of high interest in medicinal chemistry, as well as in optics due to their high π-conjugation.

Formal Insertion of Alkenes Into C(sp3)−F Bonds Mediated by Fluorine‐Hydrogen Bonding

AbstractC−F Insertion reactions represent an attractive approach to prepare valuable fluorinated compounds. The high strength of C−F bonds and the low reactivity of the fluoride released upon C−F bond cleavage, however, mean that examples of such processes are extremely scarce in the literature. Here we report a reaction system that overcomes these challenges using hydrogen bond donors that both activate C−F bonds and allow for downstream reactions with fluoride. In the presence of hexafluoroisopropanol, benzyl and propargyl fluorides undergo efficient formal C−F bond insertion across α‐fluorinated styrenes. This process, which does not require any additional fluorinating reagent, occurs under mild conditions and delivers products featuring the gem‐difluoro motif, which is attracting increasing interest in medicinal chemistry. Moreover, readily available organic bromides can be engaged directly in a one‐pot process that avoids the isolation of organic fluorides.

Formal Insertion of Alkenes Into C(sp3 )-F Bonds Mediated by Fluorine-Hydrogen Bonding.

C-F Insertion reactions represent an attractive approach to prepare valuable fluorinated compounds. The high strength of C-F bonds and the low reactivity of the fluoride released upon C-F bond cleavage, however, mean that examples of such processes are extremely scarce in the literature. Here we report a reaction system that overcomes these challenges using hydrogen bond donors that both activate C-F bonds and allow for downstream reactions with fluoride. In the presence of hexafluoroisopropanol, benzyl and propargyl fluorides undergo efficient formal C-F bond insertion across α-fluorinated styrenes. This process, which does not require any additional fluorinating reagent, occurs under mild conditions and delivers products featuring the gem-difluoro motif, which is attracting increasing interest in medicinal chemistry. Moreover, readily available organic bromides can be engaged directly in a one-pot process that avoids the isolation of organic fluorides.

A Comprehensive Review on Chemical Synthesis and Chemotherapeutic Potential of 3-Heteroaryl Fluoroquinolone Hybrids

Fluoroquinolones have been studied for more than half a century. Since the 1960s, four generations of these synthetic antibiotics have been created and successfully introduced into clinical practice. However, they are still of interest for medicinal chemistry due to the wide possibilities for chemical modification, with subsequent useful changes in the pharmacokinetics and pharmacodynamics of the initial molecules. This review summarizes the chemical and pharmacological results of fluoroquinolones hybridization by introducing different heterocyclic moieties into position 3 of the core system. It analyses the synthetic procedures and approaches to the formation of heterocycles from the fluoroquinolone carboxyl group and reveals the most convenient ways for such procedures. Further, the results of biological activity investigations for the obtained hybrid pharmacophore systems are presented. The latter revealed numerous promising molecules that can be further studied to overcome the problem of resistance to antibiotics, to find novel anticancer agents and more.

Indolyl-Derived 4H-Imidazoles: PASE Synthesis, Molecular Docking and In Vitro Cytotoxicity Assay

The strategy of the nucleophilic substitution of hydrogen (SNH) was first applied for the metal-free C-H/C-H coupling reactions of 4H-imidazole 3-oxides with indoles. As a result, a series of novel bifunctional azaheterocyclic derivatives were obtained in yields up to 95%. In silico experiments on the molecular docking were performed to evaluate the binding possibility of the synthesized small azaheterocyclic molecules to the selected biotargets (BACE1, BChE, CK1δ, AChE) associated with the pathogenesis of neurodegenerative diseases. To assess the cytotoxicity for the synthesized compounds, a series of in vitro experiments were also carried out on healthy human embryo kidney cells (HEK-293). The leading compound bearing both 5-phenyl-4H-imidazole and 1-methyl-1H-indole moieties was defined as the prospective molecule possessing the lowest cytotoxicity (IC50 > 300 µM on HEK-293) and the highest binding energy in the protein–ligand complex (AChE, −13.57 kcal/mol). The developed compounds could be of particular interest in medicinal chemistry, particularly in the targeted design of small-molecule candidates for the treatment of neurodegenerative disorders.

BIOLOGICAL ACTIVITY OF QUINAZOLINONE DERIVATIVES: A REVIEW

The heterocyclic compounds have a great importance in medicinal chemistry. Quinazolinone is a heterocyclic chemical compound. A quinazolinone with a carbonyl group in the C4N2 ring. The two isomers are possible: 2-Quinazolinone and 4-Quinazolinone, with the 4-isomer being the more common. These compounds are of interest in medicinal chemistry. Quinazolinone derivatives were reported to possess analgesic and anti-inflammatory activity, Antibacterial, Diuretic, Antihypertensive, Anti-diabetics, Anticancer, Antitumor, Anti-fungal, Anti-malarial, Anti-protozoal agent and many other biological Action. This skeleton is an important pharmacophore considered as a privileged structure.

Synthesis of α-Aminophosphonates by Umpolung-Enabled Cu-Catalyzed Regioselective Hydroamination

A copper-catalyzed regioselective hydroamination of α,β-unsaturated phosphonates has been developed to form corresponding α-aminophosphonates of interest in medicinal chemistry. The introduction of an umpolung, electrophilic amination strategy with the hydroxylamine derivative is the key to achieving the α-amination regioselectivity, which is otherwise difficult under the conventional nucleophilic hydroamination conditions with the parent amine. Asymmetric synthesis with a chiral bisphosphine ligand and application to a related silylamination reaction are also described.