Compounds 3e Research Articles

Multicomponent reaction for the synthesis of novel nicotinonitrile analogues bearing imidazole or triazole moieties: Synthesis, antioxidant activity, molecular docking, and ADMET studies

The study is aimed to synthesize, characterize and evaluate antioxidant activity of novel highly functionalized nicotinonitrile analogues bearing imidazole or triazole moieties. The targeted compounds were synthesized via one-pot four component reaction and characterized by elemental and spectrometric analyses. The newly 16-synthesized compounds were assessed as antioxidant agents using the total antioxidant capacity assay. The experimental results indicated that four out of sixteen compounds exhibited the most antioxidant effect with 38.81 and 18.66 mg AAE/g considering ascorbic acid equivalent. The molecular docking screening on the novel potential compounds, further supported by ADMET/drug-likeness screening was conducted. The outcomes of the docking simulations revealed that compounds 4e, 4f, 4g, and 6h are considered safe and non-toxic. These 4 compounds exhibited significant affinity, as evidenced by binding energies of -11.9, -10.9, -11.2, and -11.60 kcal/mol, respectively, with the active site of human cytochrome P450. Additionally, these compounds showed significant binding energies with NAD(P)H Oxidase of -9.90, -9.50, -9.90, and -9.50 kcal/mol, respectively. These interactions involved diverse types of molecular interactions and demonstrated favorable binding energies, indicating the potential of these compounds to modulate antioxidant enzymes and demonstrate promising antioxidant effects. The in-silico ADMET profiles of compounds 4e, 4f, 4g, and 6h indicated their adherence to the Lipinski rules, subsequently, they could be potential orally bioavailable drug-like molecules.

Synthesis, Characterization, and Evaluation of Antioxidant Activities of 2-(1-(Substituted phenyl)ethylidene)-1-(4,6-dimethylpyrimidin-2-yl)hydrazines

Background: Pyrimidine and hydrazones are well known for their therapeutic applications. Objective: To investigate the antioxidant activities of compounds having pyrimidine and hydrazone motifs in hope of finding molecules with robust antioxidant activities. Methods: Hydrazones were obtained by condensing pyrimidine hydrazine with aromatic ketones. The structures of these compounds were established on the basis of NMR, FTIR and mass spectral data analysis. Results: All compounds were assessed for their antioxidant potential against DPPH, hydrogen peroxide, nitric oxide and superoxide free radicals. Conclusion: A series of twelve 2-(1-(substituted phenyl)ethylidene)-1-(4,6-dimethylpyrimidin-2-yl)hydrazines was synthesized and compounds 6d, 6e, 6h, and 6j found to have good antioxidant activities.

Synthesis and in-silico Studies of 4-phenyl thiazol-2-amine Derivatives as Putative Anti-breast Cancer Agents.

Breast cancer (BC) is the second-leading cause of cancer-related fatalities in women after lung cancer worldwide. The development of BC is significantly influenced by estrogen receptors (ERs). The problem with current cancer treatments is selectivity, target specificity, cytotoxicity, and developing resistance. Thiazole scaffolds are gaining popularity in drug discovery due to their broad range of biological activity. It has the extraordinary capacity to control a variety of cellular pathways, and its potential for selective anticancer activity can be explored. Synthesis and in-silico</i> studies of 4-Phenyl thiazol-2-amine derivatives as anti-breast cancer agents and molecular docking was used to assess the compounds' capacity to bind ER-α protein target. In this study, 4-Phenylthiazol-2-amine derivatives (3a-j) have been synthesized, and using Schrodinger software, molecular docking and ADME studies of the compounds were conducted. Most of the synthesized compounds have shown dock scores ranging from -6.658 to - 8.911 kcal/mol, which is better than the standard drug tamoxifen (-6.821 kcal/mol). According to molecular docking, all compounds fit in the protein's active site and have the same hydrophobic pocket as the standard drug tamoxifen. Further, all of the compounds' ADME properties are below acceptable limits. Compound 3e showed the best docking score of -8.911. All compounds' ADME properties are within acceptable limits, and their p/o coefficients fall within a range, suggesting they will all have sufficient absorption at the site of action. These compounds can be evaluated invitro</i> and in-vivo</i> in the future.

Design, Synthesis, Anti-Cancer, Anti-inflammatory and In Silico Studies of 3-Substituted-2-Oxindole Derivatives.

This study focuses on the design and synthesis of 3-substituted-2-oxindole derivatives aimed at developing dual-active molecules with anti-cancer and anti-inflammatory properties. The molecules were designed with diverse structural and functional features while adhering to Lipinski, Veber, and Leeson criteria. Physicochemical properties were assessed using SWISSADME to ensure drug-likeness and favourable pharmacokinetics. Multistep synthetic procedures were employed for molecule synthesis. In vitro evaluations confirmed the dual activity of the derivatives, with specific emphasis on the significance of dialkyl aminomethyl substitutions for potency against various cell lines. 4 a exhibited GI50 value 3.00E-05 against MDA-MB-231, 4 b has shown GI50 value 2E-05 against MDA-MB-231, 4 c has shown GI50 value 6E-05 against VERO, 4 d has shown GI50 value 8E-05 each against both the MDA-MB-231 and MCF-7 and 4 e has shown GI50 values 2E-05 and 5E-05 each against both the MCF-7 and VERO. The analysis indicates that compounds 3 c (71.19 %), 3 e (66.84 %), and 3 g (63.04 %) exhibited significant anti-inflammatory activity. Additionally, in silico binding free energy analysis and interaction studies revealed significant correlations between in vitro and computational data, identifying compounds 4 d, 4 e, 3 b, 3 i, and 3 e as promising candidates. Key residues such as Glu917, Cys919, Lys920, Glu850, Lys838, and Asp1046 were found to play critical roles in ligand binding and kinase inhibition, providing valuable insights for designing potent VEGFR2 inhibitors. The Quantum Mechanics-based Independent Gradient Model analysis further highlighted the electronic interaction landscape, showing larger attractive peaks and higher electron density gradients for compounds 4 d and 4 e compared to Sunitinib, suggesting stronger and more diverse attractive forces. These findings support the potential of these compounds for further development and optimization in anticancer drug design.

Probing N-substituted 4-(5-mercapto-4-ethyl-4H-1,2,4-triazol-3-yl)-N-phenylpiperdine-1-carboxamides as potent 15-LOX inhibitors supported with ADME, DFT calculations and molecular docking studies

In our continuous efforts to find out leads against the enzyme 15-lipoxygenase (15-LOX), the current study deals with the synthesis of a series of new N-alkyl/aralkyl/aryl derivatives of 2-(4-ethyl-5-(1-phenylcarbamoyl)piperidine-4H-1,2,4-triazol-3-ylthio)methylacetamide (7a-n) with anti-LOX activities. The synthesis was started by reacting phenylisocyanate with isonipecotate that sequentially converted into N-substituted ester (1), hydrazide (2), semicarbazide (3) and N-ethylated 5-(1-phenylcarbamoyl)piperidine-1,2,4-triazole (4). The final compounds, 7a-n, were obtained by reacting 4 with various N-alkyl/aralkyl/aryl electrophiles. Both the intermediates and target compounds were characterized by FTIR, 1H, 13C NMR spectroscopy, EI-MS and HR-EI-MS spectrometry and screened against soybean 15-LOX by chemiluminescence method. The eight compounds 7e, 7j, 7h, 7a, 7g, 7b, 7n, 7c showed potent inhibitory activities against 15-LOX with values ranging from IC50 0.36 ± 0.15 μM (7e) to IC50 6.75 ± 0.17 μM (7c) compared with the reference quercetin (IC50 4.86 ± 0.14 μM) and baicalein (IC50 2.24 ± 0.13 μM). Two analogues (7l, 7f) had significantly outstanding inhibitory potential with IC50 values 12.15 ± 0.23 μM and 15.54 ± 0.26 μM, whereas, the derivatives 7i, and 7d displayed IC50 values of 21.56 ± 0.27 μM, 23.59 ± 0.24 μM and the compounds 7k, 7m were found inactive. All analogues exhibited blood mononuclear cells (MNCs) viability >75 % at 0.25 mM concentration as determined by MTT method. Calculated pharmacokinetic properties projected good lipophilicity, bioavailability and drug-likeness properties and did not violate Lipinski's/Veber rule. Molecular docking studies revealed lower binding free energies of all the derivatives than the reference compounds. The binding free energies were −9.8 kcal/mol, −9.70 k/mol and −9.20 kcal/mol for 7j, 7h and 7e, respectively, compared with the standard quercetin (−8.47 kcal/mol) and baicalein (−8.98 kcal/mol). The docked ligands formed hydrogen bonds with the amino acid residues Gln598 (7e), Arg260, Val 126 (7h), Gln762, Gln574, Thr443, Arg580 (7j) while other hydrophobic interactions observed therein further stabilized the complexes. The results of density functional theory (DFT) revealed that analogues with more stabilized lower unoccupied molecular orbital (LUMO) had significant enzyme inhibitory activity. The data collectively supports these molecules as leads against 15-LOX and demand further investigations as anti-inflammatory agents.

Tetrahydropyridine appended 8-aminoquinoline derivatives: Design, synthesis, in silico, and in vitro antimalarial studies

Antimalarial drug resistance is a major obstacle in the ongoing quest against malaria. The disease affects half of the world’s population. The majority of them are toddlers and pregnant women. Needed a potent compound to act on drug-resistant Pf at appropriate concentrations without endangering the host. Envisaged solving this issue through rational drug design by creating a novel hybrid drug possessing two pharmacophores that can act on two marvellous and independent aims within the cell. Synthesized a new series of substituted 4-phenyl-1,2,3,6-tetrahydropyridine (THP) 8-Aminoquinoline-based hybrid analogs which have been integrated with quinoline, chloroquine, pamaquine, and primaquine, which exhibited antimalarial activity against Pf. Out of thirteen 4-phenyl-1,2,3,6-THP appended 8-Aminoquinoline derivatives, the compounds 1j, 1e, 1b, and 1l have exhibited good antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (RKL-9) strain with the minimum inhibitory concentration. Compound 1b was the most effective and showed consistently good potency against the drug-resistant (RKL-9) strain, although all other arrays showed good antimalarial efficacy. Additional docking and molecular dynamics studies were carried out at several targeting sites to quantify the structural parameters necessary for the activity.

Synthesis of indole-functionalized isoniazid conjugates with potent antimycobacterial and antioxidant efficacy.

Aim: Developing potent medicinal alternates for tuberculosis (TB) is highly desirable due to the advent of drug-resistant lethal TB strains.Methods & results: Novel indole-isoniazid integrates have been synthesized with promising antimycobacterial action against the H37Rv strain, and the nitro analogs 4e and 4j show the highest efficacy with a minimum inhibitory concentration of 1.25μg/ml. The molecular docking studies against InhA support the experimental findings. Indole conjugates display remarkable radical quenching efficiency, and compounds 4e and 4j demonstrate maximum IC50 values of 50.19 and 52.45μg/ml, respectively. Pharmacokinetic analysis anticipated appreciable druggability for the title compounds.Conclusion: The notable bioaction of the indole-isoniazid templates projects them as potential lead in developing anti-TB medications with synergetic antioxidant action.

Discovery of Cell-Permeable Allosteric Inhibitors of Liver Pyruvate Kinase: Design and Synthesis of Sulfone-Based Urolithins.

Metabolic dysfunction-associated fatty liver disease (MAFLD) presents a significant global health challenge, characterized by the accumulation of liver fat and impacting a considerable portion of the worldwide population. Despite its widespread occurrence, effective treatments for MAFLD are limited. The liver-specific isoform of pyruvate kinase (PKL) has been identified as a promising target for developing MAFLD therapies. Urolithin C, an allosteric inhibitor of PKL, has shown potential in preliminary studies. Expanding upon this groundwork, our study delved into delineating the structure-activity relationship of urolithin C via the synthesis of sulfone-based urolithin analogs. Our results highlight that incorporating a sulfone moiety leads to substantial PKL inhibition, with additional catechol moieties further enhancing this effect. Despite modest improvements in liver cell lines, there was a significant increase in inhibition observed in HepG2 cell lysates. Specifically, compounds 15d, 9d, 15e, 18a, 12d, and 15a displayed promising IC50 values ranging from 4.3 µM to 18.7 µM. Notably, compound 15e not only demonstrated a decrease in PKL activity and triacylglycerol (TAG) content but also showed efficient cellular uptake. These findings position compound 15e as a promising candidate for pharmacological MAFLD treatment, warranting further research and studies.

Molecular Periphery Design Allows Control of the New Nitrofurans Antimicrobial Selectivity.

A series of 13 new 3-substituted 5-(5-nitro-2-furyl)-1,2,4-oxadiazoles was synthesized from different aminonitriles. All compounds were screened in the disc diffusion test at a 100 μg/mL concentration to determine the bacterial growth inhibition zone presence and diameter, and then the minimum inhibitory concentrations (MICs) were determined for the most active compounds by serial dilution. The compounds showed antibacterial activity against ESKAPE bacteria, predominantly suppressing the growth of 5 species out of the panel. Some compounds had similar or lower MICs against ESKAPE pathogens compared to ciprofloxacin, nitrofurantoin, and furazidin. In particular, 3-azetidin-3-yl-5-(5-nitro-2-furyl)-1,2,4-oxadiazole (2h) inhibited S. aureus at a concentration lower than all comparators. Compound 2e (5-(5-nitro-2-furyl)-3-[4-(pyrrolidin-3-yloxy)phenyl]-1,2,4-oxadiazole) was active against Gram-positive ESKAPE pathogens as well as M. tuberculosis. Differences in the molecular periphery led to high selectivity for the compounds. The induced-fit docking (IFD) modeling technique was applied to in silico research. Molecular docking results indicated the targeting of compounds against various nitrofuran-associated biological targets.

Synthesis of Cytotoxic Benzofurans and Ethers Derivatives of Paeonol.

Paeonol is a broadly studied natural product due to its many biological activities. Using a methodology previously employed by our research group, 11 derivatives of paeonol were synthesized (seven of them are unpublished compounds), including four ethers and seven benzofurans. Additionally, we determined the crystal structure of one of these ether derivatives (1 a) and of five benzofuran derivatives (2 a, 2 b, 2 c, 2 f and 2 g) by single crystal X-ray diffraction. To continue studying the cytotoxicity of this natural product and its derivatives, all compounds were tested against two cancer cell lines, HCT116 and MCF-7. Compounds 2 b, 2 e, and 2 g were considered active against the colorectal adenocarcinoma cells HCT116 (Growth inhibition >60 %). Compound 2 e showed an IC50 of 0.2 μM and was selected for further analysis, results reinforce its anticancer potential.

Synthesis, Antimicrobial Evaluation, DFT, in Silico-Docking, and ADMET Investigations of Novel Chromene-Based 2,4-Thiazolidinediones.

Three series of thiazolidinedione (TZD) derivatives (5a-f, 7a-f, and 9a-f) were prepared efficiently. Afterward, the synthesized candidates' antibacterial efficacy against both gram-positive and gram-negative bacteria was assessed. Compounds 7c, 7d, and 7f had values comparable to that of ampicillin, a reference antibiotic, whereas compounds 5c, 5d, and 7e exhibited the greatest values (23.0±1.0, 27.7±0.6, and 20.0±1.0, respectively) against gram-positive bacteria (Staphylococcus aureus). The optimal structure of the produced molecules was determined by DFT computing. To assess the binding energy and elucidate the interaction between the potential candidates and different proteins, in silico docking is employed. ADMET analysis to assess the synthesized compounds' toxicity, metabolism, excretion, distribution, and absorption.

Synthesis of amino juglone derivatives with adjuvant activity against clinical isolated methicillin-resistant staphylococcus aureus strains

1,4-naphthoquinones hydroxyderivatives belong to an important class of natural products and have been known as a favored scaffold in medicinal chemistry due to their multiple biological properties. Juglone is one of the most important 1,4-naphthoquinone extracted from juglandaceae family showing a good antibacterial activity. In this study, we report the synthesis of aminojuglone derivatives through Michael addition reaction using Cerium (III) chloride heptahydrate (CeCl3·7H2O) as catalyst. The synthesized aminojuglone derivatives were evaluated for their antibacterial properties against sensitive, clinical resistant Gram-positive and Gram-negative bacterial strains. Compound 3c showed a good antibacterial activity similar to cloxacillin (2 µg/mL) against the clinically resistant S.aureus. The antibiotic adjuvant activity of compounds was evaluated in combination with three clinically use antibiotics. The combination of compounds 3a, 3b, 3e, 3 h-3 l, 3n and 3o with cloxacillin showed remarkable adjuvant activity against clinically resistant S. aureus (66-fold potentiation of cloxacillin activity). 3e is the only compound consistent with the concept of antibiotic adjuvant, presenting insufficient antibacterial activity (MIC > 128 µg/mL) and potentiate the activity of cloxacillin (66-fold) with synergistic effect. A structural characterization of 3e was carried out for the first time using X-ray diffraction technic. Moreover, compound 3e did not show a cytotoxic activity on sheep red blood cells.

Drug Design, In Silico-Profiling of New Pyrrole Derivatives: Promising Anticancer Agents Against Acute Myeloid Leukemia

Molecular docking simulation and synthesis of five compounds of N2, N4-bis (2-(4-substituted phenyl)-4-oxothiazolidin-3-yl)-3,5-dimethyl-1H-pyrrole-2,4-dicarboxamide was carried out to evaluate their theoretical binding affinities, targeting acute myeloid leukemia (AML). The chemical structure of the molecules was accurately drawn using ChemDraw Professional 19.1 software. The designed compounds were evaluated for their selectivity towards FLT3's ATP pocket (PDB ID:6JQR) in comparison with the reference ligand (Gilteritinib) by using GOLD suite from the Cambridge Crystallographic Data Centre (CCDC) software (Version 2021.2.0). All the designed compounds exhibited good binding energies with the receptor active pocket and had promising activity. Compounds 2E and 3E showed the highest PLP Fitness (83.30, 80.86 respectively) and it is higher than that of Gilteritinib (71.91). In-silico ADME and drug-likeness studies were performed by using the Swiss ADME server. The results showed that most of the designed compounds expected to be absorbed from the GIT. Compounds 2B-E have high expected GI absorption. All the investigated compounds have no predicted BBB penetration. Additionally, compounds 2A, 2C, 2D, and 3A are not a substrate to P-gps which may indicate a lower expected incidence of resistance by cancer cells in vitro studies. Finally, all of the investigated compounds are not considered to inhibit CYP1A2 enzyme, except for compounds 2A and 3D.

Discovery of 1,2,3-triazole-based pleuromutilin derivatives as potent gram-positive antibacterial agents

A novel class of pleuromutilin derivatives possessing 1,2,3-triazole as the linker connected to phenyl analogues were designed. The antibacterial properties of the prepared compounds were assessed in vitro against five strains (E. coli, S. aureus, S. epidermidis, and E. faecalis). Most of the tested compounds displayed potent antibacterial activities against gram-positive bacteria and 14-O-[2-(4-((2,4-dinitrophenoxy)-methyl-1H-1,2,3-triazol-1-yl) acetamide)-2-methylpropan-2-yl) thioacetyl]mutilin (7c) exerted antibacterial activities against S. aureus, MRSA and S. epidermidis with MIC values 0.0625 μg/mL, representing 64-fold, 4-fold and 8-fold higher than tiamulin respectively. Compound 6e, 7c and 8c were chosen to carry out killing kinetics, which exhibited concentration-dependent effect. Subsequently, molecular modeling was conducted to further explore the binding of compound 6e, 7a, 7c, 8c and tiamulin with 50S ribosomal subunit from deinococcus radiodurans. The investigation revealed that the main interactions between compound 7c and the ribosomal residues were three hydrogen bonds, π-π, and p-π conjugate effects. Additionally, the free binding energy and docking score of 7c with the ribosome demonstrated the lowest values of −11.90 kcal/mol and −7.97 kcal/mol, respectively, consistent with its superior antibacterial activities.

Design and synthesis of mono/bis isoxazoline and pyrroline pendant chromone derivatives-anti-cancer activity

A simple and efficient route for the synthesis of a series of new mono/bis isoxazolines, and pyrroline linked chromone heterocyclic hybrids has been developed from 2-aminochromone via key intermediate mono and 2-(diallylamino)chromen-4-one. The intermediate subjected to the [1,3] dipolar cycloaddition with insitu generated nitrile oxides and ring-closing metathesis to generate the regio selective Isoxazolines and 3-pyrrolines. All the derivatives were screened for their anti-cancer activity (Cell viability), compared to the standard drug Imatinib. Compounds 13b and 13e, 14b and 14g showed good inhibition at 10 µM concentration.

Synthesis and biological evaluation of O4′-benzyl-hispidol derivatives and analogs as dual monoamine oxidase-B inhibitors and anti-neuroinflammatory agents

Design, synthesis, and biological evaluation of two series of O4′-benzyl-hispidol derivatives and the analogous corresponding O3′-benzyl derivatives aiming to develop selective monoamine oxidase-B inhibitors endowed with anti-neuroinflammatory activity is reported herein. The first O4′-benzyl-hispidol derivatives series afforded several more potentially active and MAO-B inhibitors than the O3′-benzyl derivatives series. The most potential compound 2e of O4′-benzyl derivatives elicited sub-micromolar MAO-B IC50 of 0.38 µM with a selectivity index >264 whereas most potential compound 3b of O3′-benzyl derivatives showed only 0.95 MAO-B IC50 and a selectivity index >105. Advancement of the most active compounds showing sub-micromolar activities to further cellular evaluations of viability and induced production of pro-neuroinflammatory mediators confirmed compound 2e as a potential lead compound inhibiting the production of the neuroinflammatory mediator nitric oxide significantly by microglial BV2 cells at 3 µM concentration without significant cytotoxicity up to 30 µM. In silico molecular docking study predicted plausible binding modes with MAO enzymes and provided insights at the molecular level. Overall, this report presents compound 2e as a potential lead compound to develop potential multifunctional compounds.

Ultrasound-assisted ring opening of epoxides in HFIP: THF: Synthesis, characterization, computational studies and molecular docking of novel 2‑hydroxy dithiocarbamates

Under the influence of ultrasonic irradiation, pyridazinone, triazinone, or phthalimide containing 2‑hydroxy dithiocarbamates, a biologically relevant novel organo-sulfur compound, was synthesized. Detailed characterization, computational, and molecular docking studies are being investigated. Molecular interactions were studied using 3D Hirshfeld surfaces and corresponding 2D fingerprint plots. Theoretical (DFT) studies on the molecular structure, HOMO, LUMO, and quantum chemical descriptors were performed at the B3LYP/6–311++G(d,p) level of theory. At the same time, the interaction energy was computed using the B3LYP/6–31G(d,p) level of theory. The FMO study revealed that molecules 4a and 4p in the gas phase have 3.545 eV and 3.263 eV HOMO-LUMO energy gaps, respectively, and they are hence kinetically stable. Quantum chemical calculations confirm the electrophilic character of compounds 4a and 4p, as the molecule is stable and highly electrophilic. The interactions of 2‑hydroxy dithiocarbamate derivatives (4a-4t) with the ligand-binding site of the target COX-2 (cyclooxygenase-2) enzyme were investigated using in-silico molecular docking experiments. Compared to the standard medicine celecoxib, the results showed that most synthesized derivatives had better glide scores and interaction. The docking study of all the synthesized compounds revealed that compounds 4a, 4e, and 4o interact well with the COX-2 enzyme as anti-inflammatory drugs. Molecular dynamic simulation was utilized to validate the docking study and explore the stable binding site and interaction of compound 4o, which is the most potent. The findings indicated that compound 4o exhibited better stability and interaction when compared to the reference drug.

Pd(II)-Catalyzed Site-Selective Cross Coupling Reaction: Synthesis of Highly Fluorescent Aryl-Formyl-Chromenes and its Iminoantipyrine Analogues as Selective AChE Inhibitors.

A versatile and efficient chemo selective synthesis of 4-aryl-3-formyl-2H-chromenes (AFC) was undertaken using Pd-catalyzed cross-coupling conditions. The key oxidative transmetalation was successfully applied to a significant range of substitutions on the chromene moiety and aryl ring in Ar(BOH)3, accommodating both electron-rich and electron-deficient groups. These π-extended scaffolds exhibited green-yellow fluorescence with a large Stokes shift and high quantum yield. Measurement of photophysical properties revealed that the compound with methoxy substitution in the chromene ring, 3t, caused a significant bathochromic shift. The AFCs obtained from this method can be transformed into biologically active 4-aryl-3-iminoantipyrine-2H-chromenes (AAC) through functionalization of the formyl chromenes. The AFCs and AACs with methoxy substitutions (3t and 4e) were docked against AChE inhibition, and compound 4e had the lowest binding energy of -11.20 kcal/mol. DFT calculations performed on representative compounds revealed that compound 4e is more reactive than 3t, which is in accordance with the docking studies.

Design, Synthesis, and the Biological Evaluation of Some New Fused Thiazolotriazine Derivatives

Thiazolotriazine is an essential medicinal chemistry molecule due to its biological properties, particularly antifungalactivity. Antifungal drug resistance is rising worldwide, necessitating the development of innovative, safer, and more effectiveantifungals. This study intended to uncover safer and more effective thiazolotriazine antifungals. ProTox II software was employedto forecast the toxicity of the designed thiazolotriazines. The pharmacokinetic parameters were calculated using the Swiss-ADMEdatabase. The Molecular Operating Environment software (2019.0102 version) was employed for the docking studies utilizing 14-α-demethylase protein (PDB ID: 3LD6). Compounds 4c, 4d, and 4e were prepared and evaluated for in vitro antifungal activity.The computational studies revealed compounds 4a, 4b, 5b, 5c, 6b, 6c and 6d as carcinogenic; 4a, 4b, 4c, 4d and 4e demonstratedbetter pharmacokinetic behaviour; and docking results of 4c, 4d, and 4e were superior than fluconazole (FLU). The moleculardocking studies establish 4c, 4d, and 4e as SDM inhibitors, suggesting a mechanism similar to FLU and ketoconazole (KET). Theantifungal activity evaluation revealed 4d (MIC = 6.25 μg/ml) as a more potent antifungal agent than KET (MIC = 12.5 μg/ml) andFLU (MIC = 12.5 μg/ml). Compounds 4c and 4e showed equal antifungal activity to KET (MIC = 12.5 μg/ml) and FLU (MIC = 12.5μg/ml). Compounds 4c, 4d, and 4e displayed encouraging antifungal activity with a favorable safety profile. Assessing the broadspectrum of 4c, 4d, and 4e against various pathogenic fungi, including resistant forms, is recommended.

Synthesis of curcumin derivatives targeting androgen receptor for castration-resistant prostate cancer therapy.

In this work, a series of curcumin derivatives (1a-1h, 2a-2g, and 3a-3c) were synthesized for the suppression of castration-resistant prostate cancer cells. All synthesized compounds were characterized by 1H NMR, 13C NMR, HRMS, and melting point. The invitro cytotoxicity study shows that compounds 1a, 1e, 1f, 1h, 2g, 3a, and 3c display similar or enhanced cytotoxicity against 22Rv1 and C4-2 cells as compared to ASC-J9, other synthesized compounds display reduced cytotoxicity against 22Rv1 and C4-2 cells as compared to ASC-J9. Molecular docking simulation was performed to study the binding affinity and probable binding modes of the synthesized compounds with androgen receptor. The results show that all synthesized compounds exhibit higher cdocker interaction energies as compared to ASC-J9. Compounds 1h, 2g, and 3c not only show strong cytotoxicity against 22Rv1 and C4-2 cells but also exhibit high binding affinity with androgen receptor. In androgen receptor suppression study, compounds 1f and 2g show similar androgen receptor suppression effect as compared to ASC-J9 on C4-2 cells, compound 3c displays significantly enhanced AR suppression effect as compared to ASC-J9, 1f and 2g. Compounds 1a, 1e, 1f, 1h, 2g, 3a and 3c prepared in this work have significant potential for castration-resistant prostate cancer therapy.