Compounds 4d Research Articles

Synthesis and evaluation of the anti-TB activity of novel 7-(2-(4-substituted-phenyl)-4,5-diphenyl-1H-imidazol-1-yl)-4-methyl-2H-chromen-2-one derivatives and their DFT studies for NLO application

A series of novel 7-(2-(4-substituted-phenyl)-4,5-diphenyl-1H-imidazol-1-yl)-4-methyl-2H-chromen-2-one derivatives 5(a-g) have been synthesized and reported as anti-TB activity and non-linear optical applications. The activity results show that compounds 5b, 5c, 5d, 5f, and 5g exhibited excellent efficacy with a MIC value of 3.12 μg/mL, one-fold greater than the reference standard streptomycin (6.26 μg/mL). An in silico molecular docking study was performed against InhA protein and the results were consistent with the experimental results. Computational studies were performed using the DFT method and results reveal that the presence of greater electronegativity atoms increases the HOMO-LUMO energy gap. The NLO properties show that the presence of stronger electron-donating substituents increases the ICT, charge delocalization and β0 values. The NBO analysis shows significant interactions between LP (Lone pair), π* and σ* in compounds account for the high polarization and enhanced NLO activity.

Organocatalytic[3 + 2]Cycloaddition: Synthesis of Quinazoline Containing Sulfonyl 1,2,3‐Triazoles as Potent EGFR Targeting Anti‐Breast Cancer Agents

ABSTRACTA general strategy was developed for the synthesis of new fully decorated 1,2,3‐triazoles (4a–4m and 5a–5g) containing quinazolines from 1‐(4‐nitrophenyl)‐2‐(quinazolin‐8‐ylsulfonyl) ethan‐1‐one and several azides using Ramachary organocatalytic azide‐ketone cycloaddition method. This reaction is reported for the synthesis of fully substituted sulfonyl‐1,2,3‐triazolyl quinazolins at a temperature of 100°C and the yields of the products produced are satisfactory to excellent. In vitro anticancer activity of all these derivatives demonstrated that six compounds, 4d, 4f, 4i, 4j, 5d, and 5e, were effective against two human breast cancer cell lines, MCF‐7 and MDA‐MB‐231. Compounds 4f, 4j, and 5d had more action against both cell lines than Erlotinib. Later, the findings of inhibitory assays of potent compounds 4d, 4f, 4i, 4j, 5d, and 5e against the tyrosine kinase EGFR revealed that compound 5d proved more potent than the reference erlotinib, while 4f and 4j had comparable efficacy. In silico molecular docking studies were also performed on six strong medicines to identify interactions with the EGFR receptor, and the energy estimations were shown to be comparable with the observed IC50 values. Ultimately, using SWISS/ADME and pkCSM, the in silico pharmacokinetic profile of potent compounds 4d, 4f, 4i, 4j, 5d, and 5e was predicted. All of the compounds precisely followed the principles established by Lipinski, Veber, Egan, and Muegge.

Systematic Evaluation of Regiochemistry and Lipidation of Aryl Trehalose Mincle Agonists.

The Macrophage-Inducible C-type Lectin receptor (Mincle) plays a critical role in innate immune recognition and pathology, and therefore represents a promising target for vaccine adjuvants. Innovative trehalose-based Mincle agonists with improved pharmacology and potency may prove useful in the development of Th17-mediated adaptive immune responses. Herein, we report on in vitro and in silico investigations of specific Mincle ligand-receptor interactions required for the effective receptor engagement and activation of Th17-polarizing cytokines. Specifically, we employed a library of trehalose benzoate scaffolds, varying the degree of aryl lipidation and regiochemistry that produce inflammatory cytokines in a Mincle-dependent fashion. In vitro interleukin-6 (IL-6) cytokine production by human peripheral blood mononuclear cells (hPBMCs) indicated that the lipid regiochemistry is key to potency and maximum cytokine output, with the tri-substituted compounds inducing higher levels of IL-6 in hPBMCs than the di-substituted derivatives. Additionally, IL-6 production trended higher after stimulation with compounds that contained lipids ranging from five to eight carbons long, compared to shorter (below five) or longer (above eight) carbon chains, across all the substitution patterns. An analysis of the additional cytokines produced by hPBMCs revealed that compound 4d, tri-substituted and five carbons long, induced significantly greater levels of interleukin-1β (IL-1β), tumor necrosis factor- α (TNF-α), interleukin-23 (IL-23), and interferon- γ (IFN-γ) than the other compounds tested in this study. An in silico assessment of 4d highlighted the capability of this analogue to bind to the human Mincle carbohydrate recognition domain (CRD) efficiently. Together, these data highlight important structure-activity findings regarding Mincle-specific cytokine induction, generating a lead adjuvant candidate for future formulations and immunological evaluations.

Microwave-Assisted Synthesis and Characterization of Novel 1,3,4-Oxadiazole Derivatives and Evaluation of In Vitro Antimycobacterial Activity.

Objective The study's goal was to come up with and make a new group of 1,3,4-oxadiazole derivatives (3a-3e) and test how well they could kill Mycobacterium tuberculosis (Mtb) H37Rv strain. Additionally, molecular docking and pharmacokinetic properties were analyzed using computational software to identify potential inhibitors, followed by in vitro antimycobacterial assays. Methods A group of 1,3,4-oxadiazoles was prepared by reacting acyl hydrazides with alanine, an N-protected α-amino acid, and a small amount of POCl3. This was carried out under microwave treatment. The structural characterization of the newly synthesized compounds was performed using infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry. The in vitro antimycobacterial activity of the 1,3,4-oxadiazole derivatives (3a-3e) was assessed using the microplate Alamar Blue assay against the Mtb H37Rv strain. The synthesized compounds were subjected to molecular docking investigations in order to gain insights into their interaction mechanisms with the mycobacterial enzyme InhA (enoyl-acyl carrier protein reductase). Computational analysis of pharmacokinetic properties was performed to predict the oral bioavailability and drug-likeness of the compounds. Results All synthesized compounds inhibited the growth of Mtbat concentrations of 50 and 100 μg/mL. At a concentration of 50 μg/mL, compounds 3c and 3d exhibited the most prominent antimycobacterial action. Molecular docking results revealed that compound 3d exhibited the highest binding energy interaction with the InhA enzyme (-9.1 kcal/mol). Pharmacokinetic predictions indicated that all compounds possess favorable drug-like properties suitable for oral administration. Conclusion This study successfully synthesized a novel series of oxadiazole derivatives (3a-3e) using a microwave-assisted method with high yields. The synthesized compounds demonstrated significant antimycobacterial activity, particularly compounds 3c and 3d. Molecular docking and pharmacokinetic analyses further confirmed the potential of these compounds as promising leads for the development of anti-tubercular agents.

β-enaminoester derivatives exhibit promising in vitro and in silico antiviral potential against Mayaro virus.

Mayaro virus (MAYV) is the causative agent of Mayaro fever, which is characterized mainly by acute fever and long-term severe arthralgia, common manifestations of other arbovirus infections, making the correct diagnosis a challenge. Besides, MAYV infections have been reported in South America, especially in Brazil. However, the lack of vaccines or specific antiviral drugs to control these infections makes the search for new antivirals an urgent need. Herein, we evaluated the antiviral potential of synthetic β-enaminoesters derivatives against MAYV replication and their pharmacokinetic and toxicological (ADMET) properties using in vitro and in silico strategies. For this purpose, Vero cells were infected with MAYV at an MOI of 0.1, treated with compounds (50 µM) for 24h, and virus titers were quantified by plaque reduction assays. Compounds 2b (83.33%) and 2d (77.53%) exhibited the highest activity with inhibition rates of 83.33% and 77.53%, respectively. The most active compounds 2b (EC50 = 18.92 µM; SI > 52.85), and 2d (EC50 = 14.52 µM; SI > 68.87) exhibited higher potency and selectivity than the control drug suramin (EC50 = 38.97 µM; SI > 25.66). Then, we investigated the mechanism of action of the most active compounds. None of the compounds showed virucidal activity, neither inhibited virus adsorption, but compound 2b inhibited virus entry (62.64%). Also, compounds 2b and 2d inhibited some processes involved with the release of new virus particles. Finally, in silico results indicated good ADMET parameters of the most active compounds and reinforced their promising profile as drug candidates against MAYV.

Synthesis, Characterization, and In vitro and In Silico Studies of New Triazole Derivatives as Aromatase Inhibitors

Introduction: Breast cancer is the most common type of cancer among women. Steroidal or non-steroidal aromatase inhibitors (NSAIs) are used clinically, and in most cancer diseases, resistance is the most important problem. Method: The nitrogenous heterocyclic ring is noteworthy in the structure of non-steroidal aromatase inhibitors. This is the pharmacophore structure for aromatase inhibition. Because the enzyme interacts with the Fe2+ cation of the HEM structure in its active site, the most used agents in the clinic, such as anastrozole and letrozole, contain triazoles in their structures. Within the scope of this study, hybrid compounds containing both imidazole and triazole were synthesized. Result: The synthesis was carried out by a 4-step reaction. The anticancer effects of the compounds were evaluated by MTT assay performed on A549 and MCF-7 cancer cells. Compound 4d showed anticancer activity against the MCF-7 cell line with IC50=6.7342 uM value. This compound exhibited anticancer activity against the A549 cell line with an IC50 = 17.1761 μM. In the MTT test performed on a healthy cell line to determine the cytotoxic effects of the compounds, the compound showed activity with a value of 4d IC50=13.2088 uM. This indicates that the compound is not cytotoxic. Additionally, BrdU analysis was performed to evaluate whether the compound inhibits DNA synthesis. These selective effects of the compounds on breast cancer strengthened their aromatase enzyme inhibitor potential. For this reason, experiments conducted with both in vitro and in silico methods revealed a compound with high aromatase inhibitor potential. Conclusion: The interactions observed as a result of molecular docking and dynamics studies are in harmony with activity studies. In particular, interactions with HEM600 demonstrate the activity potential of the compound.

Design, Synthesis, Investigation, and Biological Activity Assessments of (4-Substituted-Phenyl)-N-(3-morpholinopropyl)-3-phenylthiazol-2(3H)-imine Derivatives as Antifungal Agents.

In this study, a series of novel thiazol-2(3H)-imine (2a-2j) were designed, synthesized, and characterized by means of 1H NMR, 13C NMR, and HRMS spectral analyses. In vitro antifungal activity was performed using a modified EUCAST protocol. Two of the synthesized compounds (2d and 2e) showed activity against Candida albicans and Candida parapsilosis. Compound 2e showed activity against C. parapsilosis (MIC50 = 1.23 μg/mL) for 48 h. This value is very similar to ketoconazole. The dynamic analysis of the potential compounds 2d and 2e revealed notable stability while interacting with the 14α-demethylase enzyme substrate. The absorption, distribution, metabolism, and excretion (ADME) studies of the candidate compound showed acceptable ADME parameter data and verified their drug-likeness characteristics. According to the results of this study, compound 4-(4-fluorophenyl)-N-(3-morpholinopropyl)-3-phenylthiazol-2(3H)-imine (2e) and its derivatives as 14α-demethylase inhibitors can be used as a new antifungal for further structural improvements and additional research.

Rational Design and Synthesis of Novel Benzimidazole Derivatives as Potential β-Glucosidase Inhibitors

Background: β-Glucosidase has a variety of biological functions. A structural model for a potential β-glucosidase inhibitor has been proposed in the previous studies. Objective: A series f new diaryl derivatives linked through benzimidazole have been randomly and rationally designed, synthesized, and evaluated for their inhibitory activities against β-glucosidase (almond). The proposed structural model provides a new strategy for the design of potent β-glucosidase inhibitors. Methods: According to the model, a series of benzimidazole derivatives were designed and synthesized, and their inhibitory activity, Ki value, inhibitory type, and binding mode analysis (PDB ID: 2J7C) on β-glucosidase (almond) were evaluated. Results: Two compounds 7b and 7d were the best inhibitors with IC50 values of 7.86 M and 3.52 μM, respectively. Their Ki values were calculated to be 9.91 μM and 5.81 μM, respectively. Conclusion: The SAR analysis suggested that such benzimidazole derivatives might bind to the active site of β-glucosidase mainly through hydrogen bonds on o-trihydroxyphenol; the additional phenyl ring on the other side towards the solvent-exposed region played a very important role in improving their inhibitory activity against β-glucosidase

Design, Synthesis and In-Vitro Antimicrobial and Cytotoxic Activity Screening of 5-Carboxamide Substituted 3, 4-Dihydropyrimidine-2 (1H) Ones

This paper describes the synthesis and in vitro biological evaluation of new compounds designated as 5(a-h) and 8(a-f). These compounds were synthesized by the reaction of thiazole derivative (3) or thiadiazole derivative (7) with urea and various aromatic aldehydes 4(a-h) in ethanol. The structures of the synthesized compounds were checked by IR,1H,13C NMR, and Mass spectroscopy. The antibacterial and antifungal activities of the compounds were evaluated against Escherichia coli (Gram-negative), Staphylococcus aureus (Gram-positive), and Candida albicans (fungus) using agar well diffusion, minimum inhibitory concentration (MIC), and minimum bactericidal/fungicidal concentration methods. The cytotoxic activities of these compounds against HT-29 and A-549 cancer cell lines were assessed in vitro by the MTT method. Our studies showed compounds 8c and 8f to have the most expressed antibacterial activity against S. aureus, while compounds 8c and 8d were the most potent against E. coli. Compounds 5h and 8e showed the highest antifungal activity against C. albicans, and compound 5f showed the most potent activity against the tested cancer cell lines.

7D, a small molecule inhibits dengue infection by increasing interferons and neutralizing-antibodies via CXCL4:CXCR3:p38:IRF3 and Sirt1:STAT3 axes respectively

There are a limited number of effective vaccines against dengue virus (DENV) and significant efforts are being made to develop potent anti-virals. Previously, we described that platelet-chemokine CXCL4 negatively regulates interferon (IFN)-α/β synthesis and promotes DENV2 replication. An antagonist to CXCR3 (CXCL4 receptor) reversed it and inhibited viral replication. In a concurrent search, we identified CXCR3-antagonist from our compound library, namely 7D, which inhibited all serotypes of DENV in vitro. With a half-life of ~2.85 h in plasma and no significant toxicity, 7D supplementation (8 mg/kg-body-weight) to DENV2-infected IFNα/β/γR−/−AG129 or wild-type C57BL6 mice increased synthesis of IFN-α/β and IFN-λ, and rescued disease symptoms like thrombocytopenia, leukopenia and vascular-leakage, with improved survival. 7D, having the property to inhibit Sirt-1 deacetylase, promoted acetylation and phosphorylation of STAT3, which in-turn increased plasmablast proliferation, germinal-center maturation and synthesis of neutralizing-antibodies against DENV2 in mice. A STAT3-inhibitor successfully inhibited these effects of 7D. Together, these observations identify compound 7D as a stimulator of IFN-α/β/λ synthesis via CXCL4:CXCR3:p38:IRF3 signaling, and a booster for neutralizing-antibody generation by promoting STAT3-acetylation in plasmablasts, capable of protecting dengue infection.

Pyridine Derivatives as Insecticides: Part 6. Design, Synthesis, Molecular Docking, and Insecticidal Activity of 3-(Substituted)methylthio-5,6,7,8-tetrahydroisoquinoline-4-carbonitriles Toward Aphis gossypii (Glover, 1887).

Three new series of 3-(substituted)methylthio-4-cyano-5,6,7,8-tetrahydroisoquinolines were designed and synthesized starting from readily available materials, 7-acetyl-4-cyano-1,6-dimethyl-6-hydroxy-8-(4-pyridyl, 3-pyridyl, phenyl, 4-methoxyphenyl, or 4-chlorophenyl)-5,6,7,8-tetrahydrosoquinoline-3(2H)-thiones 2a-e in high yields and very pure states. Thus, compounds 2a-e were reacted with some chloro reagents, namely, N-aryl-2-chloroacetamides 3a-f and N-(naphthalen-2-yl)-2-chloroacetamide (3g) under mild basic conditions to give the first two series of the target compounds, 3-(N-aryl)carbamoylmethylthio-5,6,7,8-tetrahydroisoquinoline-4-carbonitriles 4a-l and 5a-e, respectively. Reaction of compounds 2d,e with ethyl chloroacetate under the same conditions gave the other series, 3-ethoxycarbonyl-methylthio-5,6,7,8-tetrahydroisoquinoline-4-carbonitriles 6d,e. Structural formulas of all of the new compounds were elucidated and confirmed by elemental and spectral analyses. The insecticidal activity of all synthesized 5,6,7,8-tetrahydrosoquinolines toward the nymphs and adults of Aphis gossypii were screened. The results revealed the promising insecticidal activity of some tested compounds. Moreover, the structure-activity relationships as well as molecular docking of some representative compounds were evaluated.

Novel Pesticide Candidates Inspired by Natural Neolignan: Preparation and Insecticidal Investigation of Honokiol Analogs Containing 2-Aminobenzoxazole-Fused Core Scaffold.

As a continuation of our efforts to develop new agrochemicals with typical architecture and efficient bioactivity from plant natural products, natural neolignan honokiol was used as a lead compound to prepare novel analogs bearing the core 2-aminobenzoxazole scaffold. Their insecticidal potency against two representative agricultural pests, Plutella xylostella Linnaeus and Mythimna separata (Walker), were evaluated in vivo. The pesticide bioassay results revealed that compounds 7″a, 9, 10d, and 10j exhibited prominent larvicidal activity against the larvae of P. xylostella (LC50 = 7.95, 11.85, 15.51, and 12.06 μg/mL, respectively), superior to the precursor honokiol (LC50 = 43.35 μg/mL) and two botanical insecticides, toosendanin (LC50 = 26.20 μg/mL) and rotenone (LC50 = 23.65 μg/mL). Compounds 7d, 10d, and 10j displayed a more pronounced nonchoice antifeedant effect (AFC50 = 9.48, 9.14, and 12.41 μg/mL, respectively) than honokiol (AFC50 = 54.81 μg/mL) on P. xylostella. Moreover, compounds 7b, 7″a, 9, 10d, 10f, and 10j showed better growth inhibitory activity against M. separata (LC50 = 0.36, 0.34, 0.28, 0.16, 0.26, and 0.11 mg/mL, respectively) than honokiol, toosendanin, and rotenone (LC50 = 1.48, 0.53, and 0.46 mg/mL, respectively). A potted plant assay under greenhouse conditions illustrated that compounds 10d and 10j continued to provide good control efficacy against P. xylostella and an apparent protective effect on plants. Further cytotoxicity assay revealed that the aforementioned potent compounds showed relatively moderate toxicity and a good safety profile for non-target mammalian cells. Overall, the current work provides valuable insight into the agrochemical innovation of honokiol-derived analogs for use as natural-inspired pesticides in agricultural pest management.

6-Substituted benzo[d]thiazole linked 2-(2-(bis (1H-benzo[d]imidazol-2-yl) methylene) hydrazineyl compounds: Synthesis, computational studies, and in-vitro anticancer assessment

In this study, four novel 6-substituted benzothiazole-linked bis-benzimidazoles (3a–d) were synthesized and characterized using 1H NMR, 13C NMR, FTIR, and HRMS techniques. The physicochemical properties of these compounds were examined, and experimental data validated the computed values. The absorption and emission properties were also investigated using carbonate, acetate, and phosphate buffers at various pH levels.In-silico studies revealed that methoxy derivative (3c) possesses the highest docking affinity for tyrosine kinase. Pharmacokinetic studies showed that, like the marketed drug erlotinib, none of the compounds act as substrates for p-glycoprotein, and all except compound 3d do not inhibit CYP-2C9. The gastrointestinal absorption profiles, including blood-brain barrier permeability, were also studied. Drug-likeness assessments based on Lipinski's rule of five and Ghose criteria suggested favourable properties, though some compounds showed deviations in molecular weight and logP values. In-vitro anticancer study via MTT assay includes its potency against MCF-7 and MDA-MB-231 breast cancer cell lines, including 3c as the most potent against MCF-7 cells, which coincides with the In-silico study.

Neurotoxicity, Neuroprotection, In Vitro MAOA/MAOB Inhibitory Activity Assessment, Molecular Docking, and Permeability Assay Studies of Newly Synthesized Hydrazones Containing a Pyrrole Ring.

Neurodegenerative diseases such as Parkinson's and Alzheimer's continue to be some of the most significant challenges in modern medicine. Recent research related to the molecular mechanisms of parkinsonism has opened up new approaches to antiparkinsonian therapy. In response to this, we present the evaluation of the potential neuroprotective and MAOA/MAOB inhibitory effects of newly synthesized hydrazones, containing a pyrrole moiety in the carboxyl fragment of the structure. The substances were studied on different brain subcellular fractions, including rat brain synaptosomes, mitochondria, and microsomes. The single application of 50 µM of each compound to the subcellular fractions showed that all substances exhibit a weak neurotoxic effect, with 7b, 7d, and 8d being the least neurotoxic representatives. The corresponding neuroprotective and antioxidant effects were also evaluated in different injury models on subcellular fractions, single out 7b, 7d, and 8d as the most prominent derivatives. A 1 µM concentration of each molecule from the series was also studied for potential hMAOA/hMAOB inhibitory effects. The results revealed a lack of hMAOA activity for all evaluated structures and the appearance of hMAOB effects, with compounds 7b, 7d, and 8d showing effects similar to those of selegiline. The best hMAOB selectivity index (>204) was determined for 7d and 8d, distinguishing these two representatives as the most promising molecules for further studies as potential selective MAOB inhibitors. The performed molecular docking simulations defined the appearance of selective MAOB inhibitory effects based on the interaction of the tested molecules with Tyr398, which is one of the components of the aromatic cage of MAOB and participated in π-π stabilization with the aromatic pyrrole ring. The preliminary PAMPA testing indicated that in relation to the blood-brain barrier (BBB) permeability, the tested pyrrole-based hydrazones may be considered as high permeable, except for 8a and 8e, which were established to be permeable in the medium range with -logP of 5.268 and 5.714, respectively, compared to the applied references.

Design, Synthesis, molecular dynamic analysis, and In-Vivo anti-diabetic evaluation of novel hydrazine carboximidamide derivatives

Diabetes is one of the most rapidly growing health problems globally, and researchers working hard to develop novel efficient therapies against it. In this regard, hydrazine carboximidamide has a great deal of attention owing to its diverse biological activities. Herein, a new series of N, N-disubstituted hydrazine carboximidamide derivatives was designed, synthesized, and assessed for their antidiabetic activity. Docking studies were performed to initially evaluate the binding of the designed compounds to the target enzyme. It was found that all of the pivotal ligand-enzyme interactions, including the interactions with Glu205/Glu206 aminoacids were observed in docking studies. The molecular dynamic analysis showed that the antidiabetic activity of the newly developed compounds may be implemented through the inhibition of dipeptidyl peptidase 4 (DPP-4), an important target that involves enhancing insulin release and suppressing glucagon discharge from the pancreas. The target molecules were synthesized practically and all the newly-developed chemical structures were confirmed via spectrophotometric methods, including IR, LC-MS, 1H NMR, and 13C NMR techniques. Finally, the in-vivo studies were carried out to confirm the results obtained from the docking and molecular dynamics studies. Compounds 6b and 6d demonstrated improved glucose tolerance through oral glucose tolerance tests in NMRI mice (at a dose of 10 mg/kg). Furthermore, prolonged administration of compounds 6b and 6d to diabetic Wistar rats for 14 days led to a noteworthy reduction in blood levels of glucose, akin to the effects observed with sitagliptin, a standard diabetes medication.

Impurity affected transport properties of quantum well heterostructures with electronic and high-κ dielectric quantum screening

The effect of electronic and high-κ dielectric quantum screening (ES and DS) on the impurity-limited electron transport properties of quantum well/high-κ dielectric barrier type heterostructures with two-dimensional electron gas (2DEG) is studied theoretically. Characteristic of these heterosystems the 2D compound forms of screened impurity potential are employed for the first time. In the framework of 2D Debye-Hückel potential form an electron momentum relaxation time (τ) expression depending on the impurity 2D screening radius is obtained analytically. A numerical analysis of τ is carried out for the realistic HfO/InSb/HfO2QW heterostructure taking account both the finite mismatch of the energy bands at the heterointerface and the energy band non-parabolicity of InSb. The contributions of screened potential compound 2D forms to τ are established depending on QW width. A significant suppression of the scattering rate τ−1 (by an order of magnitude) is received with accounting of ES + DS combined effect.

Synthesis, biological evaluation and molecular modeling studies of methyl indole-isoxazole carbohydrazide derivatives as multi-target anti-Alzheimer’s agents

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects the elderly population globally and there is an urgent demand for developing novel anti-AD agents. In this study, a new series of indole-isoxazole carbohydrazides were designed and synthesized. The structure of all compounds was elucidated using spectroscopic methods including FTIR, 1H NMR, and 13C NMR as well as mass spectrometry and elemental analysis. All derivatives were screened for their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activity. Out of all synthesized compounds, compound 5d exhibited the highest potency as AChE inhibitor with an IC50 value of 29.46 ± 0.31 µM. It showed significant selectivity towards AChE, with no notable inhibition against BuChE. A kinetic study on AChE for compound 5d indicated a competitive inhibition pattern. Also, 5d exhibited promising BACE1 inhibitory potential with an IC50 value of 2.85 ± 0.09 µM and in vitro metal chelating ability against Fe3+. The molecular dynamic studies of 5d against both AChE and BACE1 were executed to evaluate the behavior of this derivative in the binding site. The results showed that the new compounds deserve further chemical optimization to be considered potential anti-AD agents.

Design, synthesis, and evaluation of novel oxyacanthine derivatives for anti-SARS-CoV-2 activity

Here, we report the synthesis of a series of oxyacanthine derivatives and evaluation for their anti-SARS-CoV-2 activity in Vero E6 cells. In order to eliminate the potential metabolic activation caused by para-methylene phenol moiety in oxyacanthine, totally 29 derivatives were designed and synthesized, resulting in 23 compounds with antivirus IC50 below 5.00 μM and 9 compounds with antivirus IC50 below 1.00 μM. Among them, amides compound 4a and 4d exhibited potent anti-SARS-CoV-2 activity and the most favorable selectivity index (SI) in vitro with the SI values of 115 and 70, respectively. The pharmacokinetic properties of 4a and 4d were also assessed. Much more improved exposure in mice, longer half-life (T1/2), and increased oral bioavailability were observed for both compounds 4a and 4d compared with oxyacanthine.

One-Pot Total Synthesis of Natural Products Nitramarine, Nitraridine, and Analogues via a Cascade Oxidation/Pictet-Spengler Condensation/Annulation Process.

A cascade oxidation/Pictet-Spengler condensation/annulation process has been developed for the one-pot total synthesis of nitramarine, nitraridine, and their analogues. The procedure proceeded with easily available quinolines and tryptophan derivatives. A simple and metal-free approach, wide substrate scope, and functional group tolerance make it applicable for the synthesis of diverse bioactive nitramarine, nitraridine, and their derivatives. Furthermore, the bioactivity evaluation has identified two promising leading compounds 5d and 5e with potent antitumor proliferative activity against breast cancer cells.

Molecular hybridization, synthesis, in vitro α-glucosidase inhibition, in vivo antidiabetic activity and computational studies of isatin based compounds

In the pursuit of novel antidiabetic agents, a series of isatin-thiazole derivatives (7a-7j) were synthesized and characterized using a range of spectroscopic techniques. The enzyme inhibitory activities of the target analogues were assessed using both in vitro and in vivo assays. The tested compounds 7a-7j demonstrated In vitro inhibitory potential against α-glucosidase, as indicated by their IC50 values ranging from 28.47 to 46.61 µg/ml as compared to standard drug acarbose IC50 value of 27.22 ± 2.30 µg/ml. Additionally, compounds 7d and 7i were chosen for in vivo evaluation of their antidiabetic efficacy in streptozotocin-induced diabetic Wistar rats. These compounds exhibited significant antidiabetic activity both in vitro and in vivo, compound 7d produces therapeutic effects compared to standard pioglitazone by decreasing glycaemia and triglyceride levels in diabetic animals. Furthermore, a molecular docking study was conducted to elucidate the binding interactions of the compounds within the α-glucosidase enzyme binding pocket (PDB ID 3A47) and stability was confirmed by dynamics simulation trajectories. Thus, from the above findings, it may demonstrate that isatin-thiazole hybrids constitute promising candidates in the pursuit of developing newer oral antidiabetic agents.