Rational Design, Synthesis, In Vitro, and In Silico Studies of Dihydropyrimidinone Derivatives as β-Glucuronidase Inhibitors

In the current study, a series of dihydropyrimidinone derivatives were rationally designed as β-glucuronidase inhibitors. These designed compounds were successfully synthesized and characterized through various spectroscopic techniques such as IR, 1H-NMR, 13C-NMR, and EI-MS. A structure-activity relationship (SAR) of synthesized derivatives to inhibit β-glucuronidase was also established. In vitro biological evaluations revealed that 4i as the most potent compound in this series has an IC50 value of 31.52 ± 2.54 μM compared to the standard D-saccharic acid 1,4-lactone (IC50 = 41.32 ± 1.82 µM). Also, molecular docking and dynamics studies of the most potent compound are performed to evaluate interactions between the active compound and binding site.

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Exploring novel fluorine rich fuberidazole derivatives as hypoxic cancer inhibitors: design, synthesis, pharmacokinetics, molecular docking and DFT evaluations

10.1101/2022.01.06.475235 ◽

2022 ◽

Author(s):

Muhammad Babar Taj ◽

Omar Makarm Ali

Keyword(s):

Dna Damage ◽

Dipole Moment ◽

Molecular Docking ◽

Human Serum Albumin ◽

Dft Calculations ◽

Cancer Cells ◽

Design Synthesis ◽

Structure Activity ◽

In Silico Studies

Sixteen fuberidazole derivatives as potential new anticancer bioreductive prodrugs are prepared and characterized. The in vitro anticancer potential is examined to explore their cytotoxic properties employing apoptosis, DNA damage, and proliferation tests on chosen hypoxic cancer cells. Overall, eight substances (Compound 5a, 5c, 5d, 5e, 5g, 5h, 5i, and 5m) showed good cytotoxic properties. The potential of compounds is also examined through in silico studies (against human serum albumin), including chem-informatics to understand the structure-activity relationship (SAR), pharmacochemical strength, and the mode of interactions responsible for their action. The DFT calculations revealed that only 5b compound showed the lowest ΔET (2.29 eV) while 5i showed relatively highest βtot (69.89 x 10-31 esu), highest αave (3.18 x 10-23 esu), and dipole moment (6.49 Debye). This study presents a novel class of fuberidazole derivatives with selectivity toward hypoxic cancer cells.

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Design, Synthesis and Molecular Docking Analysis of Flavonoid Derivatives as Potential Telomerase Inhibitors

Molecules ◽

10.3390/molecules24173180 ◽

2019 ◽

Vol 24 (17) ◽

pp. 3180 ◽

Cited By ~ 3

Author(s):

Zhan-Fang Fan ◽

Sai-Tim Ho ◽

Rui Wen ◽

Ya Fu ◽

Lei Zhang ◽

...

Keyword(s):

Natural Products ◽

Molecular Docking ◽

Rational Design ◽

Binding Mode ◽

Design Synthesis ◽

Telomerase Inhibitors ◽

Ic50 Value ◽

Human Telomerase ◽

Dynamics Analyses

Based on the structural scaffolds of natural products, two series of flavonoid derivatives, for a total of twelve compounds, were designed and synthesized as potential human telomerase inhibitors. Using a modified TRAP-PCR assay, compound 5c exhibited the most potent inhibitory activity against human telomerase with an IC50 value of less than 50 μM. In vitro, the results demonstrated that compound 5c had potent anticancer activity against five classes of tumor cell lines. The molecular docking and molecular dynamics analyses binding to the human telomerase holoenzyme were performed to elucidate the binding mode of active compound 5c. This finding helps the rational design of more potent telomerase inhibitors based on the structural scaffolds of natural products.

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Design, synthesis, characterization, in vitro screening, molecular docking, 3D-QSAR, and ADME-Tox investigations of novel pyrazole derivatives as antimicrobial agents

New Journal of Chemistry ◽

10.1039/d1nj05621b ◽

2022 ◽

Author(s):

Mohammed CHALKHA ◽

Mohamed Akhazzane ◽

Fatima Zahrae Moussaid ◽

Ossama Daoui ◽

Asmae Nakkabi ◽

...

Keyword(s):

Molecular Docking ◽

Antimicrobial Agents ◽

3D Qsar ◽

Spectroscopic Techniques ◽

In Vitro Screening ◽

Pyrazole Derivatives ◽

Design Synthesis ◽

Practical Procedure

In this work, we report the synthesis of some new pyrazole derivatives via an efficient and practical procedure. The structures of the obtained compounds were established using different spectroscopic techniques...

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α-Glucosidase Inhibition and Molecular Docking Studies of Natural Brominated Metabolites from Marine Macro Brown Alga Dictyopteris hoytii

Marine Drugs ◽

10.3390/md17120666 ◽

2019 ◽

Vol 17 (12) ◽

pp. 666 ◽

Cited By ~ 8

Author(s):

Najeeb Ur Rehman ◽

Kashif Rafiq ◽

Ajmal Khan ◽

Sobia Ahsan Halim ◽

Liaqat Ali ◽

...

Keyword(s):

Molecular Docking ◽

Brown Alga ◽

Docking Studies ◽

Spectroscopic Techniques ◽

Molecular Docking Studies ◽

Ethyl Methyl ◽

2D Noesy ◽

Ic50 Value ◽

Ic50 Values

Bioassay guided isolation of the methanolic extract of marine macro brown alga Dictyopteris hoytii afforded one new metabolite (ethyl methyl 2-bromobenzene 1,4-dioate, 1), one new natural metabolite (diethyl-2-bromobenzene 1,4-dioate, 2) along with six known metabolites (3–8) reported for the first time from this source. The structure elucidation of all these compounds was achieved by extensive spectroscopic techniques including 1D (1H and 13C) and 2D (NOESY, COSY, HMBC and HSQC) NMR and mass spectrometry and comparison of the spectral data of known compounds with those reported in literature. The in vitro α-glucosidase inhibition studies confirmed compound 7 to be the most active against α-glucosidase enzyme with IC50 value of 30.5 ± 0.41 μM. Compounds 2 and 3 demonstrated good inhibition with IC50 values of 234.2 ± 4.18 and 289.4 ± 4.91 μM, respectively, while compounds 1, 5, and 6 showed moderate to low inhibition. Furthermore, the molecular docking studies of the active compounds were performed to examine their mode of inhibition in the binding site of the α-glucosidase enzyme.

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Design, Synthesis, Molecular Docking Study and Anti-Hepatocellular Carcinoma Evaluation of New Bis-Triazolothiadiazines

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557519666191015130037 ◽

2020 ◽

Vol 20 (9) ◽

pp. 788-800 ◽

Cited By ~ 2

Author(s):

Sobhi M. Gomha ◽

Zeinab A. Muhammad ◽

Elham Ezz El-Arab ◽

Amira M. Elmetwally ◽

Abdelaziz A. El-Sayed ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Molecular Docking ◽

Docking Study ◽

Docking Studies ◽

Binding Modes ◽

Molecular Docking Study ◽

Design Synthesis ◽

Reference Drug ◽

Ic50 Value

Objective: The reaction of bis(4-amino-4H-1,2,4-triazole-3-thiol) with hydrazonoyl halides and α-halo-ketones gave a new series of bis-1,2,4-triazolo[3,4-b]thiadiazine derivatives. Methods: The structure of the new products was established on the basis of their elemental and spectral data (mass, 1H NMR, 13C NMR and IR) and an alternate method. Results: Several of the synthesized products were subjected to in vitro anticancer screening against human hepatocellular carcinoma (HepG-2) and the results showed that compounds 16, 14 and 12 have promising activities (IC50 value of 24.8±9.1, 28.3±0.5, and 31±2.9μM, respectively) compared with Harmine reference drug (IC50 value of 22.4±1.11 μM). Conclusion: Moreover, molecular docking studies were performed to analyze the binding modes of the discovered hits into the active site of DYRK1A using iGEMDOCK.

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Design, Synthesis, In Vitro and In Silico Studies of New Thiazolylhydrazine-Piperazine Derivatives as Selective MAO-A Inhibitors

Molecules ◽

10.3390/molecules25184342 ◽

2020 ◽

Vol 25 (18) ◽

pp. 4342

Author(s):

Begüm Nurpelin Sağlık ◽

Osman Cebeci ◽

Ulviye Acar Çevik ◽

Derya Osmaniye ◽

Serkan Levent ◽

...

Keyword(s):

Enzyme Inhibition ◽

In Silico ◽

Drug Targets ◽

Binding Property ◽

Spectroscopic Techniques ◽

Design Synthesis ◽

Piperazine Derivatives ◽

In Silico Studies ◽

Mao A

Monoamine oxidase (MAO) isoenzymes are very important drug targets among neurological disorders. Herein, novel series of thiazolylhydrazine-piperazine derivatives were designed, synthesized and evaluated for their MAO-A and -B inhibitory activity. The structures of the synthesized compounds were assigned using different spectroscopic techniques such as 1H-NMR, 13C-NMR and HRMS. Moreover, the prediction of ADME (Absorption, Distribution, Metabolism, Elimination) parameters for all of the compounds were performed using in silico method. According to the enzyme inhibition results, the synthesized compounds showed the selectivity against MAO-A enzyme inhibition. Compounds 3c, 3d and 3e displayed significant MAO-A inhibition potencies. Among them, compound 3e was found to be the most effective derivative with an IC50 value of 0.057 ± 0.002 µM. Moreover, it was seen that this compound has a more potent inhibition profile than the reference inhibitors moclobemide (IC50 = 6.061 ± 0.262 µM) and clorgiline (IC50 = 0.062 ± 0.002 µM). In addition, the enzyme kinetics were performed for compound 3e and it was determined that this compound had a competitive and reversible inhibition type. Molecular modeling studies aided in the understanding of the interaction modes between this compound and MAO-A. It was found that compound 3e had significant and important binding property.

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Novel C-2 Symmetric Molecules as α-Glucosidase and α-Amylase Inhibitors: Design, Synthesis, Kinetic Evaluation, Molecular Docking and Pharmacokinetics

Molecules ◽

10.3390/molecules24081511 ◽

2019 ◽

Vol 24 (8) ◽

pp. 1511 ◽

Cited By ~ 2

Author(s):

Danish Shahzad ◽

Aamer Saeed ◽

Fayaz Ali Larik ◽

Pervaiz Ali Channar ◽

Qamar Abbas ◽

...

Keyword(s):

Molecular Docking ◽

Antioxidant Activities ◽

Competitive Inhibitor ◽

Docking Studies ◽

Design Synthesis ◽

Kinetic Evaluation ◽

Ic50 Value ◽

Amylase Inhibitors ◽

Burk Plot

A series of symmetrical salicylaldehyde-bishydrazine azo molecules, 5a–5h, have been synthesized, characterized by 1H-NMR and 13C-NMR, and evaluated for their in vitro α-glucosidase and α-amylase inhibitory activities. All the synthesized compounds efficiently inhibited both enzymes. Compound 5g was the most potent derivative in the series, and powerfully inhibited both α-glucosidase and α-amylase. The IC50 of 5g against α-glucosidase was 0.35917 ± 0.0189 µM (standard acarbose IC50 = 6.109 ± 0.329 µM), and the IC50 value of 5g against α-amylase was 0.4379 ± 0.0423 µM (standard acarbose IC50 = 33.178 ± 2.392 µM). The Lineweaver-Burk plot indicated that compound 5g is a competitive inhibitor of α-glucosidase. The binding interactions of the most active analogues were confirmed through molecular docking studies. Docking studies showed that 5g interacts with the residues Trp690, Asp548, Arg425, and Glu426, which form hydrogen bonds to 5g with distances of 2.05, 2.20, 2.10 and 2.18 Å, respectively. All compounds showed high mutagenic and tumorigenic behaviors, and only 5e showed irritant properties. In addition, all the derivatives showed good antioxidant activities. The pharmacokinetic evaluation also revealed promising results

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Design, Synthesis, and Activity Evaluation of Novel N-benzyl Deoxynojirimycin Derivatives for Use as α-Glucosidase Inhibitors

Molecules ◽

10.3390/molecules24183309 ◽

2019 ◽

Vol 24 (18) ◽

pp. 3309 ◽

Cited By ~ 1

Author(s):

Zeng ◽

Yin ◽

Chen ◽

Nie ◽

Lin ◽

...

Keyword(s):

Hydrogen Bonds ◽

Hydroxyl Group ◽

Inhibition Activity ◽

Promising Candidate ◽

Design Synthesis ◽

Structure Activity ◽

Glucosidase Inhibitors ◽

Ic50 Value ◽

Ic50 Values

To obtain α-glucosidase inhibitors with high activity, 19 NB-DNJDs (N-benzyl-deoxynojirimycin derivatives) were designed and synthesized. The results indicated that the 19 NB-DNJDs displayed different inhibitory activities towards α-glucosidase in vitro. Compound 18a (1-(4-hydroxy-3-methoxybenzyl)-2-(hydroxymethyl) piperidine-3,4,5-triol) showed the highest activity, with an IC50 value of 0.207 ± 0.11 mM, followed by 18b (1-(3-bromo-4-hydroxy-5-methoxybenzyl)-2-(hydroxymethyl) piperidine-3,4,5-triol, IC50: 0.276 ± 0.13 mM). Both IC50 values of 18a and 18b were significantly lower than that of acarbose (IC50: 0.353 ± 0.09 mM). According to the structure-activity analysis, substitution of the benzyl and bromine groups on the benzene ring decreased the inhibition activity, while methoxy and hydroxyl group substitution increased the activity, especially with the hydroxyl group substitution. Molecular docking results showed that three hydrogen bonds were formed between compound 18a and amino acids in the active site of α-glucosidase. Additionally, an arene‒arene interaction was also modelled between the phenyl ring of compound 18a and Arg 315. The three hydrogen bonds and the arene‒arene interaction resulted in a low binding energy (–5.8 kcal/mol) and gave 18a a higher inhibition activity. Consequently, compound 18a is a promising candidate as a new α-glucosidase inhibitor for the treatment of type Ⅱ diabetes.

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Design, Synthesis, Molecular Docking and Biological Evaluation of 1-(benzo[d]thiazol-2-ylamino)(phenyl)methyl)naphthalen-2-ol Derivatives as Antiproliferative Agents

Letters in Organic Chemistry ◽

10.2174/1570178616666190408101233 ◽

2019 ◽

Vol 16 (10) ◽

pp. 837-845

Author(s):

Sandhya Jonnala ◽

Bhaskar Nameta ◽

Murthy Chavali ◽

Rajashaker Bantu ◽

Pallavi Choudante ◽

...

Keyword(s):

Molecular Docking ◽

Inhibitory Activity ◽

Chinese Hamster Ovary Cells ◽

Chinese Hamster ◽

Mouse Skin ◽

Coupling Reaction ◽

Binding Mode ◽

Biological Evaluation ◽

Design Synthesis

A class of 1-((benzo[d]thiazol-2-ylamino)(phenyl)methyl)naphthalen-2-ol derivatives (4a-t) has been synthesized in good yields through a three component coupling reaction. The newly synthesized compounds were evaluated for their in vitro antiproliferative activity against five cell lines such as DU145 (human prostate cancer), MDA-MB-B231 (human breast cancer), SKOV3 (human ovarian cancer), B16-F10 (mouse skin melanoma) and CHO-K1 (Chinese hamster ovary cells), a noncancerous cell line. In vitro inhibitory activity indicates that compounds 4a, 4b, 4c, 4d, 4g, 4j, and 4o exhibited potent anti-proliferative behavior. Among them, compounds 4g, 4j and 4o found to be the most active members exhibiting remarkable growth inhibitory activity. Molecular docking facilitates to investigate the probable binding mode and key active site interactions in tubulins α and β proteins. The docking results are complementary to experimental results.

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