Structure-activity Relationship Research Articles

Schiff Bases: A Captivating Scaffold with Potential Anticonvulsant Activity.

One of the most important organic compounds, also known as a Schiff base, imine, or azomethine, has been associated with several biological processes. The group is a component of both natural or synthetic chemicals and functions as both a precursor and an intermediary in the synthesis of therapeutically active substances. The review highlights the various non-metal Schiff bases' structure-activity relationship (SAR) studies, general model, docking, and design approach for anticonvulsant actions. Schiff bases serve as linkers in numerous synthetic compounds with a variety of activities, according to the findings of several investigations. As a result, the current review will give readers a thorough understanding of the key ideas put forth by different researchers regarding the anticonvulsant properties of Schiff bases. It will serve as a valuable information source for those planning to synthesize new anticonvulsant molecules that contain Schiff bases as pharmacophores or biologically active moieties.

Synthetic Protocols, Structural Activity Relationship, and Biological Activity of Piperazine and its Derivatives.

The versatile basic structure of piperazine allows for the development and production of newer bioactive molecules that can be used to treat a wide range of diseases. Piperazine derivatives are unique and can easily be modified for the desired pharmacological activity. The two opposing nitrogen atoms in a six-membered piperazine ring offer a large polar surface area, relative structural rigidity, and more acceptors and donors of hydrogen bonds. These properties frequently result in greater water solubility, oral bioavailability, and ADME characteristics, as well as improved target affinity and specificity. Various synthetic protocols have been reported for piperazine and its derivatives. In this review, we focused on recently published synthetic protocols for the synthesis of the piperazine and its derivatives. The structure-activity relationship concerning different biological activities of various piperazine-containing drugs was also highlighted to provide a good understanding to researchers for future research on piperazines.

Molecular Mechanism and Structure-activity Relationship of the Inhibition Effect between Monoamine Oxidase and Selegiline Analogues.

To investigate the inhibition properties and structure-activity relationship between monoamine oxidase (MAO) and selected monoamine oxidase inhibitors (MAOIs, including selegiline, rasagiline and clorgiline). The inhibition effect and molecular mechanism between MAO and MAOIs were identified via the half maximal inhibitory concentration (IC50) and molecular docking technology. It was indicated that selegiline and rasagiline were MAO B inhibitors, but clorgiline was MAO-A inhibitor based on the selectivity index (SI) of MAOIs (0.000264, 0.0197 and 14607.143 for selegiline, rasagiline and clorgiline, respectively). The high-frequency amino acid residues of the MAOIs and MAO were Ser24, Arg51, Tyr69 and Tyr407 for MAO-A and Arg42 and Tyr435 for MAO B. The MAOIs and MAO A/B pharmacophores included the aromatic core, hydrogen bond acceptor, hydrogen bond donor-acceptor and hydrophobic core. This study shows the inhibition effect and molecular mechanism between MAO and MAOIs and provides valuable findings on the design and treatment of Alzheimer's and Parkinson's diseases.

Nucleoside Scaffolds and Carborane Clusters for Boron Neutron Capture Therapy: Developments and Future Perspective.

Nucleosides containing carboranes are one of the most important boron delivery agents for boron neutron capture therapy, BNCT, which are good substrates of hTK1. The development of several nucleosides containing carboranes at early stages led to the discovery of the first generation of 3CTAs by incorporating a hydrocarbon spacer between the thymidine scaffold and carborane cluster and attaching dihydroxylpropyl group on the second carbon (C2) atom of the carborane cluster (e.g., N5 and N5-2OH). Phosphorylation rate, tumor cellular uptake, and retention have been evaluated in parallel to change the length of the tether arm of spacers in these compounds. Many attempts were reported and discussed to overcome the disadvantage of the first generation of 3CTAs by a) incorporating modified spacers between thymidine and carborane clusters, such as ethyleneoxide, polyhydroxyl, triazole, and tetrazole units, b) attaching hydrophilic groups at C2 of the carborane cluster, c) transforming lipophilic closo-carboranes to hydrophilic nidocarborane. The previous modifications represented the second generation of 3CTAs to improve the hydrogen bond formation with the hTK1 active site. Moreover, amino acid prodrugs were developed to enhance biological and physicochemical properties. The structure-activity relationship (SAR) of carboranyl thymidine analogues led to the roadmap for the development of the 3rd generation of the 3CTAs for BNCT.

Structural Perspectives in the Development of Novel EGFR Inhibitors for the Treatment of NSCLC.

Non-small cell Lung cancer (NSCLC) is the most common type of lung cancer, which is caused by high consumption of tobacco and smoking. It is an epithelial lung cancer that affects about 2.2 million people across the globe, according to International Agency for Research on Cancer (IARC). Non-small cell lung cancer is a malignant tumor caused by EGFR mutation that occurs in the in-frame deletion of exon 19 and L858R point mutation in exon 21. Presently, clinically available inhibitors of EGFR (including erlotinib, lapatinib, gefitinib, selumetinib, etc.) are not specific and responsible for undesirable adverse effects. Moreover, to solve this problem search for newer EGFR inhibitors is the utmost need for the treatment and/or management of increasing lung cancer burden. The discovery of therapeutic agents that inhibit the specific target in tumorous cells, such as EGFR, is one of the successful strategies in treating many cancer therapies, including lung cancer. The exhaustive literature survey (2018-2023) has shown the importance of medicinally privileged pyrimidine derivatives together, fused and/or clubbed with other heterocyclic rings to design and develop novel EGFR inhibitors. Pyrimidine derivatives substituted with phenylamine, indole, pyrrole, piperazine, pyrazole, thiophene, pyridine and quinazoline derivatives substituted with phenylamine, pyrimidine, morpholine, pyrrole, dioxane, acrylamide, indole, pyridine, furan, pyrimidine, pyrazole etc. are privileged heterocyclic rings shown promising activity by inhibiting EGFR and TKIs. The present review summarizes the structure-activity relationship (SAR) and enzyme inhibitory activity, including IC50 values, percentage inhibition, and kinetic studies of potential compounds from various literature. The review also includes various aspects of molecular docking studies with compounds under clinical trials and patents filed on pyrimidine-based EGFR inhibitors in treating non-small cell lung cancer. The present review may benefit the medicinal chemist for developing novel compounds such as EGFR inhibitors.

Biochar from Malt Residue: Toward a Circular Economy for Sustainable Fluoroquinolone Removal in Aqueous Systems

Malt bagasse holds potential as a high-value material, contributing to a circular economy. Biochars were synthesized via pyrolysis (PC-500) and hydrothermal carbonization (HC-150), with one-pot activation using phosphoric acid. Additionally, PC-500 activated with H3PO4 was synthesized for comparison. Various analytical methods were used to characterize the materials. The PC-500 and PCA-500 samples exhibited higher degrees of carbonization, whereas the HC-150 sample retained its functional groups more effectively. Biochars showed higher porosity than biomass, with microspheres present in HC-150. Evaluations were conducted on the removal of fluoroquinolones from water using biochars. Maximum removal efficiency was obtained at pH 8, favoring neutral fluoroquinolone species with a Brønsted acid-base nature. The experimental outcomes were further rationalized by the computational calculation of the physicochemical properties of the adsorbates, in analogy with the structural activity relationship approach in medicinal chemistry. The pseudo-second-order kinetic model proved to be the most suitable for fitting the experimental data, while the Langmuir model effectively described the adsorption isotherms. Ciprofloxacin, enrofloxacin, and norfloxacin showed maximum adsorption capacities (qmax) of 95, 164, and 99mgg-1, respectively, when HC-150 was used. On the other hand, with PC-500, qmax of 57, 12, and 20mgg-1 were obtained for ciprofloxacin, enrofloxacin, and norfloxacin, respectively. Although PCA-500 enhanced adsorption capacity compared to PC-500, the qmax remained lower than the results obtained with HC-500, measuring at 51, 102, and 95mgg-1. These findings emphasize malt bagasse biochar as a viable adsorbent.

A Mini-Review on the Structural Characteristics and Anticancer Activity of Nagilactones

Abstract: Natural products provide abundant resources for the development of new drugs. Podocarpus nagi is an arbor of Podocarpus L'Hér. ex Persoon. Its fruits, leaves, and roots exhibit a broad spectrum of pharmacological activities (such as antitumor, plant growth regulation, termite killing, and insect larval toxicity), which have been used in Yao folk for a long history. Nagilactone is one of the key components discovered in Podocarpus nagi, which has a variety of structures and a broad spectrum of antitumor activities. In this mini-review, the structures and spectral characteristics, together with the antitumor activities and the structure-activity relationships of nagilactones, are summarized by searching the database in order to provide detailed references for researchers to elucidate and modify their structures.

Recent Developments in Coumarin Derivatives as Neuroprotective Agents.

Neurodegenerative diseases are among the diseases that cause the foremost burden on the health system of the world. The diseases are multifaceted and difficult to treat because of their complex pathophysiology, which includes protein aggregation, neurotransmitter breakdown, metal dysregulation, oxidative stress, neuroinflammation, excitotoxicity, etc. None of the currently available therapies has been found to be significant in producing desired responses without any major side effects; besides, they only give symptomatic relief otherwise indicated off-episode relief. Targeting various pathways, namely choline esterase, monoamine oxidase B, cannabinoid system, metal chelation, -secretase, oxidative stress, etc., may lead to neurodegeneration. By substituting various functional moieties over the coumarin nucleus, researchers are trying to produce safer and more effective neuroprotective agents. This study aimed to review the current literature to produce compounds with lower side effects using coumarin as a pharmacophore. In this review, we have attempted to compile various synthetic strategies that have been used to produce coumarin and various substitutional strategies used to produce neuroprotective agents from the coumarin pharmacophore. Moreover, structure-activity relationships of substituting coumarin scaffold at various positions, which could be instrumental in designing new compounds, were also discussed. The literature review suggested that coumarins and their derivatives can act as neuroprotective agents following various mechanisms. Various studies have demonstrated the neuroprotective activity of coumarin due to an oxaheterocyclic loop, which allows binding with a broad array of proteins, thus motivating researchers to explore its potential as a lead against various neurodegenerative diseases.

Structural Insights into Potent Anti-ulcer Agents for the Eradication of Helicobacter pylori

: Helicobacter pylori is the primary bacterium in the development of gastric cancer; thus, its eradication for the prevention and management of peptic ulcers is of utmost importance. Most primary or unexplained peptic ulcers are brought on by Helicobacter pylori infection, which also causes chronic inflammation. The lack of therapeutic compliance, antibiotic resistance, and the breakdown of antibiotics at gastric pH all contribute to the current eradication rates. Therefore, a recent area of focus is the hunt for novel therapeutics with great selectivity against H. pylori. : This review focuses on elucidating the landscape of anti-H. pylori compounds derived from both synthetic drug design programs and natural sources. Emphasis is placed on understanding the structure-activity relationships of these compounds and their mechanisms of action. : Furthermore, the potential of drug repurposing strategies to combat H. pylori infection is explored. By providing a comprehensive overview of major classes of anti-H. pylori compounds, this study aims to guide the development of new medications for the treatment of Helicobacter pylori infection. Ultimately, this review highlights promising avenues for future research and therapeutic interventions in the management of H. pylori -associated gastric cancer.

Advances in Drug Discovery and Design using Computer-aided Molecular Modeling.

Computer-aided molecular modeling is a rapidly emerging technology that is being used to accelerate the discovery and design of new drug therapies. It involves the use of computer algorithms and 3D structures of molecules to predict interactions between molecules and their behavior in the body. This has drastically improved the speed and accuracy of drug discovery and design. Additionally, computer-aided molecular modeling has the potential to reduce costs, increase the quality of data, and identify promising targets for drug development. Through the use of sophisticated methods, such as virtual screening, molecular docking, pharmacophore modeling, and quantitative structure-activity relationships, scientists can achieve higher levels of efficacy and safety for new drugs. Moreover, it can be used to understand the activity of known drugs and simplify the process of formulating, optimizing, and predicting the pharmacokinetics of new and existing drugs. In conclusion, computer-aided molecular modeling is an effective tool to rapidly progress drug discovery and design by predicting the interactions between molecules and anticipating the behavior of new drugs in the body.

Investigating the electronic properties of edge glycine/biopolymer/graphene quantum dots

This study systematically investigated four types of graphene quantum dots (GQDs) AHEX, ZTRI, ZHEX, and ATRI, and their interactions with glycine to form GQD-glycine complexes. Utilizing density functional theory (DFT) and the PM6 semiempirical method, the study analyzed electronic properties and structure-activity relationships. Global reactivity indices were calculated using Koopmans’ theorem, and quantitative structure-activity relationship (QSAR) parameters were assessed via SCIGRESS 0.3. The study further explored interactions using density of states (DOS) and quantum theory of atoms in molecules (QTAIM) analyses. Key findings revealed that glycine interaction significantly increased the total dipole moment (TDM) and decreased the HOMO/LUMO energy gap (ΔE) for the GQD-glycine complexes. Notably, ZTRI/glycine showed a TDM of 4.535 Debye and a reduced ΔE of 0.323 eV, indicating enhanced reactivity. Further interactions with cellulose, chitosan, and sodium alginate identified the ZTRI/glycine/sodium alginate composite as the most reactive, with a TDM of 8.020 Debye and the lowest ΔE of 0.200 eV. This composite also exhibited the highest electrophilicity index (56.421) and lowest chemical hardness (0.145 eV), underscoring its superior reactivity and stability. DOS analysis revealed that biomolecules contributed the most to molecular orbitals, with carbon atoms contributing the least. QTAIM analysis confirmed the greater stability of the ZTRI/glycine/sodium alginate complex compared to other studied composites. These results highlight the enhanced reactivity and stability of GQDs when interacting with glycine and sodium alginate.

Development of Machine Learning-Based Quantitative Structure-Activity Relationship Models for Predicting Plasma Half-Lives of Drugs in Six Common Food Animal Species

Abstract Plasma half-life is a crucial pharmacokinetic parameter for estimating extralabel withdrawal intervals of drugs to ensure the safety of food products derived from animals. This study focuses on developing a quantitative structure−activity relationship (QSAR) model incorporating multiple machine learning and artificial intelligence algorithms, and aims to predict the plasma half-lives of drugs in six food animals, including cattle, chickens, goats, sheep, swine, and turkeys. By integrating four machine learning algorithms with five molecular descriptor types, 20 QSAR models were developed using data from the Food Animal Residue Avoidance Databank (FARAD) Comparative Pharmacokinetic Database. The deep neural network (DNN) algorithm demonstrated the best prediction ability of plasma half-lives. The DNN model with all descriptors achieved superior performance with a high coefficient of determination (R 2) of 0.82±0.19 in 5-fold cross-validation on the training sets and a R 2 of 0.67 on the independent test set, indicating accurate predictions and good generalizability. The final model was converted to a user-friendly web dashboard to facilitate its wide application by the scientific community. This machine learning-based QSAR model serves as a valuable tool for predicting drug plasma half-lives and extralabel withdrawal intervals in six common food animals based on physicochemical properties. It also provides a foundation to develop more advanced models to predict the tissue half-life of drugs in food animals.

Exploring Biosurfactants as Antimicrobial Approaches

Antibacterial resistance is one of the most important global threats to human health. Several studies have been performed to overcome this problem and infection-preventive approaches appear as promising solutions. Novel antimicrobial preventive molecules are needed and microbial biosurfactants have been explored in that scope. Considering their structure, these biomolecules can be divided into different classes, glycolipids and lipopeptides being the most studied. Besides their antimicrobial activity, biosurfactants have the advantage of being biocompatible, biodegradable, and non-toxic, which favor their application in several areas, including the health sector. Often, the most difficult infections to fight are associated with biofilm formation, particularly in medical devices. Strategies to overcome micro-organism attachment are thus emergent, and it is possible to take advantage of the antimicrobial/antibiofilm properties of biosurfactants to produce surfaces that are more resistant to the deposition/attachment of bacteria. Approaches such as the covalent bond of biosurfactants to the medical device surface leading to repulsive physical–chemical interactions or contact killing can be selected. Simpler strategies such as the absorption of biosurfactants on surfaces are also possible, eliminating micro-organisms in the vicinity. This review will focus on the physical and chemical characteristics of biosurfactants, their antimicrobial activity, antimicrobial/antibiofilm approaches, and finally on their structure–activity relationship.

Pharmacological Evaluation of Bioisosterically Replaced and TriazoleTethered Derivatives for Anticancer Therapy

Cancer has been the cause of the highest number of deaths in the human population despite the development and advancement in treatment therapies. The toxicity, drug resistance, and side effects of the current medicaments and therapies have left the void for more research and development. One of the possibilities to fill this void is by incorporating Triazole moieties within existing anticancer pharmacophores to develop new hybrid drugs with less toxicity and more potency. The placement of nitrogen in the triazole ring has endowed its characterization of being integrated with anticancer pharmacophores via bioisosteric replacement, click chemistry and organocatalyzed approaches. This review paper emphasizes the discussions from articles published from the early 2000s to the current 2020s about the triazole-based derivatives used in anticancer therapy, elaborating more on their chemical structures, target receptors or enzymes, mechanism of action, structure-activity relationships, different triazole-derived hybrid drugs under clinical and nonclinical trials, and recent advancements toward developing more potent and less toxic anticancer agents.

Development of Mycobacterium tuberculosis Enoyl Acyl Reductase (InhA) Inhibitors: A Mini-Review

This review article delves into the critical role of Enoyl acyl carrier protein Reductase (InhA; ENR), a vital enzyme in the NADH-dependent acyl carrier protein reductase family, emphasizing its significance in fatty acid synthesis and, more specifically, the biosynthesis of mycolic acid. The primary objective of this literature review is to elucidate diverse scaffolds and their developmental progression targeting InhA inhibition, thereby disrupting mycolic acid biosynthesis. Various scaffolds, including thiourea, piperazine, thiadiazole, triazole, quinazoline, benzamide, rhodanine, benzoxazole, and pyridine, have been systematically explored for their potential as InhA inhibitors. Noteworthy findings highlight thiadiazole and triazole derivatives, demonstrating promising IC50 values within the nanomolar concentration range. The review offers comprehensive insights into InhA's structure, structure-activity relationships, and a detailed overview of distinct scaffolds as effective inhibitors of InhA.

Structure–activity relationships study of N -ethylene glycol-comprising alkyl heterocyclic carboxamides against A549 lung cancer cells

Structure–activity relationships study of <i>N</i> -ethylene glycol-comprising alkyl heterocyclic carboxamides against A549 lung cancer cells

AI-assisted models to predict chemotherapy drugs modified with C60 fullerene derivatives

Employing quantitative structure–activity relationship (QSAR)/ quantitative structure–property relationship (QSPR) models, this study explores the application of fullerene derivatives as nanocarriers for breast cancer chemotherapy drugs. Isolated drugs and two drug–fullerene complexes (i.e., drug–pristine C60 fullerene and drug–carboxyfullerene C60–COOH) were investigated with the protein CXCR7 as the molecular docking target. The research involved over 30 drugs and employed Pearson’s hard–soft acid–base theory and common QSAR/QSPR descriptors to build predictive models for the docking scores. Energetic descriptors were computed using quantum chemistry at the density functional-based tight binding DFTB3 level. The results indicate that drug–fullerene complexes interact more with CXCR7 than isolated drugs. Specific binding sites were identified, with varying locations for each drug complex. Predictive models, developed using multiple linear regression and IBM Watson artificial intelligence (AI), achieved mean absolute percentage errors below 12%, driven by AI-identified key variables. The predictive models included mainly quantitative descriptors collected from datasets as well as computed ones. In addition, a water-soluble fullerene was used to compare results obtained by DFTB3 with a conventional density functional theory approach. These findings promise to enhance breast cancer chemotherapy by leveraging fullerene-based drug nanocarriers.

Design, synthesis, evaluation, pharmacophore modeling, and 3D-QSAR of lappaconitine analogs as potential analgesic agents.

Alleviating pain is crucial for patients with various diseases. This study aimed to enhance the analgesic properties of lappaconitine, a natural drug, through structural modifications. Specifically, carbamate analgesic active fragments were innovatively introduced at multiple sites on the benzene ring of lappaconitine. A total of 53 lappaconitine analogs were synthesized and evaluated. Compounds 5a, 5c, 5e, 6, and 15j addressed the narrow therapeutic window of lappaconitine, enhancing drug safety. Notably, carbamate analogs exhibited significantly enhanced analgesic activity, with compounds 5a and 5c having ED50 values of 1.2 and 1.6 mg/kg, respectively, indicating higher potency than lappaconitine (3.5 mg/kg). A metabolic analysis of compound 5e was conducted in mice, revealing its primary metabolic processes and metabolites, and providing preliminary exploration for the druggability. Given the multiple analgesic targets of lappaconitine, its analgesic mechanism remains inconclusive. This study, for the first time, analyzed the pharmacological activity characteristics of the lappaconitine analogs using a pharmacophore model and established a three-dimensional quantitative structure-activity relationship (3D-QSAR) to elucidate the quantitative relationship between the structures of the synthesized compounds and their analgesic activities. These findings provide valuable guidance for future structural modification and optimization of analgesic drugs.

Design, Synthesis, and Antimicrobial Evaluation of Novel Schiff Bases Derived from Thymol

Schiff bases, a significant class of organic compounds, are synthesized through the reaction of a primary amine with an aldehyde or ketone under specific conditions. In this study, we report the synthesis of novel Schiff bases derived from thymol (2-Isopropyl-5-methylphenol). The synthesis began with the esterification of thymol to produce (2-Isopropyl-5-methylphenoxy)-acetic acid ethyl ester (1), followed by hydrazination to yield (2-Isopropyl-5-methylphenoxy)-acetic acid hydrazide (2). The hydrazide (2) was then treated with various aromatic aldehydes to synthesize a series of Schiff bases (3A-J). The chemical structures of these compounds were elucidated using infrared (IR) spectroscopy, proton nuclear magnetic resonance (1H-NMR), and mass spectrometry. The synthesized Schiff bases were evaluated for their antibacterial and antifungal activities using standard screening methods. The results indicated that all synthesized compounds exhibited varying degrees of antimicrobial activity. Among the series, compound 3C showed the highest antibacterial and antifungal potency, suggesting it could be a promising candidate for further development. This study highlights the potential of Schiff bases as bioactive compounds with broad-spectrum antimicrobial properties. The structure-activity relationship (SAR) suggests that the presence of specific substituents on the aromatic aldehyde moiety could enhance biological activity. Further investigation into the mechanisms of action and optimization of these Schiff bases could contribute to the development of novel antimicrobial agents

Design, Synthesis, Anti-TMV Activity, and Structure-Activity Relationships of Seco-pregnane C21 Steroids and Their Derivatives.

seco-pregnane C21 steroids exhibit high antiviral activity against the tobacco mosaic virus (TMV). However, the structural modification of seco-pregnane C21 steroids and the structure-activity relationship (SAR) of the modified compounds remain unevaluated. Hence, the present study investigated how variations in the original skeletons of natural seco-pregnane C21 steroids affect their antiviral activity. A series of glaucogenin C and A derivatives were designed and synthesized for the first time, and their anti-TMV activity was evaluated. Bioassay results showed that most of the newly designed derivatives exhibited good to excellent antiviral activity; among these derivatives, 5g, 5j, and 5l with higher antiviral activity than that of ningnanmycin emerged as new antiviral candidates. Reverse transcription-polymerase chain reaction and Western blotting assay revealed reduced levels of TMV coat protein (TMV-CP) gene transcription and TMV-CP protein expression, which confirmed the antiviral activity of these derivatives. These compounds also downregulated the expression of NtHsp70-1 and NtHsp70-061. Computational simulations indicated that 5l displayed strong van der Waals energy and electrostatic with the TMV coat protein, affording a lower binding energy (ΔGbind = -56.2 kcal/mol) compared with Ribavirin (ΔGbind = -47.6 kcal/mol). The SAR of these compounds was also evaluated, which demonstrated for the first time that substitutions at C-3 and double bonds of C-5/C-6 and C-13/C-18 are crucial for maintaining high anti-TMV activity.