Med Chem [JOURNAL]
Sun
200 papers
Synthesis and Antibacterial Evaluation of Novel Small-Molecule Antibacterials of a Reduced Acridine Structure in Strains Including MRSA.
Werner P, Kreutzer D, Szemeredi N … +2 more , Spengler G, Hilgeroth A
Med Chem · 2024 · PMID 38726790 · Publisher ↗
BACKGROUND: The increasing antibacterial drug resistance remains a threat to global health with increasing mortality and morbidity. There is an urgent need to find novel antibacterials and develop alternative strategies...
BACKGROUND: The increasing antibacterial drug resistance remains a threat to global health with increasing mortality and morbidity. There is an urgent need to find novel antibacterials and develop alternative strategies to combat the increasing antibacterial drug resistance. OBJECTIVE: We aimed to synthesize novel small-molecule antibacterials to evaluate the structuredependent antibacterial compound activities against S. aureus and MRSA. METHODS: Compounds were synthesized by primary N-alkylation to form alkyl acridinium salts that were further functionalized with substituted phenyl residues and finally purified by column chromatography. The antibacterial growth inhibition activity was determined as MIC value. RESULTS: The substituent effects on the determined antibacterial growth inhibitory properties have been discussed. CONCLUSION: The best activities have been found for compounds with methoxy functions, exceeding the activities of reported novel antibacterial peptides. The compounds have also shown antibacterial drug-enhancing effects, which have been manifested as a reduction in the MIC values of the used antibiotics.
PPARs (Peroxisome Proliferator-activated Receptors) and Their Agonists in Alzheimer's Disease.
Kumar M, Sharma AA, Datusalia AK … +1 more , Khatik GL
Med Chem · 2024 · PMID 38726789 · Publisher ↗
Alzheimer's disease (AD) is a neurodegenerative disease leading to dementia because of complex phathomechanisms like amyloid β (Aβ) aggregation, tau aggregates, and neurofibrillary tangles. Peroxisome proliferator-activa...
Alzheimer's disease (AD) is a neurodegenerative disease leading to dementia because of complex phathomechanisms like amyloid β (Aβ) aggregation, tau aggregates, and neurofibrillary tangles. Peroxisome proliferator-activated receptor (PPAR) agonists have been reported recently with neuroprotective and anti-inflammatory properties. PPARs belong to the superfamily of nuclear hormone receptors and function as ligand-activated transcription factors. These have emerged as crucial players in the pathogenesis of AD. This review presented the potential of PPARs and their agonists in treating neurodegenerative diseases like AD. PPARs regulate the expression of specific genes vital for synaptic function and neurotransmitter release. PPAR agonists play a critical role in increasing the clearance of Aβ peptides by lowdensity lipoprotein receptor-related protein 1 (LRP1) in the microvascular endothelial cells of the human brain. Studies have shown that PPAR agonists reduce the level of APoE-mRNA, contributing to the accumulation of Aβ plaques and up-regulation of PPAR. A knockout of miR-128 has been found to inhibit AD-like cognitive decline, amyloid precursor protein (APP) amyloidogenic processing, and inflammatory responses in AD. PPARs are involved in the pathomechanism of AD, and therefore, PPAR agonists could be viable options for controlling the neurodegenerative symptoms and may be useful in treating AD.
Synthetic Protocols, Structural Activity Relationship, and Biological Activity of Piperazine and its Derivatives.
Faizan M, Kumar R, Mazumder A … +4 more , Salahuddin, Kukreti N, Kumar A, Chaitanya MVNL
Med Chem · 2024 · PMID 38685782 · Publisher ↗
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 m...
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.
Substituted 4H-3,1-benzoxazine-4-one Derivatives as Inhibitors of Cathepsin G.
Aliter KF, Al-Horani RA
Med Chem · 2024 · PMID 38676528 · Full text
BACKGROUND: Cathepsin G (CatG) is a cationic serine protease with a wide substrate specificity. CatG has been reported to play a role in several pathologies, including rheumatoid arthritis, ischemic reperfusion injury, a...
BACKGROUND: Cathepsin G (CatG) is a cationic serine protease with a wide substrate specificity. CatG has been reported to play a role in several pathologies, including rheumatoid arthritis, ischemic reperfusion injury, acute respiratory distress syndrome, and cystic fibrosis, among others. OBJECTIVE: We aim to develop a new class of CatG inhibitors and evaluate their potency and selectivity against a series of serine proteases. METHODS: We exploited chemical synthesis as well as chromogenic substrate hydrolysis assays to construct and evaluate the new inhibitors. RESULTS: In this communication, we report on a new class of CatG inhibitors of 4H-3,1-benzoxazin- 4-one derivatives. We constructed a small library of seven substituted 4H-3,1-benzoxazin-4-one derivatives and identified their inhibition potential against CatG. Five molecules were identified as CatG inhibitors with values of 0.84-5.5 μM. Inhibitor 2 was the most potent, with an IC of 0.84 ± 0.11 μM and significant selectivity over representative serine proteases of thrombin, factor XIa, factor XIIa, and kallikrein. CONCLUSION: Thus, we propose this inhibitor as a lead molecule to guide subsequent efforts to develop clinically relevant potent and selective CatG inhibitors for use as anti-inflammatory agents.
Synthesis, Molecular Docking Studies and Biological Evaluation of Thiazolyl Hydrazone Derivatives of Chromone-3-carbaldehyde as Potent Anti-Oxidant and Anti-Inflammatory Agents.
Gawali R, Bhosale R, Bavi R … +2 more , Jadhav S, Peerzade N
Med Chem · 2024 · PMID 38676527 · Publisher ↗
INTRODUCTION: A series of 15 thiazolyl hydrazone derivatives of chromone-3- carbaldehyde have been designed and synthesized by the cyclization of thiosemicarbazone derivatives of chromone-3-carbaldehydes with 4'-substitu...
INTRODUCTION: A series of 15 thiazolyl hydrazone derivatives of chromone-3- carbaldehyde have been designed and synthesized by the cyclization of thiosemicarbazone derivatives of chromone-3-carbaldehydes with 4'-substituted-2-bromo acetophenones. METHODS: All these derivatives were evaluated for antioxidant activity by their direct scavenging activity objects to reactive oxygen species such as DPPH, and nitric oxide, as well as antiinflammatory activity by a protein denaturation method. Most of these synthesized compounds have shown significant antioxidant activity, among which the compounds 5b, 5c, 5e, 5g, and 5j showed very good antioxidant activities in comparison with the standard ascorbic acid. The in vitro anti-inflammatory activity revealed that the compounds 5b, 5g, and 5h possessed significant activity compared to standard diclofenac sodium. RESULTS: Additionally, molecular docking studies of these molecules using ovalbumin as the protein showed remarkable interactions with its active site residues, and the results indicated that the binding mode of these compounds closely resembled that of the reference compound, diclofenac sodium. CONCLUSION: Thus, these compounds represent an attractive template for the evaluation of new antiinflammatory and antioxidant agents and might be useful for exploring new therapeutic tools.
Unveiling Therapeutic Avenues for Crohn's Disease Management: Exploring Inhibitors for Adherent-Invasive Propanediol Dehydratase.
Bourhia M, Hosen ME, Faruqe MO … +6 more , Tasnim F, Taibi M, Elbouzidi A, Bin Jardan YA, Ibenmoussa S, Asehraou A
Med Chem · 2024 · PMID 38659270 · Publisher ↗
INTRODUCTION: Inflammatory Bowel Disease (IBD) encompasses a group of chronic disorders distinguished by inflammation of the gastrointestinal tract. Among these, Crohn's Disease (CD) stands out as a complex and impactful...
INTRODUCTION: Inflammatory Bowel Disease (IBD) encompasses a group of chronic disorders distinguished by inflammation of the gastrointestinal tract. Among these, Crohn's Disease (CD) stands out as a complex and impactful condition due to challenges for both diagnosis and management, making it a cynosure of research. METHODS: In CD, there is the predominance of proinflammatory bacteria, including the Adherentinvasive Escherichia coli (AIEC) with virulence-associated metabolic enzyme Propanediol Dehydratase (pduC), which has been identified as a therapeutic target for the management of CD. Herein, molecular modeling techniques, including molecular docking, Molecular Mechanics with Generalized Born and Surface Area (MMGBSA), drug-likeness, and pharmacokinetics profiling, were utilized to probe the potentials of eighty antibacterial compounds to serve as inhibitors of pduC. RESULTS: The results of this study led to the identification of five compounds with promising potentials; the results of the molecular docking simulation revealed the compounds as possessing better binding affinities for the target compared to the standard drug (sulfasalazine), while Lipinski's rule of five-based assessment of their drug-likeness properties revealed them as potential oral drugs. MMGBSA free energy calculation and Molecular Dynamics (MD) simulation of the complexes formed a sequel to molecular docking, revealing the compounds as stable binders in the active site of the protein. CONCLUSION: Ultimately, the results of this study have revealed five compounds to possess the potential to serve as inhibitors of pduC of AIEC. However, experimental studies are still needed to validate the findings of this study.
Computational Chemistry: Prediction of Compound Accessibility of Targeted Synthesized Compounds.
Babu V, Ahmed S, Rahiman AK … +4 more , Kawsar SMA, Berredjem M, Bhat AR, Basha KA
Med Chem · 2025 · PMID 38638049 · Publisher ↗
INTRODUCTION: In the present work, a series of novel pyridine carboxamides 3(a-h) were synthesized and screened with antibacterial activity. This research explores the application of Density Functional Theory (DFT) in st...
INTRODUCTION: In the present work, a series of novel pyridine carboxamides 3(a-h) were synthesized and screened with antibacterial activity. This research explores the application of Density Functional Theory (DFT) in studying biological systems at the quantum mechanical level, particularly in the context of drug design. DFT offers a streamlined approach to quantum mechanical calculations, making it indispensable in various scientific fields, and for its exceptional accuracy, reduced computational time, and cost-effectiveness has become a pivotal tool in computational chemistry. This research work highlights the integration of DFT studies with POM analyses, which effectively identify pharmacophoric sites. Moreover, the research incorporates pharmacokinetics analyses to assess the pharmacokinetic properties of synthesized compounds. The paper focused on a series of compounds previously reported, aiming to provide a comprehensive understanding of their electronic structure, pharmacophoric features, and potential as drug candidates. This study not only contributes to the evolving field of computational chemistry but also holds implications for advancing drug design processes by combining theoretical insights with practical analyses. METHODS: The compounds 3(a-h) were subjected to Density Functional Theory (DFT) computations using the B3LYP/6-31G(d) basis set to get optimized geometric structures. GaussViewis used to display the contributions of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO). The determination of energy gaps was conducted using Gaussian 09W. The pharmacokinetic profiles were evaluated using existing techniques such as Osiris, Petra, and Molinspiration, as well as a novel platform called POM Analyse. RESULTS: The computational studies DFT, POM and pharmacokinetics studies revealed that the studied compounds are biologically active, non-toxic, non-carcinogenic in nature and may be utilized as drug candidates. CONCLUSION: Density functional theory (DFT) investigations emphasize the exceptional stability of complex 3d, which possesses the biggest energy gap and the lowest softness. In contrast, compound 3h demonstrates poorer stability among the tested compounds, characterized by the lowest energy gap and the highest softness values. These findings are further substantiated by absolute energy calculations. The negligible energy difference in compound 3h indicates an increased transfer of electric charge within the molecule, which is associated with its enhanced biological effectiveness. The drug-likeness of the compounds is confirmed by POM and in silico pharmacokinetics investigations, with compound 3h being identified as the most biologically active among the investigated compounds.
A Computational Study of Green Tea Extracts and their Derivatives as Potential Inhibitors for Squalene Monooxygenase.
Mokgopa KP, Lobb KA, Tshiwawa T
Med Chem · 2024 · PMID 38584555 · Publisher ↗
BACKGROUND: According to the World Health Organisation, cardiovascular complications have been recognized as the leading course of death between 2000 and 2019. Cardiovascular complications are caused by excess LDL choles...
BACKGROUND: According to the World Health Organisation, cardiovascular complications have been recognized as the leading course of death between 2000 and 2019. Cardiovascular complications are caused by excess LDL cholesterol in the body or arteries that can build up to form a plaque. There are drugs currently in clinical use called statins that target HMGCoA reductase. However, these drugs result in several side effects. This work investigated using computational approaches to lower cholesterol by investigating green tea extracts as an inhibitors for squalene monooxygenase (the second-rate-controlling step in cholesterol synthesis). METHODS: Pharmacophore modeling was done to identify possible pharmacophoric sites based on the pIC50 values. The best hypothesis generated by pharmacophore modeling was further validated by atom-based 3D QSAR, where 70% of the data set was treated as the training set. Prior molecular docking ADMET studies were done to investigate the physiochemical properties of these molecules. Glide docking was performed, followed by molecular dynamics to evaluate the protein conformational changes. RESULTS: Pharmacophore results suggest that the best molecules to interact with the biological target should have at least one hydrogen acceptor (A5), two hydrogen donors (D9 and D10), and two benzene rings (R14 and R15) for green tea polyphenols and theasinensin A. ADMET result shows that all molecules in this class have low oral adsorption. Molecular docking results showed that some green tea polyphenols have good binding affinities, with most of these structures having a docking score of less than -10 kcal/mol. Molecular dynamics further illustrated that the best-docked ligands perfectly stay within the active site over a 100 ns simulation. CONCLUSION: The results obtained from this study suggest that green tea polyphenols have the potential for inhibition of squalene monooxygenase, except for theasinensin A.
Antimicrobial Potential of Polyphenols: An Update on Alternative for Combating Antimicrobial Resistance.
Sharma A, Anurag, Kaur J … +2 more , Kesharwani A, Parihar VK
Med Chem · 2024 · PMID 38584534 · Publisher ↗
The last decade has encountered an increasing demand for plant-based natural antibiotics. This demand has led to more research-based investigations for natural sources of antimicrobial agents and published reports demons...
The last decade has encountered an increasing demand for plant-based natural antibiotics. This demand has led to more research-based investigations for natural sources of antimicrobial agents and published reports demonstrating that plant extracts are widely applied in modern medicine, reporting potential activity that may be due to polyphenol compounds. Interestingly, the effects of polyphenols on the sensitivity of bacteria to antibiotics have not been well-studied. Hence, the current review encompasses the prospective application of plant-based phenolic extracts from plants of Indian origin. The emergence of resistance to antimicrobial agents has increased the inefficacy of many antimicrobial drugs. Several strategies have been developed in recent times to overcome this issue. A combination of antimicrobial agents is employed for the failing antibiotics, which restores the desirable effect but may have toxicity-related issues. Phytochemicals such as some polyphenols have demonstrated their potent activity as antimicrobial agents of natural origin to work against resistance issues. These agents alone or in combination with certain antibiotics have been shown to enhance the antimicrobial activity against a spectrum of microbes. However, the information regarding the mechanisms and structure-activity relationships remains elusive. The present review also focuses on the possible mechanisms of natural compounds based on their structure- activity relationships for incorporating polyphenolic compounds in the drug-development processes. Besides this work, polyphenols could reduce drug dosage and may diminish the unhidden or hidden side effects of antibiotics. Pre-clinical findings have provided strong evidence that polyphenolic compounds, individually and in combination with already approved antibiotics, work well against the development of resistance. However, more studies must focus on in vivo results, and clinical research needs to specify the importance of polyphenol-based antibacterials in clinical trials.
Promising Potential of Curcumin and Related Compounds for Antiviral Drug Discovery.
Sharma A, Sharma T, Bhaskar R … +3 more , Ola M, Sharma A, Sharma PC
Med Chem · 2024 · PMID 38571348 · Publisher ↗
Viruses are acellular, microscopic, and mobile particles containing genetic particles, either DNA/RNA strands as nucleoproteins, responsible for 69,53,743 deaths till the year 2023. Curcumin and related compounds are amo...
Viruses are acellular, microscopic, and mobile particles containing genetic particles, either DNA/RNA strands as nucleoproteins, responsible for 69,53,743 deaths till the year 2023. Curcumin and related compounds are among the areas of pivotal interest for researchers because of their versatile pharmacological profile. Chemically known as diferuloylmethane, which is a main constituent of turmeric along with demethoxycurcumin and bisdemethoxycurcumin, they have a broad spectrum of antiviral activity against viruses such as human immunodeficiency virus, herpes simplex virus, influenza virus (Avian influenza) and Hepatitis C virus HIV. The possible role of curcumin as an antiviral agent may be attributed to the activation of the 20S proteasome, a cellular machinery responsible for degrading unfolded or misfolded proteins in a ubiquitin-independent manner. It shows suppression of HBV entry at various infection stages by inhibiting cccDNA replication by inhibiting the Wnt/β-catenin signaling pathway to attenuate IAV-induced myocarditis.
Trends in the Synthesis of Antimicrobial Derivatives by using the Gewald, Strecker, and Groebke-Blackburn-Bienaymé (GBB) Reactions.
Naithani K, Bhowmik S
Med Chem · 2024 · PMID 38523542 · Publisher ↗
BACKGROUND: Multicomponent reactions are highly useful in synthesizing natural products and bioactive molecules. Out of several MCRs, although utilized widely, some remain neglected in review articles. The Gewald and Gro...
BACKGROUND: Multicomponent reactions are highly useful in synthesizing natural products and bioactive molecules. Out of several MCRs, although utilized widely, some remain neglected in review articles. The Gewald and Groebke-Blackburn-Bienaymé (GBB) reactions are two such reactions. This comprehensive review assimilates applications of Gewald and Groebke-Blackburn- Bienayme reactions in synthesizing novel antimicrobial agents. It presents the antimicrobial properties of the synthesized molecules, providing an overview of their potential druggability. OBJECTIVE: Developing novel antimicrobial agents is the need of the hour. Toward this objective, the scientific community is developing new methods for constructing novel architectures with potential antimicrobial properties. This review will showcase the usefulness of the Gewald, Strecker, and Groebke-Blackburn-Bienaymé (GBB) reactions in synthesizing antimicrobial molecules. METHODS: The articles are searched by using the Sci-finder search tool and summarize the chemistry of their synthesis and antimicrobial evaluation of the molecules. RESULTS: This review focuses on synthesizing antimicrobial molecules using the Gewald, Strecker, and Groebke-Blackburn-Bienaymé (GBB) reactions. The antimicrobial activities of the synthesized molecules are also summarized in tables. CONCLUSION: This review will briefly overview the application of the Gewald, Strecker, and Groebke- Blackburn-Bienaymé (GBB) reactions in synthesizing novel antimicrobial molecules. It contains several molecules with promising activity against resistant and non-resistant microbial strains. These promising molecules could be studied further to develop novel antibiotics.
Predicting the Efficacy of Novel Synthetic Compounds in the Treatment of Osteosarcoma Anti-Receptor Activator of Nuclear Factor-κB Ligand (RANKL)/Receptor Activator of Nuclear Factor-κB (RANK) Targets.
Zhang W, Xu S, Liu P … +3 more , Li X, Yu X, Kang B
Med Chem · 2024 · PMID 38468522 · Full text
BACKGROUND: Osteosarcoma (OS) currently demonstrates a rising incidence, ranking as the predominant primary malignant tumor in the adolescent demographic. Notwithstanding this trend, the pharmaceutical landscape lacks th...
BACKGROUND: Osteosarcoma (OS) currently demonstrates a rising incidence, ranking as the predominant primary malignant tumor in the adolescent demographic. Notwithstanding this trend, the pharmaceutical landscape lacks therapeutic agents that deliver satisfactory efficacy against OS. OBJECTIVE: This study aimed to authenticate the outcomes of prior research employing the HM and GEP algorithms, endeavoring to expedite the formulation of efficacious therapeutics for osteosarcoma. METHODS: A robust quantitative constitutive relationship model was engineered to prognosticate the IC values of innovative synthetic compounds, harnessing the power of gene expression programming. A total of 39 natural products underwent optimization heuristic methodologies within the CODESSA software, resulting in the establishment of a linear model. Subsequent to this phase, a mere quintet of descriptors was curated for the generation of non-linear models through gene expression programming. RESULTS: The squared correlation coefficients and 2 values derived from the heuristics stood at 0.5516 and 0.0195, respectively. Gene expression programming yielded squared correlation coefficients and mean square errors for the training set at 0.78 and 0.0085, respectively. For the test set, these values were determined to be 0.71 and 0.0121, respectively. The s2 of the heuristics for the training set was discerned to be 0.0085. CONCLUSION: The analytic scrutiny of both algorithms underscores their commendable reliability in forecasting the efficacy of nascent compounds. A juxtaposition based on correlation coefficients elucidates that the GEP algorithm exhibits superior predictive prowess relative to the HM algorithm for novel synthetic compounds.
Biochemical and Studies on Triazole Derivatives as Tyrosinase Inhibitors: Potential Treatment of Hyperpigmentation Related Skin Disorders.
Choudhary Y, Atia-Tul-Wahab, Zafar H … +6 more , Siddiqui S, Khan M, Khan KM, Asseri AH, Choudhary MI, Atta-Ur-Rahman
Med Chem · 2024 · PMID 38425108 · Publisher ↗
INTRODUCTION: Tyrosinase is a versatile, glycosylated copper-containing oxidase enzyme that mainly catalyzes the biosynthesis of melanin in mammals. Its overexpression leads to the formation of excess melanin, resulting...
INTRODUCTION: Tyrosinase is a versatile, glycosylated copper-containing oxidase enzyme that mainly catalyzes the biosynthesis of melanin in mammals. Its overexpression leads to the formation of excess melanin, resulting in hyperpigmentary skin disorders, such as dark spots, melasma, freckles, etc. Therefore, inhibition of tyrosinase is a therapeutic approach for the treatment of hyperpigmentation. METHODS: The current study focused on evaluating tyrosinase inhibitory activities of triazole derivatives 1-20, bearing different substituents on the phenyl ring. 17 derivatives have shown a potent tyrosinase inhibition with IC values between 1.6 to 13 μM, as compared to the standard drug, i.e., kojic acid (IC = 24.1 ± 0.5 μM). Particularly, compounds 11 and 15 displayed 12 times more potent inhibitory effects than the kojic acid. RESULTS: The structure-activity relationship revealed that substituting halogens at the C-4 position of the benzene ring renders remarkable anti-tyrosinase activities. Compounds 1-3 and 8 showed a competitive type of inhibition, while compounds 5, 11, and 15 showed a non-competitive mode of inhibition. Next, we performed molecular docking analyses to study the binding modes and interactions between the ligands (inhibitors) and the active site of the tyrosinase enzyme (receptor). Besides this, we have assessed the toxicity profile of inhibitors on the BJ human fibroblast cell line. CONCLUSION: The majority of the newly identified tyrosinase inhibitors were found to be noncytotoxic. The results presented herein form the basis of further studies on triazole derivatives as potential drug leads against tyrosinase-related diseases.
Synthesis, Antimicrobial Evaluation, and Interaction of Emodin Alkyl Azoles with DNA and HSA.
Zhou YH, Wang Y, Zhang HZ
Med Chem · 2024 · PMID 38351695 · Publisher ↗
OBJECTIVE: This study aimed to overcome the growing antibiotic resistance. Moreover, the new series of emodin alkyl azoles were synthesized. METHOD: The novel emodin alkyl azoles were synthesized using commercial emodin...
OBJECTIVE: This study aimed to overcome the growing antibiotic resistance. Moreover, the new series of emodin alkyl azoles were synthesized. METHOD: The novel emodin alkyl azoles were synthesized using commercial emodin and azoles by alkylation. The NMR and HRMS spectra were employed to confirm the structures of novel prepared compounds. The antibacterial and antifungal activities of the prepared emodin compounds were studied by the 96-well plate method. The binding behavior between emodin 4-nitro imidazole compound 3c and DNA was researched using an ultraviolet-visible spectrophotometer. Furthermore, fluorescence spectrometry was used to explore the interaction with human serum albumin (HSA). RESULTS: The antimicrobial results displayed that compound 3c gave relatively strong activities with MIC values of 4-16 μg/mL. Notably, this compound exhibited 2-fold more potent activity against (MIC = 4 μg/mL) and (MIC = 8 μg/mL) strains than clinical drug Chloromycin (MIC = 8 and 16 μg/mL). The UV-vis absorption spectroscopy showed that 4-nitro imidazole emodin 3c could form the 3c-DNA complex by intercalating into DNA, inhibiting antimicrobial activities. The simulation results displayed that the emodin 3c and DNA complex were formed by hydrogen bonds. The spectral experiment demonstrated that compound 3c could be transported by human serum albumin (HSA) hydrogen bonds. The molecular simulation found that the hydroxyl group and the nitroimidazole ring of the emodin compound showed an important role in transportation behavior. CONCLUSION: This work may supply useful directions for the exploration of novel antimicrobial agents.
Pharmacochemical Study of Multitarget Amino Acids' Hybrids: Design, Synthesis, , and Studies.
Fotopoulos I, Pontiki E, Hadjipavlou-Litina D
Med Chem · 2024 · PMID 38347768 · Full text
INTRODUCTION: Neuro-inflammation is a complex phenomenon resulting in several disorders. ALOX-5, COX-2, pro-inflammatory enzymes, and amino acid neurotransmitters are tightly correlated to neuro-inflammatory pathologies....
INTRODUCTION: Neuro-inflammation is a complex phenomenon resulting in several disorders. ALOX-5, COX-2, pro-inflammatory enzymes, and amino acid neurotransmitters are tightly correlated to neuro-inflammatory pathologies. Developing drugs that interfere with these targets will offer treatment for various diseases. OBJECTIVE: Herein, we extend our previous research by synthesizing a series of multitarget hybrids of cinnamic acids with amino acids recognized as neurotransmitters. METHODS: The synthesis was based on an study of a library of cinnamic amide hybrids with glycine, γ- aminobutyric, and L - glutamic acids. Drug-likeness and ADMET properties were subjected to analysis. Cinnamic acids were derived from the corresponding aldehydes by Knoevenagel condensation. The synthesis of the amides followed a two-step reaction with 1- hydroxybenzotriazole monohydrate and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride in dry dichloromethane and the corresponding amino acid ester hydrochloride salt in the presence of N,N,-diisopropyl-Nethylamine. RESULTS: The structure of the synthesized compounds was confirmed spectrophotometrically. The new compounds, such as lipoxygenase, cyclooxygenase-2, lipid peroxidation inhibitors, and antiinflammatories, were tested . The compounds exhibited LOX inhibition with IC values in the low μM region). CONCLUSION: Compounds 18a, 23b, and 11c are strong lipid peroxidation inhibitors (99%, 78%, and 92%). Compound 28c inhibits SLOX-1 with IC =8.5 μM whereas 11a and 22a highly inhibit COX-2 (IC 6 and 5 μM Hybrids 14c and 17c inhibit both enzymes. Compound 29c showed the highest anti-inflammatory activity (75%). The ADMET properties of 14c and 11a support their drug-likeness.
Heterocyclic-Based Analogues against Sarcine-Ricin Loop RNA from : Molecular Docking Study and Machine Learning Classifiers.
Sharma S, Choubey R, Gupta M … +1 more , Singh S
Med Chem · 2024 · PMID 38333980 · Publisher ↗
BACKGROUND: Heterocyclic-based drugs have strong bioactivities, are active pharmacophores, and are used to design several antibacterial drugs. Due to the diverse biodynamic properties of well-known heterocyclic cores, su...
BACKGROUND: Heterocyclic-based drugs have strong bioactivities, are active pharmacophores, and are used to design several antibacterial drugs. Due to the diverse biodynamic properties of well-known heterocyclic cores, such as quinoline, indole, and its derivatives, they have a special place in the chemistry of nitrogen-containing heterocyclic molecules. OBJECTIVES: The objective of this study is to analyze the interaction of several heterocyclic molecules using molecular docking and machine learning approaches to find out the possible antibacterial drugs. METHODS: The molecular docking analysis of heterocyclic-based analogues against the sarcin-Ricin Loop RNA from with a C2667-2'-OCF3 modification (PDB ID: 6ZYB) is discussed. RESULTS: Many heterocyclic-based derivatives show several residual interaction, affinity, and hydrogen bonding with sarcin-Ricin Loop RNA from with a C2667-2'-OCF3 alteration which are identified by the investigation of molecular docking analysis of such heterocyclic derivatives. CONCLUSION: The dataset from the molecular docking study was used for additional optimum analysis, and the molecular descriptors were classified using a variety of machine learning classifiers, including the GB Classifier, CB Classifier, RF Classifier, SV Classifier, KNN Classifier, and Voting Classifier. The research presented here showed that heterocyclic derivatives may operate as potent antibacterial agents when combined with other compounds to produce highly efficient antibacterial agents.
New Analogues of the Nicotinamide Phosphoribosyltransferase Inhibitor FK866 as Potential Anti-Pancreatic Cancer Agents.
Conforti I, Benzi A, Caffa I … +3 more , Bruzzone S, Nencioni A, Marra A
Med Chem · 2024 · PMID 38333979 · Publisher ↗
BACKGROUND: During the past two decades, many nicotinamide phosphoribosyltransferase (NAMPT) inhibitors were prepared and tested because this enzyme is overexpressed in pancreatic cancer. Although FK866 is a well-known,...
BACKGROUND: During the past two decades, many nicotinamide phosphoribosyltransferase (NAMPT) inhibitors were prepared and tested because this enzyme is overexpressed in pancreatic cancer. Although FK866 is a well-known, strong NAMPT inhibitor, it suffers severe drawbacks. OBJECTIVE: Our work aimed to synthesize efficient NAMPT inhibitors featuring better pharmacokinetic properties than the pyridine-containing FK866. To this aim, the new anticancer agents were based on benzene, pyridazine, or benzothiazole moieties as a cap group instead of the pyridine unit found in FK866 and other NAMPT inhibitors. METHODS: The new compounds, prepared exploiting standard heterocycle chemistry and coupling reactions (e.g., formation of amides, ureas, and cyanoguanidines, copper-mediated azide-alkyne cycloaddition), have been fully characterized using NMR and HRMS analyses. Their activity has been evaluated using cytotoxicity and intracellular NAD depletion assays in the human pancreatic cancer cell line MiaPaCa-2. RESULTS: Among the 14 products obtained, compound 28, bearing a pyridazine unit as the cap group and a thiophene moiety as the tail group, showed 6.7 nanomolar inhibition activity in the intracellular NAD depletion assay and 43 nanomolar inhibition in the MiaPaCa-2 cells cytotoxicity assay, comparable to that observed for FK866. CONCLUSION: The positive results observed for some newly synthesized molecules, particularly those carrying a thiophene unit as a tail group, indicate that they could act as in vivo anti-pancreatic cancer agents.
Systematic Review on Major Antiviral Phytocompounds from Common Medicinal Plants against SARS-CoV-2.
Ghosh S, Singha PS, Das LK … +1 more , Ghosh D
Med Chem · 2024 · PMID 38317467 · Publisher ↗
BACKGROUND: Viral infections are rising around the globe and with evolving virus types and increasing varieties of viral invasions; the human body is developing antimicrobial resistance continuously. This is making the f...
BACKGROUND: Viral infections are rising around the globe and with evolving virus types and increasing varieties of viral invasions; the human body is developing antimicrobial resistance continuously. This is making the fight of mankind against viruses weak and unsecured. On the other hand, changing lifestyle, globalization and human activities adversely affecting the environment are opening up risks for new viral predominance on human race. In this context the world has witnessed the pandemic of the human Coronavirus disease (COVID-19) recently. The disease is caused by the Coronavirus namely Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV- 2). METHODS AND MATERIALS: Developing potential and effective vaccine is also time consuming and challenging. The huge resource of plants around us has rich source of potent antiviral compounds. Some of these molecules may serve as tremendously potent lead molecules whose slight structural modifications may give us highly bioactive antiviral derivatives of phytocompounds. Every geographical region is rich in unique plant biodiversity and hence every corner of the world with rich plant biodiversity can serve as abode for potential magical phytocompounds most of which have not been extensively explored for development of antiviral drug formulations against various viruses like the HIV, HPV , and the Coronavirus, also known as SARS-CoV-2 which causes the disease COVID-19. RESULTS: Several phytocompounds from various medicinal plants have already been screened using in silico tools and some of them have yielded promising results establishing themselves as potent lead molecules for development of drugs against the highly mutating SARS-CoV-2 virus and thus these phytocompounds may be beneficial in treating COVID-19 and help human to win the life threatening battle against the deadly virus. CONCLUSION: The best advantage is that these phytocompounds being derived from nature in most of the cases, come with minimum or no side effects compared to that of chemically synthesized conventional bioactive compounds and are indigenously available hence are the source of cost effective drug formulations with strong therapeutic potentials.
Structure-Activity Relationship Studies on VEGFR2 Tyrosine Kinase Inhibitors for Identification of Potential Natural Anticancer Compounds.
Verma M, Sarfraz A, Hasan I … +2 more , Vasudev PG, Khan F
Med Chem · 2024 · PMID 38299297 · Publisher ↗
BACKGROUND: Over-expression of Vascular Endothelial Growth Factor Receptors (VEGFRs) leads to the hyperactivation of oncogenes. For inhibition of this hyperactivation, the USA Food Drug Administration (FDA) has approved...
BACKGROUND: Over-expression of Vascular Endothelial Growth Factor Receptors (VEGFRs) leads to the hyperactivation of oncogenes. For inhibition of this hyperactivation, the USA Food Drug Administration (FDA) has approved many drugs that show adverse effects, such as hypertension, hypothyroidism, etc. There is a need to discover potent natural compounds that show minimal side effects. In the present study, we have taken structurally diverse known VEGFR2 inhibitors to develop a Quantitative Structure-Activity Relationship (QSAR) model and used this model to predict the inhibitory activity of natural compounds for VEGFR2. METHODS: The QSAR model was developed through the forward stepwise Multiple Linear Regression (MLR) method. A developed QSAR model was used to predict the inhibitory activity of natural compounds. Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) assessment and molecular docking studies were performed. The binding stability of the natural compounds with VEGFR2 was elucidated through Molecular Dynamics (MD) simulation. RESULTS: The developed QSAR model against VEGFR2 showed the regression coefficient of the training dataset (r) as 0.81 and the external regression coefficient of the test dataset (r2 test) 0.71. Descriptors, viz., electro-topological state of potential hydrogen bonds (maxHBint2, nHBint6), atom types (minssNH), maximum topological distance matrix (SpMAD_Dt), and 2D autocorrelation (ATSC7v), have been identified. Using this model, 14 natural compounds have been selected that have shown inhibitory activity for VEGFR2, of which six natural compounds have been found to possess a strong binding affinity with VEGFR2. In MD simulation, four complexes have shown binding stability up to 50ns. CONCLUSION: The developed QSAR model has identified 5 conserved activity-inducing physiochemical properties, which have been found to be correlated with the anticancer activity of the nonidentical ligand molecules bound with the VEGFR2 kinase. Lavendustin_A, 3'-O-acetylhamaudol, and arctigenin have been obtained as possible lead natural compounds against the VEGFR2 kinase.
Oxadiazole Derivatives of Diclofenac as an Anti-proliferative Agent for B-cell Non-Hodgkin Lymphoma: An and Studies.
Qayyum S, Jabeen A, Ashraf S … +4 more , Seraj F, Khan KM, Siddiqui RA, Ul-Haq Z
Med Chem · 2024 · PMID 38279758 · Publisher ↗
BACKGROUND: Non-Hodgkin lymphoma of B cell origin is the common type of lymphoma- related malignancy with poor response rate with conventional front-line therapies. AIM: The aim of the present study was to investigate th...
BACKGROUND: Non-Hodgkin lymphoma of B cell origin is the common type of lymphoma- related malignancy with poor response rate with conventional front-line therapies. AIM: The aim of the present study was to investigate the potential of new anti-inflammatory oxadiazole derivatives of Diclofenac as an anti-lymphoma agent through and approaches. METHODS: Anti-lymphoma potential was evaluated by alamar blue technique. MTT assay employed for cytotoxicity. Gene and protein expression studies was performed by qRT-PCR and ELISA respectively. Docking studies was performed by using MOE program. RESULTS: Among five diclofenac derivatives, (II) showed promising anti-lymphoma effects, where it inhibited the expression of BCL-2, p-38 MAPK and TGF-β in both follicular and Burkitt's lymphoma cells and was non-toxic against normal human fibroblast cells. The studies against BCL-2 revealed that the unsubstituted Sulphur group in (II) is involved in the crucial interactions with the binding site residue. CONCLUSION: The compound (II) can be a potential therapeutic candidate for B-cell non-Hodgkin lymphoma and deserves further development as a novel anti-lymphoma agent.
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