Compounds 4d Research Articles

New Quinazolinone‐Thiouracil Derivatives: Design, Synthesis, Anticancer Evaluation, and In Silico Analysis

AbstractQuinazolinone and thiouracil derivatives are key scaffolds in anticancer development. This study used a molecular hybridization approach to synthesize new quinazolinone‐thiouracil derivatives and evaluated their anticancer activity against three human cancer cell lines, namely breast, lung, and glioblastoma, using SRB assay. Structural elucidation was performed using IR spectroscopy, 1H‐NMR, 13C‐NMR, mass spectrometry, and elemental analysis. Most compounds show moderate to significant cytotoxic effects, with compound 5d displaying the highest potency (IC50 values of 5.28, 4.02, and 2.88 µM, respectively). Compound 5d also demonstrated comparable potency to positive controls cisplatin and temozolomide in lung and glioblastoma cancer cell lines and was nearly as effective as mitochondrial division inhibitor‐1 (mdivi‐1). Furthermore, molecular docking analyses revealed strong binding interactions of the synthesized compounds with dynamin‐related protein‐1 (drp1). Protein–ligand stability studies and all‐atom simulation confirmed the stable binding of compound 5d with drp1. In conclusion, this study identified compound 5d as a potent drp1 inhibitor and promising anticancer drug candidate, deserving further investigation.

Synthesis of para‐Carboxamidostilbene Derivatives as Antihyperglycemia Agents and Their In Silico ADMET and Molecular Docking Studies

AbstractIn this project, para‐carboxamidostilbene derivatives were synthesized using the Heck coupling reaction, confirmed through various analytical techniques such as FT‐IR, HRMS, and NMR analyses, and tested in vitro to evaluate their α‐amylase inhibitory activity. In silico molecular docking was employed to model the binding interactions of compounds with α‐amylase. Pharmacokinetic properties (ADME) and drug‐likeness were also examined. Structure activity relationship (SAR) analysis was conducted to establish the relationship between the chemical structure and α‐amylase inhibitory activity. The synthesized compounds exhibited significant α‐amylase inhibitory activity with IC50 values ranging from 15.0 to 37.5 µM in comparison with acarbose (IC50 = 30.2 ± 1.9 µM). Among them, compounds 6d–6f and 7c–7f demonstrated promising inhibitory activity. Furthermore, molecular docking studies revealed strong interactions between the studied molecules and the α‐amylase binding pocket. The drug‐likeness prediction results indicated that all synthesized compounds adhered to Lipinski's rule of five, suggesting their suitability as drug‐like molecules. Additionally, the assessment of ADMET properties indicated favorable absorption profiles, particularly in terms of human intestinal absorption (HIA). Overall, this study successfully identified several para‐carboxamidostilbene derivatives as potential α‐amylase inhibitors for the treatment of T2DM.

Investigating the efficacy of naphthalene-thiazole hybrid hydrazones as α-glucosidase inhibitors

In this study, a series of hydrazone derivatives containing naphthalene and thiazole hybrids were synthesized through the condensation of (E)-4-methyl-2-(2-(naphthalen-1-ylmethylene)hydrazineyl) thiazole-5-carbohydrazide with various carbonyl compounds, including aldehydes and ketones, whether carbocyclic aromatic or heterocyclic, using a grinding method with drops of acetic acid. The elucidation of the structures of the synthesized hydrazone derivatives was achieved through the analysis of NMR, IR, and mass spectrometry data. All the newly prepared compounds were assessed for their in vitro α-glucosidase inhibition profiles and the results revealed a diverse range of inhibitory potentials, ranging from 9.3 ± 1.0 to 70.5 ± 1.8 μM, in contrast to the reference acarbose (with an IC50 value of 45.2 ± 1.3 μM). In an attempt to explain the observed inhibitions of synthesized naphthalene containing thiazole compounds, molecular docking was performed to determine the binding modes between the synthesized compounds from one side and the active residues of α-glucosidase from the other side. Compounds 4d, 4e, 4c, and 8 demonstrated the strongest binding affinities, with binding energies of -10.5, -9.8, -9.6, and -9.5 kcal/mol, respectively.

Non-food renewable and bioactive products for pesticides: Synthesis, anti-oomycete and anti-fungal activities of 9R-acyloxyquinine derivatives bearing an 1,3,4-oxadiazole moiety

Quinine is the main alkaloids in the bark of Cinchona and its homologous plants of Rubiaceae. To discover biorational natural product-based pesticides, a series of 9R-acyloxyquinine derivatives containing 1,3,4-oxadiazole moieties were prepared by ingeniously introducing an active ester group and a 1,3,4-oxadiazole five membered heterocyclic ring at its C-9 position, and their structures were well characterized by 1H NMR, 13C NMR, HRMS, and m.p. The stereochemical configuration of target compound 6 t was unambiguously subjected to single-crystal X-ray diffraction. Furthermore, bioactivities of these compounds as anti-oomycete and anti-fungal agents against two serious agricultural diseases, Phytophthora capsici and Fusarium graminearum we assessed. Among all tested compounds, 1) Compounds 6c and 6d displayed promising anti-oomycete against P. capsici, with EC50 values of 38.42 and 35.49 mg/L, respectively. 2) Compound 6i exhibited promising anti-fungal against F. graminearum, with an EC50 value of 29.92 mg/L. Moreover, some interesting results of structure-activity relationships were also observed. The results of this study pave the way for further design, structural modification, and development of quinine derivatives as plant anti-oomycetes and anti-fungal agents in crop protection.

Design and Synthesis of Benzimidazole Carboxamide Cysteine Protease Inhibitors as Promising Anti-leishmanial Agents.

More than 20 protozoan species of Leishmania are responsible for causing Leishmaniasis, an infection spread by blood-feeding phlebotomine sandflies. A narrow pool of drugs is currently available rendering the current drug stratagem to treat this infection . Development of novel, less toxic, and more effective regimens is thus a need of the hour. Design and synthesis of benzo[d]imidazole carboxamides as agents to combat Leishmaniasis are also required. 14 benzo[d]imidazole carboxamides were synthesized and gauged against L. donovani promastigotes and intramacrophage amastigote forms. All of the tested compounds exhibited significant anti-promastigote properties with IC50 well below 10 uM. Compounds 4a, 4b, and 4d, showing the highest anti-parasitic activity against promastigote forms (IC50 0.91- 1.33 μM), were also found to be associated with better anti-leishmanial potential (IC50 0.78- 1.67 μM) against the intramacrophage amastigotes comparable to Amphotericin-B (0.13 μM), a drug used for Leishmaniasis. Compound (4a), namely N-(2-(trifluoromethyl)-1Hbenzo[ d]imidazol-5-yl)benzo[d][1,3]-5-carboxamide-dioxole, was found to be most potent against L. donovani amastigotes among all the tested compounds, and demonstrated better antileishmanial properties (IC50 0.78 μM) when compared to the standard. Compound 4a was also assessed for its toxicity profile against THP-1 human monocytic cells. To establish the molecular target(s) in silico, molecular docking studies were performed against cysteine protease, a putative virulence factor of Leishmania parasites, and nucleoside diphosphate kinase, an enzyme with a critical role in nucleotide recycling, also associated with resistance in Leishmania strains. Compound 4a showed better binding affinity than the standard to these targets; furthermore, the molecular dynamic simulation studies further affirmed the stability of compound 4a, within the active site of the targets. In vitro, cysteine protease inhibitory activity (IC50 8.53 μM) using Bz-Arg-AMC hydrochloride fluorogenic peptide substrate established the promising potential of 4a as a cysteine protease inhibitor. Computational ADMET analysis indicated appropriate pharmacokinetic profile and physicochemical characteristics for all members of the synthesized library. Both in vitro and in silico studies indicate that the synthesized imidazole carboxamides can act as potent hits and that N-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5- yl)benzo[d][1,3]-5-carboxamide-dioxole 4a can be an effective hit molecule which can be further developed into potent lead molecule (s) to fight Leishmania donovani.

Indium‐Catalyzed Direct Amidation Reaction of Carboxylic Acids and In Silico Study for Screening the Activity of Potential Therapeutics of the Synthesized Products

AbstractAmide bonds are ubiquitous and valuable motifs in synthetic chemistry, found in a wide range of applications such as the backbone of proteins and pharmaceutical agents. Thus, environmentally friendly and selective methods for synthesizing amide bonds are important. Herein, we report a simple, efficient, and rapid route to access a range of functionalized amides from non‐activated carboxylic acids and amines using indium (III) trifluoromethanesulfonate as an efficient catalyst. A wide range of carboxylic acids – including aliphatic, aromatic, heterocyclic, and dicarbonyl acids – participate smoothly in these reactions, generating structurally diverse amides in moderate to good yields (up to 91 % in 24 examples). The reactions are conducted in dry tetrahydrofuran (THF) under reflux conditions. Furthermore, this amidation strategy provides a method for addressing challenging molecules, such as protected amino acids, to produce biocompatible products. These products can then be used as substrates for various organic transformations, including C−H functionalization reactions. We also demonstrate the synthetic utility of our protocol through the synthesis of essential substrates in organic and medicinal chemistry by reacting N‐protected carboxylic acids with 8‐aminoquinoline to produce a series of biologically valuable compounds. Five of these products, named 4 f, 4p, 9a, 9c, and 9d, have been biologically evaluated through an in‐silico study. The interaction of these compounds with receptor protein 8DQT was examined to assess their potential as drug candidates for hypertension treatment. Effective binding was detected between these compounds and the receptor. Data from molecular docking studies show that compounds 4d and 4 m are the most active, with binding scores of −8.8 and −8.6 kcal/mol, respectively. However, compound 4 m exhibited a stronger binding affinity than compound 4d over the course of dynamic simulation. Our ADMET study suggests that all five compounds are highly safe in the body. Based on the BOILED‐Egg model study, good absorption is suggested for all the molecules, and they can cross the blood‐brain barrier.

Naphthyl-functionalized acetamide derivatives: Promising agents for cholinesterase inhibition and antioxidant therapy in Alzheimer’s disease

This study presents the synthesis and characterization of a series of 13 novel acetamides. These were subjected to Ellman’s assay to determine the efficacy of the AChE and BChE inhibitors. Finally, we report their antioxidant activity as an alternative approach for the search for drugs to treat AD. These studies revealed that compounds 1a–1k and 2l–2m were obtained in moderate yield. Four amides (1h, 1j, 1k, and 2l) were selective for one of the enzymes (BChE); thus, those that inhibited BChE were more active than the positive control (galantamine) and showed better IC50 values (3.30–5.03 µM). The theoretical free binding energies calculated by MM-GBSA indicated that all inhibitors were more stable than rivastigmine, and the inhibition mechanisms involved the entire active site: peripheral anionic site, oxyanion hole, acyl-binding pockets, and catalytic site. We examined the cytotoxicity of compounds 1h, 1j, 1k, and 2l in human dermal cells and found that they did not exhibit any toxic effects under the tested conditions. Additionally, these compounds, which also inhibited BChE, displayed mixed inhibition and did not exhibit hemolytic effects on human erythrocytes. Furthermore, the ABTS and DPPH assays indicated that, although none of the compounds showed activity in the DPPH assay, the EC50 values for radical trapping by the ABTS method showed that compounds 1a, 1d, 1e, and 1g had EC50 values lower than 10 µg/mL, indicating their strong radical scavenging capacity. We also report the crystal structures of compounds 1c, 1d, 1f, and 1g, which are found in monoclinic crystal systems.

Development of Novel 1,3,4‐Trisubstituted Pyrazole Derivatives Bearing Sulfonamide Moiety as Anticancer Agents Targeting JNK Kinases

AbstractIn the present work, a new set of N‐(2‐((4‐(1,3‐diphenyl‐1H‐pyrazol‐4‐yl)pyridine sulfonamide derivatives was synthesized. Final target compounds were tested against JNK1 and JNK2 isoforms. Compounds 8f and 8d showed the highest activity over both JNK isoforms. They showed submicromolar activity over JNK1 (IC50 0.90 µM and 0.96 µM, respectively). They also showed excellent activity over JNK2 (IC50 0.62 µM and 1.07 µM, respectively). Moreover, the final target compounds were tested over HL‐60 and K‐562 cell lines for assessing the in vitro anticancer activity using sorafenib as a positive control. Compound 8f showed the highest potency at IC50 values of 6.21 and 7.43 µM, respectively. Furthermore, compounds 8e and 8g exhibited strong effects on both acute leukemia cancer cell lines with IC50 values of 13.83 and 10.02 µM, respectively, as well as chronic leukemia cancer cell line with IC50 of 12.65 and 9.51 µM, respectively. Compound 8f was also tested to examine its effect on the cell cycle. Finally, a molecular docking study was conducted to understand the plausible binding modes of the most active compounds 8d and 8f within the JNK1 and JNK2 binding sites.

Tuning the photophysical and NLO properties of β-diketonates derived from coumarin-triphenylamine-chalcones: effect of the BF2 group.

Herein the synthesis of three difluoroboron β-diketonate complexes (7a-c) and one chalcone (7d) with coumarin and triphenylamine fragments is described. The effect of the inclusion of the difluoroboron (BF2) group and a phenyl linker on the photophysical properties, intramolecular charge transfer (ICT) and nonlinear optical (NLO) properties was studied. These dyes exhibited excellent ICT properties due to their A-π-D and D-π-A-π-D type push-pull configuration. Thus, all compounds presented a strong solvatochromism, given the absorption and emission maxima shifted to red because of the increase in the polarity of the medium. In addition to this, 7a-d showed the formation of a twisted intramolecular charge transfer (TICT) state, which quenched fluorescence in polar solvents. Compounds 7a, 7b and 7d exhibited aggregation-induced emission (AIE) in MeCN/H2O mixtures, while 7c did not have this behavior. In addition, all compounds showed emission in the solid state. Using DFT and TD-DFT calculations, the molecular geometries of the ground state S0 and the first excited state S1 were elucidated, which confirmed the formation of a TICT state. Furthermore, the theoretical and experimental absorption electronic transitions were correlated by testing different functionals: B3LYP, CAM-B3LYP, PBE0, wB97XD, HSEH1PBE and M062X. Frontier molecular orbitals (FOMs) and molecular electrostatic potentials (MEPs) supported the ICT from the donor to the acceptor group. The global reactivity descriptors were studied and the NLO properties were predicted by calculating first (βtot) and second-order (γave) hyperpolarizabilities, revealing that 7a-d would present promising NLO behavior.

New quinoxaline-oxadiazole hybrids as tubulin inhibitors: Synthesis, cytotoxicity, and molecular dynamics simulations

This study describes the synthesis and biological evaluation of a series of novel quinoxaline-oxadiazole hybrid compounds. These compounds were designed to enhance anticancer activity through the incorporation of specific pharmacophoric groups. Structural characterization using NMR and HRMS spectroscopy confirmed the successful synthesis of the hybrids. Cytotoxicity assays revealed that several compounds exhibited significant activity against various cancer cell lines. Compounds 8a and 8f demonstrated potent activity against A549 cells, while 8a, 8b, and 8c were effective against HaCaT cells. Additionally, compounds 8i and 8a showed activity against HepG2 cells. Molecular docking and dynamics simulations suggested that compounds 8c and 8d bind strongly to the tubulin protein, a target for anticancer drugs. These compounds exhibited binding affinities comparable to known anticancer compounds. The results of this study highlight the potential of quinoxaline-oxadiazole hybrids, especially those with halogen substitutions, as promising candidates for the development of novel anticancer therapeutics.

Synthesis, biological evaluation, docking and molecular dynamics studies of Biginelli-type tetrahydropyrimidine analogues: Antimicrobial, cytotoxicity and antioxidant activity

Tetrahydropyrimidines have a fascinating scaffold that has garnered substantial attention from pharmacists and medicinal chemists. They are heterocyclic compounds used in anti-cancer, anti-microbial, and antioxidants therapies. Herein, a group of tetrahydropyrimidines were provided by using urea, α-ketoacid/β-ketoester, and appropriate aromatic aldehydes. Then, the antioxidant properties of the derivatives were investigated by the DPPH assay. Besides, the cytotoxicity activity of derivatives was evaluated on two MCF-7 and HepG-2 cell lines. The anti-microbial activity of derivatives was also assessed on two positive gram strains, two negative gram strains, and a fungal strain. Derivatives 4a and 4e showed the strongest antioxidant properties, with IC50s of 0.83 and 0.07 mg/mL, respectively. Compounds 4a and 4d were the most potent compounds, with IC50s of 15.81 and 12.34 µM, respectively, on both cancer cell lines. Furthermore, compounds 4b, 4j, and 4i showed the highest anti-microbial activity on S. aureus (MIC = 7.31 µM), B. subtilis (MIC = 10.81 µM), and E. coli (MIC = 11.45 µM), P. aeruginosa (MIC = 8.12 µM), and C. albicans (MIC = 12.03 µM), respectively. Then, the oral bioavailability and pharmacokinetic properties of compounds were predicted. Moreover, the most possible sites of the molecules that are metabolized by the main cytochromes were estimated. Then, the in silico cardiotoxicity and Cyto-safe properties of the compounds were studied. Finally, to determine the stability of the analogues in the Eg5 active site, docking and molecular dynamics simulations were performed.

Rational design, synthesis, and anticancer evaluation of pyridine and substituted aryl linked 1,3,4-oxadiazole derivatives

A new series of Pyridine and substituted aryl linked 1,3,4-oxadiazole derivatives (7a-j) were designed, synthesized and evaluated for their anticancer activities against HeLa, MDA-MB-231, MCF-7, and A549 cell lines by using standard MTT reduction assay protocol with doxorubicin as standard drug. It is very important to mention that all these synthesized derivatives do not show any cytotoxicity on HEK-293 kidney cell lines. Among them, the compound 7d showed better activity against HeLa and MCF-7 cell lines with IC50 values of 1.8 ± 0.3 µM and 1.3 ± 0.11 µM.

Fragment Addition-Based Design of Heteroaromatic-Biphenyl-DAPYs as Potent and Orally Available Non-nucleoside Reverse Transcriptase Inhibitors Featuring Significantly Enhanced Safety.

Our previously disclosed biphenyl-DAPY 3 emerged as a potent inhibitor against WT HIV-1 and various mutant strains. Yet, its journey toward clinical application was thwarted by pronounced cytotoxicity and low selectivity (CC50 = 6 μM, SI = 3515). The safety improvement approach we employed in this work entailed the incorporation of diverse heteroaromatic substituents at the C5 position to exploit the tolerant regions of the NNRTIs' binding pocket through fragment addition-based drug design strategy, ultimately leading to the identification of a series of novel heteroaromatic-biphenyl-DAPYs. The exemplary compound 10d revealed a striking reduction in cytotoxicity (CC50 > 272.81 μM), nearly 45.5 times lower than 3, while showcasing 15-fold increase in selectivity (SI > 52632). This analog sustained exceptional anti-HIV-1 activity against both WT HIV-1 (EC50 = 5 nM) and various mutant strains. Compared to 3, a markedly slower rate of metabolism in human liver microsomes of 10d was observed. Its pharmacokinetic profile was equally captivating, featuring excellent oral bioavailability (F = 57.4%). Moreover, 10d exhibited a delicate sensitivity toward CYP, minimal inhibition of hERG, and no detectable acute toxicity in vivo. These enchanting findings illuminated the potential of 10d as a promising candidate for HIV-1 therapy.

Discovery of 4-(isopentyloxy)-3-nitrobenzamide derivatives as xanthine oxidase inhibitors through a non-anthraquinone exploration.

In our previous study, we reported a series of N-(9,10-anthraquinone-2-carbonyl) amino acid derivatives as novel inhibitors of xanthine oxidase (XO). Recognizing the suboptimal drug-like properties associated with the anthraquinone moiety, we embarked on a nonanthraquinone medicinal chemistry exploration in the current investigation. Through systematic structure-activity relationship (SAR) studies, we identified a series of 4-(isopentyloxy)-3-nitrobenzamide derivatives exhibiting excellent in vitro potency against XO. The optimized compound, 4-isopentyloxy-N-(1H-pyrazol-3-yl)-3-nitrobenzamide (6k), demonstrated exceptional in vitro potency with an IC50 value of 0.13 μM. Compound 6k showed favorable drug-like characteristics with ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of 0.41 and 3.73, respectively. In comparison to the initial compound 1d, 6k exhibited a substantial 24-fold improvement in IC50, along with a 1.6-fold enhancement in LE and a 3.7-fold increase in LLE. Molecular modeling studies provided insights into the strong interactions of 6k with critical amino acid residues within the active site. Furthermore, in vivo hypouricemic investigations convincingly demonstrated that 6k significantly reduced serum uric acid levels in rats. The MTT results revealed that compound 6k is nontoxic to healthy cells. The gastric and intestinal stability assay demonstrated that compound 6k exhibits good stability in the gastric and intestinal environments. In conclusion, compound 6k emerges as a promising lead compound, showcasing both exceptional in vitro potency and favorable drug-like characteristics, thereby warranting further exploration.

Novel quinolin-4-ylcarbonylhydrazine having N-(3-arylacryloyl) moiety: Design, synthesis and biological evaluation as potential cytotoxic agents against MDA-MB-231 via tubulin assembly inhibition

A new set of quinolin-4-ylcarbonylhydrazine derivatives 7a-i and 9a,b bearing 3-arylacryloyl moiety has been synthesized and investigated for their potential anticancer activity. The synthetic protocol involves the following step: the target quinoline derivatives 7a-i and 9a,b appended to the acryloyl moiety were synthesized from quinolin-4-carbohydrazide intermediate with respective ethyl 2-arylamido-3-arylacrylate compounds. The cytotoxic activity study was evaluated using the functional MTT method. The most of target compounds displayed potent cytotoxic activity against MDA-MB-231 cell line. Among them, compounds 7d and 7 h were found to be promising antiproliferative agents with IC50 values of 4.04 and 1.78 μM, respectively, relative to the effective anticancer drug, Dox (IC50 = 5.33 μM). Compound 7 h exhibited cytotoxic activity by causing cell cycle to block at G2/M phase in addition to pro-apoptotic effect, as shown by flow cytometric measurement. In addition, the inhibitory action against β-tubulin polymerization was investigated. Finally, compound 7 h diminished the level of mitochondrial potential by almost 2.8-fold compared to control, indicating that the cellular death proceeds through the provoke of the intrinsic mitochondrial pathway of apoptosis.

Multi-step synthesis, kinetics and in silico explorations of indole-Phenyl-1,2,4-triazole Bi-heterocyclic hybrids unified with 3-substituted benzamides as elastase inhibitors

In the present research work, a library of unique indole-phenyltriazole hybrids comprising 3-substituted-benzamide moiety was synthesized through convergent multi-step strategy. The structural confirmation of all synthesized molecules was corroborated by IR, 1H NMR, 13C MMR, EI-MS and CHN analysis data. The results of in vitro inhibitory potential of novel benzamides against elastase enzyme revealed that all molecules were potent inhibitors and 10d was most active compound among them having IC50 value of (0.197 ± 0.027 µM), relative to the standard (13.421 ± 0.016 µM). The Kinetics mechanism analyzed by Lineweaver-Burk plots which exposed that 10d inhibited this enzyme competitively by forming an enzyme-inhibitor complex. The inhibition constant Ki determined from Dixon plot for compound 10d was 0.85 µM. Moreover, cytotoxicity of these compounds was also profiled by hemolytic activity and it was observed that almost all these benzamides compounds displayed low cytotoxicity. These molecules also exhibited mild cytotoxicity toward red blood cell membrane. In addition, the in silico computational explorations fully supported the in vitro enzyme inhibitory results. The binding energy ranges from -7.1 to -9.1 kcal/mol, which showed that compound possessed good interaction tendencies to the pancreatic elastase target protein. So, it was anticipated from the experimental results and computational investigations of the current research that these derivatives might lead to further research gateways for obtaining better and safe nontoxic medicinal scaffolds for dealing with the elastase related ailments such as lungs diseases, pruritic skin disease and liver infection.

Synthesis, Structural, DFT studies, Biological Effectiveness, and Molecular Docking Aspects of Multitarget Novel N-(4-Phenylthiazol-2-yl)hydrazine carboxamide Hybrids as COX inhibitors, Anti-TB, and Anti-oxidant activity

We herein report, a series of N-(4-phenylthiazol-2-yl)hydrazinecarboxamide based multitarget compounds 3(a-i) were designed and synthesized. Ten compounds 2, and 3(a-i) were characterized by FTIR, NMR (1H and 13C), and mass analysis and subsequently, tested for their potential COX inhibitors, anti-TB, and anti-oxidant activities. The physicochemical and ADME studies for newly synthesized compounds were disclosed. The DFT calculations were taken for the selected molecules using CAM-B3LYP hybrid functional with a 6–31+g(d) all-electron basis set using the Gaussian 09 package. The compounds 3d, 3e, and 3f recognized outstanding COX-II inhibitions with IC50 values of 0.62, 0.78, and 0.72 μM compared to standard drugs. The compounds 3d, 3e, and 3f showed outstanding anti-TB activity with a MIC value of 0.78μg/mL. The compound 3d, and 3f attested outstanding antioxidant activity at 10 μg/mL with a rate of inhibition of 68.12%, and 68.85% respectively. Finally, the molecular docking studies carried out with cyclooxygenase-2 (PDB ID: 6COX), M. tuberculosis enoyl reductase (INHA) (PDB ID: 4TZK), and cytochrome c peroxidase (PDB ID: 2×08), for all the newly synthesized derivatives. Finally, selected compounds were taken for their molecular dynamic studies.

A Step Towards Optimization of Amide-Linked Coumarin Pharmacophore: As an Anti-HIV Agent.

The aim of the present investigation is to identify effective anti-HIV drugs through the in-silico virtual screening of the coumarin pharmacophore with or without substituents. Virtual screening started with target identification through computation docking and interactions, binding affinity through molecular dynamics, and the ADMET profile through the use of various enzymes. The target study suggests that the target is involved in various stages of HIV replication and in determining the ways in which non-nucleoside reverse transcriptase inhibitors (RTIs) influence it. The interaction pattern and simulation study conclude the specific affinity of coumarin pharmacophore to the HIV's reverse transcriptase enzyme, especially 3HVT. Moreover, the amide linkage worked as a synergistic bridge to provide more interaction to the pharmacophore. The initial results led to the determination of 83 virtual amide-like molecules, which were screened through docking and MD studies (100 ns) on the best-suited enzyme HIV's reverse transcriptase enzyme, such as PDB ID "3HVT". The virtual screening study revealed the high affinity of compounds 7d and 7e with the lowest IC50 values of 0.729 and 0.658 μM; moreover, their metabolism pattern study, toxicity, and QED values in a range of 0.31-0.40 support a good drug candidate. The two compounds were also synthesized and characterized for future in vitro and in vivo studies. The in silico-based descriptor of compounds 7d and 7e indicates the potential future and provides the best two molecules and their synthetic route for the development of a more effective drug to combat HIV/AIDS epidemics.

Exploring the Therapeutic Potential of Coumarin-thiazolotriazole Pharmacophores for SARS-CoV-2 Spike Protein through In-vitro and In-silico Evaluation.

The pandemic caused by SARS-CoV-2 significantly impacted human life around the globe. Numerous unexpected modifications of the SARS-CoV-2 genome have resulted in the emergence of new types and have caused great concern globally. Inhibitory effects of bioactive phytochemicals derived from natural and synthetic sources are promising for pathogenic viruses. in vitro and in silico techniques were used in the current study to identify novel inhibitors of coumarin clubbed thiazolo[3,2-b][1,2,4]triazoles against the SARS-CoV-2 spike protein. Interestingly, all the tested molecules demonstrated substantial inhibition of spike protein with 91.81-57.90% inhibition. The spike protein was remarkably inhibited by compounds 6k (91.83%), 6j (89.75%), 6m (87.69%),6i (86.60%), 6l (85.40%), 6h (84.70%), 6l (84.70%), 6g (83.40%), 6b (82.60%), 6f (81.90%), while compounds 6d 6a, 6c, and 6e exhibited significant activity against spike protein with 79.60%, 77.10%, 75.30%, and 57.90% inhibition, respectively. The binding mechanism of these novel inhibitors with spike protein was deduced in silico, which reflects that the active molecules firmly bind with the receptor binding domain (RBD) of spike protein, thereby inhibiting its function. The combined in vitro and in silico investigations unfold the therapeutic potential of coumarin-thiazolotriazole scaffolds in the treatment of SARS-CoV-2 infection.

Novel N-Substituted Isatin-Oxoindolin-1H-Benzo[D] Imidazole Fumarate as a New Class of JNK3 Inhibitor: Design, Synthesis, Molecular Modeling and its Biological Activity

Background: A direct synthesis of functionalized dimethyl fumarate derivatives of 2-(2-((E)-(2-oxoindolin-3-ylidene)methyl)-1H-benzo[d]imidazol-1-yl) is achieved via one-pot reac-tion involving 2-methyl-1H-benzo[d]imidazole and appropriate isatin in the presence of DMAD. Methods: Conversely, this one-pot reaction furnished, upon conduction at 60 o C, the 2-(2-((E)-(2-oxoindolin-3-ylidene)methyl)-1H-benzo[d]imidazol-1-yl) products. The biological activities were evaluated against JNK3 kinase. We chose to dock the compounds into the JNK3 binding site in order to comprehend the molecular underpinnings of the observed bioactivities. Results: The structures of the synthesized compound adduct were evidenced from NMR and MS spectral data and further confirmed by single-crystal X-ray diffraction. The biological activities revealing that the introduction of an alkyl group at the 1-position of the isatin moiety produced JNK3 inhibitors with IC50 values in the low micromolar range. Conclusion: This study synthesized a unique compound using a three-component method. Com-pound 4d showed high antitumor activity (IC50 = 6.5 μM) against JNK3 inhibitors, while com-pounds 4c, 4d, and 4f exhibited high selectivity. The research highlights the effectiveness of the one-pot reaction in creating medically useful hybrid compounds, marking a significant advance in medicinal chemistry.