Biology-oriented drug synthesis of nitrofurazone derivatives: Their α-glucosidase inhibitory activity and molecular docking studies

In the present study, twenty (20) structural variants of nitrofurazone were synthesized based on BIODS (Biology-oriented drug synthesis) approach. The structure elucidation of the synthetic molecules (1–20) was carried out using different spectroscopic techniques, and their α-glucosidase inhibitory activity was also determined. The synthetic molecules 1–20 exhibited good α-glucosidase inhibition than the parent, nitrofurazone. Four compounds 2, 4, 6, and 7 showed potential inhibition against α-glucosidase with IC₅₀ values ranging between 0.63 ± 0.25–1.29 ± 0.46 µM as compared to the standard acarbose (IC₅₀ = 2.05 ± 0.41 µM). Nevertheless, compounds 15 (IC₅₀ = 0.74 ± 0.12 µM), and 19 (IC₅₀ = 0.54 ± 0.3 µM) also displayed good α-glucosidase inhibition and compound 19 was the most active compound of the series. Kinetic study of the active compounds 7 and 19 was also carried out to confirm the mode of inhibition. The binding interactions of the most active compounds within the active site of enzyme were determined by molecular docking. Moreover, molecular dynamic simulation of compound 19 was also performed in order to determine the stability of the overall complex (α-glucosidase + c19) in an explicit watery environment. The synthetic molecules were predicted as non-cytotoxic, however, seven compounds 1, 3, 4, 9, 10, 11, and 12 were predicted as carcinogenic.     

Microscopic binding of butyrylcholinesterase with quinazolinimine derivatives and the structure–activity correlation

Butyrylcholinesterase (BChE) is not only an important protein for development of anti-cocaine medication but also an established drug target to develop new treatment for Alzheimer’s disease (AD). The molecular basis of interaction of a new series of quinazolinimine derivatives as BChE inhibitors has been studied by molecular docking and molecular dynamics (MD) simulations. The molecular docking and MD simulations revealed that all of these inhibitors bind with BChE in similar binding mode. Based on the similar binding mode, we have carried out three-dimensional quantitative structure–activity relationship (3D-QSAR) studies on these inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), to understand the structure–activity correlation of this series of inhibitors and to develop predictive models that could be used in the design of new inhibitors of BChE. The study has resulted in satisfactory 3D-QSAR models. We have also developed ligand-based 3D-QSAR models. The contour maps obtained from the 3D-QSAR models in combination with the simulated binding structures help to better interpret the structure–activity relationship and is consistent with available experimental activity data. The satisfactory 3D-QSAR models strongly suggest that the determined BChE-inhibitor binding modes are reasonable. The identified binding modes and developed 3D-QSAR models for these BChE inhibitors are expected to be valuable for rational design of new BChE inhibitors that may be valuable in the treatment of Alzheimer’s disease.     

Design,synthesis and cholinesterase inhibitory activity of α-mangostin derivatives

Abstract

α-mangostin, a polyphenol xanthone derivative, was mainly isolated from pericarps of the mangosteen fruit (Garcinia mangostana L.). In present investigation, a series of derivatives were designed, synthesised and evaluated in vitro for their inhibitory activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among the synthesised xanthones, compounds 1, 9, 13 and 16 showed AChE selective inhibitory activity, 15 was a BuChE selective inhibitor while 2, 3, 5, 6, 7, 12 and 14 were dual inhibitors. The most potent inhibitor of AChE was 16 while 5 was the most potent inhibitor of BuChE with IC₅₀ values of 5.26?μM and 7.55?μM respectively.     

Synthesis and α-glucosidase inhibitory activity of chrysin,diosmetin, apigenin,and luteolin derivatives

Several derivatives have been synthesized from chrysin, diosmetin, apigenin, and luteolin, which were isolated from diverse natural plants. The α-glucosidase inhibitory activity of these compounds was evaluated. The glucosidase inhibitory activity of all derivatives （IC50 〈 24.396 μmol]L） was higher compared with that of the reference drug, acarbose （IC50=563.601 ±40.492μmol/L）, and 1- deoxynojirimycin （IC50 = 226.912± 12.573 μmol/L）. O3＇,O7-Hexyl diosmetin （IC50 = 2.406 ± 0.101μmol/L） was the most potent inhibitor identified. These compounds showed a higher inhibitory ability compared with their precursors except the luteolin derivatives. In general, the inhibitory activity of the synthetic derivatives was enhanced with long alkyl chains at positions 3＇, 4＇ and 7 of the flavonoid.     

One-pot synthesis of benzoquinoline and coumarin derivatives using Meldrum’s acid in three-component reactions

A series of 1-aryl-1,2-dihydrobenzo[f]quinolin-3(4H)-one derivatives and 4-aryl-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydrocoumarin derivatives have been synthesized by one-pot multicomponent reaction of Meldrum’s acid with benzaldehyde, naphthalene-2-amine, or cyclohexanedione in PEG-400. The method has the advantages of mild reaction conditions, good yields, and easy processing, and is environmentally benign.     

C-methyl flavonoid from the leaves of Cleistocalyx conspersipunctatus: α-glucosidase inhibitory,molecular docking simulation and biosynthetic pathway

We extracted one new C-methyl flavonoid, farrerol 7-O-β-d-(6-O-galloyl)glucopyranoside (1), along with 11 known flavonoids, from the Cleistocalyx (C.) conspersipunctatus leaves. Elucidation of these flavonoid structures was accomplished through spectroscopic investigation and electronic circular dichroism (ECD) computation. Compared to corosolic acid (IC₅₀: 15.5 ± 0.9 μM), an established inhibitor, the compound 1 (IC₅₀: 6.9 ± 1.2 μM) was found more active in suppressing α-glucosidase. These findings imply the potential of compound 1 as a valid α-glucosidase inhibitor, which also offer evidence for future animal experiments and clinical trials. Besides, molecular docking was employed to explore the probable mechanism for α-glucosidase–compound 1 interaction. The biosynthetic pathway of these flavonoids in C. conspersipunctatus were proposed.     

One-pot synthesis of methyl piperazinyl–quinolinyl nicotinonitrile derivatives under microwave conditions and molecular docking studies with DNA

Derivatives of methyl piperazinyl–quinolinyl nicotinonitrile were synthesised by one-pot method under microwave conditions. This was achieved using the Knoevenagel condensation reaction. The novel derivatives described above were purified by column chromatography and characterised by FT-IR, ¹H, ¹³C, 2D-NMR and HRMS spectroscopic techniques. Furthermore, molecular docking was used to determine the binding sites of DNA with selected compounds. The synthetic method developed in this study showed several advantages including simplicity, high yield of products, coupled with safety and a short reaction time of 15 min.     

Synthesis, bioactivity and DFT structure–activity relationship study of novel 1,2,3-thiadiazole derivatives

A series of novel 1,2,3-thiadiazole derivatives were designed and synthesized. Their structures were characterized by ¹H NMR, MS and HRMS. The bioactivity tests indicated that compound 9b exhibits a favorable KARI inhibition rate, and some of these novel compounds also showed moderate herbicidal activity against Brassica campestris.     

Catalyst-free synthesis of 1,2,4,5-tetrasubstituted imidazoles from arylamins,benzonitriles, arylglyoxals,and Meldrum’s acid

An efficient and catalyst-free for the synthesis of 1,2,4,5-tetrasubstituted imidazoles has been developed using a one-pot, two-step reaction of arylamins, benzonitriles, arylglyoxals, and Meldrum’s acid. All the products were obtained in good to excellent yields and their structures were established from their spectroscopic data.     

Novel bridged and caged C4-podophyllotoxin derivatives as microtubule disruptors: synthesis,cytotoxic evaluation and structure–activity relationship

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An alternative,practical, and ecological protocol for synthesis of arylidene analogues of Meldrum’s acid as useful intermediates

Research on Chemical Intermediates - This paper presents an ecological protocol for Knoevenagel condensation using a catalytic amount of 4,4′-trimethylenedipiperidine as a versatile,...     

A meglumine catalyst–based synthesis,molecular docking,and antioxidant studies of dihydropyrano[3, 2-b]chromenedione derivatives

A simple method was employed for the synthesis of dihydropyrano[3, 2-b]chromenedione derivatives ( 4a-o) in high yields by condensation of 5, 5-dimethylcyclohexane-1, 3-dione( 1 ), different aromatic aldehydes ( 2a-o ), and 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one( 3 ), using meglumine as a stable and reusable catalyst. Meglumine, an amino sugar, was employed as an environmentally benign catalyst, due to its splendid properties such as being inexpensive, recyclable, and biodegradable. The accomplished protocol employs low catalyst loading and easy work-up for the synthesis of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one derivatives. A great asset is that without any significant loss, the catalyst could be recovered and reused for extended synthetic steps. This offer huge advantage to overcome recyclability issues. Our synthesized compounds were analyzed by IR, ¹H, ¹³C NMR, mass spectra and evaluated for their antioxidant properties by 1, 1-diphenyl-2-picryl hydrazyl radical (DPPH), hydrogen peroxide(H₂O₂), and nitric oxide (NO) scavenging methods. The correlation in exhibition of antioxidant activity was effective at all doses. The binding interactions and molecular docking studies for entitled compounds were studied against 3MNG protein; 4k exhibited marked binding affinity with excellent docking score of −7.6 Kcal/mol and emerged as a lead compound.     

Design,synthesis, biological evaluation,and docking study of new acridine-9-carboxamide linked to 1,2,3-triazole derivatives as antidiabetic agents targeting α-glucosidase

A new series of acridine-9-carboxamide-1,2,3-triazole derivatives 7a-m were designed, synthesized, and evaluated as novel α-glucosidase inhibitors. Acridine-9-carboxamide-1,2,3-triazole scaffold has been designed by combination of effective moieties from potent α-glucosidase inhibitors. Most of the synthesized compounds were more potent than standard inhibitor acarbose. Among the title compounds, the most potent compounds were compounds 7j , 7k , and 7a with IC₅₀ values of 120.2 ± 1.0, 151.1 ± 1.4, and 157.6 ± 1.6 μM, respectively (IC₅₀ value of acarbose = 750.0 ± 10.0 μM). Docking study of the most potent compounds demonstrated that these compounds formed stable complexes with α-glucosidase active site. Anti-α-amylase assay of compounds 7j , 7k , and 7a was performed and no activity was observed. in vitro cytotoxicity assay of the latter compounds revealed that these compounds were not cytotoxic toward human normal (HDF) and cancer (MCF-7) cell lines. ADME and toxicity prediction of compounds 7j , 7k , and 7a were also performed.     

Anticancer drug IUdR and other 5-halogen derivatives of 2′-deoxyuridine: conformers,hydrates, and structure–activity relationships

The effect of hydration on the molecular structure and energetics of the most stable conformers of the nucleoside analog 5-iodo-2′-deoxyuridine (IUdR) was carried out. To simulate the first hydration shell, two models were considered: the PCM model and the Discrete model (DM), including a variable number (1–20) of explicit water molecules surrounding the nucleoside. More than two hundred hydrated structures with water were analyzed by B3LYP and MP2 quantum chemical methods. Conformer B1 (syn-gg-gg) is the most stable by B3LYP and MP2, in the isolated state and in the first hydration shell. The CP-corrected formation and interaction energies for IUdR and water molecules were determined. The effect of the hydration on the total atomic charges and intermolecular distances were also discussed. 5-fluoro- (FUdR), 5-chloro- (ClUdR), and 5-bromo- (BrUdR) 2′-deoxyuridine derivatives were full optimized, and the effect of the halogen atom on the molecular structure was analyzed. In these, three derivatives was simulated the first hydration shell with 20 explicit water molecules within the DM. Several relationships/tendencies structure–activity were established that can help for the design of new drugs.     

DNA binding,docking studies,artificial nuclease activity and in vitro cytotoxicity of newly synthesized steroidal 1H–pyrimidines

A new series of steroidal pyrimidines (7–9) has been synthesized by reacting steroidal thiosemicarbazones (4–6) with ethyl cyanoacetate. The compounds were characterized by IR, ¹H NMR, ¹³C NMR, MS and analytical data. The interaction studies of compounds 7–9 with DNA were carried out by UV–vis and luminescence spectroscopy. Compounds (7–9) bind to DNA preferentially through electrostatic and hydrophobic interactions, with K_b values found to be 6.56 × 10³ M⁻¹, 1.54 × 10⁴ M⁻¹ and 9.34 × 10³ M⁻¹, respectively, indicating the higher binding affinity of compound 8 towards DNA. Gel electrophoresis pattern demonstrated that compound 8 shows strong interaction with DNA and that, during its cleavage activity with pBR322 DNA, it seems to follow the mechanistic pathway involving the generation of singlet oxygen and a superoxide anion, which are responsible for initiating DNA strand scission. The docking study suggested that the intercalation of compounds in between the nucleotide base pairs is due to the presence of a pyrimidine moiety in the steroid molecule. MTT assay was carried out to check the toxicity of new compounds 7–9 against the different human cancer as well as non-cancer cell lines A545, MCF-7, HeLa, HL-60, SW480, HepG2, HT-29, A549, 184B5, MCF10A, NL-20, HPC, and HPLF. Apoptotic degradation of DNA in the presence of steroidal pyrimidines 7–9 was analysed by agarose gel electrophoresis and visualized by ethidium bromide staining (comet assay).     

In vitro evaluation of novel mefenamic acid derivatives as potential α-glucosidase and urease inhibitors: Design,synthesis, in silico and cytotoxic studies

This study aim to synthesize new 1,3,4-oxadiazole derivatives incorporating mefenamic acid as promising α-glucosidase and urease inhibitors, potentially leading to the treatment of postprandial hyperglycemia as well as H. pylori related disorders. In this regards, we have designed a series of Mefenamic acid derivatives. The synthetic compounds were structurally elucidated through ¹H NMR, ¹³C NMR and HR-EIMS analysis. The biological evaluation of these derivatives against α-glucosidase and urease enzyme depicted some novel derivatives with potent inhibition against the said enzymes. All the derivatives exhibited potent inhibition against α-glucosidase enzymes with IC₅₀ ranging from 25.81 ± 1.63–113.61 ± 1.31 µM against standard drug acarbose (IC₅₀ = 375.82 ± 1.76 µM) while with respect to urease these derivatives possessed inhibitory potential varied between IC₅₀ = 8.04 ± 1.01–58.18 ± 1.03 µM against the standard thiourea (IC₅₀ = 21.0 ± 1.76 µM). The cell viability results revealed that all of the derivatives were found least cytotoxic. Furthermore, molecular docking studies of the most potent derivatives identify number of key features involved in binding interactions between potential inhibitors and the enzyme's active site.     

Identification of novel oxadiazole-based benzothiazole derivatives as potent inhibitors of α-glucosidase and urease: Synthesis,in vitro bio-evaluation and their in silico molecular docking study

This research work represents a synthetic approach for the development of hybrids derivatives of oxadiazole-based benzothiazole (1–17) and diversity in derivatives was achieved using variety of aryl ring of S-substituted benzothiazole to see the effect on the biological activities. All the synthesized derivatives were evaluated for their in vitro α-glucosidase and urease inhibitory potential. The α-glucosidase and urease inhibition profile of the new derivatives represents moderate to good inhibitory potential with IC₅₀ values ranging from 4.60 ± 1.20 µM to 48.40 ± 7.70 µM (α-glucosidase) and 8.90 ± 2.80 to 57.30 ± 7.70 µM (urease) respectively. The results were compared to standard acarbose (38.60 ± 4.50 µM) and thiourea (58.70 ± 6.80 µM) drugs respectively. Among the synthesized series, the analogs 1 having IC₅₀ values of and 4.60 ± 1.20 (α-glucosidase), 8.90 ± 2.80 (urease) and 2 with IC₅₀ values of 5.60 ± 1.60 (α-glucosidase) and 10.90 ± 2.10(urease) were found to be significantly active against targeted α-glucosidase and urease enzymes. The structure of all the newly synthetics scaffolds were confirmed by using different types of spectroscopic techniques such as HREI-MS, ¹H- and ¹³C- NMR spectroscopy. The molecular docking studies of the synthesized derivatives showed good correlations with the experimental findings. The binding modes of active compounds and their interactions with active site residues revealed them as possible anti-diabetics and anti-urease leads. The degree of activity and docking studies displayed by the novel innovative structural hybrids of oxadiazole-based benzothiazole moieties make these compounds new active leads and promising candidates for the development of anti-diabetics and anti-urease agents.     

One-pot synthesis of Claisen–Schmidt reaction through (E)-chalcone derivatives: Spectral studies in human serum albumin protein binding and molecular docking investigation

An efficient and environmentally benign one-pot multicomponent synthesis of E-chalcones was developed using a mild and reusable new boron nitride-sulphonic acid catalyst. The catalyst was prepared by activating the boron nitride surface with nitric acid, followed by a simple reaction with 3-mercaptopropyl trimethoxysilane. The catalyst was characterized and morphological properties were studied by Fourier transform infrared, X-ray diffraction, transmission electron spectroscopy, scanning electron microscopy, Brunauer–Emmett–Teller theory, and Raman spectroscopy techniques. The solid acid catalyst was recycled five times in a Claisen–Schmidt reaction to synthesize new chalcone derivatives, and X-ray crystallography was used to elucidate the structure of (E)-1-(anthracen-9-yl)-3-(2-(4-methylpiperazin-1-yl)quinolin-3-yl)prop-2-en-1-one. A fluorescence quench titration method was used to assess its binding ability with human serum albumin (HSA), while molecular docking was also performed to get a more detailed insight into their interaction at the binding site of HSA.