Febuxostat-based Amides and Some Derived Heterocycles Targeting Xanthine Oxidase and COX Inhibition. Synthesis, in vitro and in vivo Biological Evaluation, Molecular Modeling and in silico ADMET Studies

Background: Human Epidermal development factor Receptor-2 (HER2) is a membrane tyrosine kinase which is overexpressed and gene amplified in human breast cancers. HER2 amplification and overexpression have been linked to important tumor cell proliferation and survival pathways for 20% of instances of breast cancer. 9-aminoacridines are significant DNA-intercalating agents because of their antiproliferative properties. Objective: Some novel isoxazole substituted 9-anilinoacridines(1a-z) were designed by in-silico technique for their HER2 inhibitory activity. Docking investigations of compounds 1a-z are performed against HER2 (PDB id-3PP0) by using Schrodinger suit 2016-2. Methods: Molecular docking study for the designed molecules 1a-z are performed by Glide module, in-silico ADMET screening by QikProp module and binding free energy by Prime-MMGBSA module of Schrodinger suit. The binding affinity of designed molecules 1a-z towards HER2 was chosen based on GLIDE score. Results: Many compounds showed good hydrophobic communications and hydrogen bonding associations to hinder HER2. The compounds 1a-z, aside from 1z have significant Glide scores in the scope of - 4.91 to - 10.59 when compared with the standard Ethacridine (- 4.23) and Tamoxifen (- 3.78). The in-silico ADMET properties are inside the suggested about drug likeness. MM-GBSA binding of the most intense inhibitor is positive. Conclusion: The outcomes reveal that this study provides evidence for the consideration of isoxazole substituted 9-aminoacridine derivatives as potential HER2 inhibitors. The compounds, 1s,x,v,a,j,r with significant Glide scores may produce significant anti breast cancer activity and further in vitro and in vivo investigations may prove their therapeutic potential.

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Design, Sustainable Synthesis, Characterization, Antimicrobial Evaluation and in silico ADMET Prediction of New Functionalized Imidazolium Based Ionic Liquids

Asian Journal of Chemistry ◽

10.14233/ajchem.2020.22747 ◽

2020 ◽

Vol 32 (8) ◽

pp. 1972-1980

Author(s):

Anas R. Al Johani ◽

Saud M. Almutairi ◽

Wael S. El-Sayed ◽

Pramod K. Sahu ◽

Praveen K. Sahu ◽

...

Keyword(s):

Ionic Liquids ◽

In Silico ◽

Phenyl Group ◽

Antimicrobial Activities ◽

Spectral Techniques ◽

In Silico Admet ◽

Antimicrobial Evaluation ◽

Ft Ir

A series of sixteen new ionic liquids (ILs) bearing imidazolium moiety were designed and synthesized under sustainable and green conditions which were confirmed by analytical and spectral techniques using 1H- & 13C-NMR, FT-IR, mass and elemental analysis. A panel of clinically isolated strains was used for in vitro inhibitory antimicrobial activities screening of synthesized ionic liquids. The results of antimicrobial assay showed that some of synthesized ionic liquids showed moderate to good activity. Among these ILs, ionic liquids 3, 4 and 5 (bearing alkyl chain with a phenyl group) significantly inhibited cell growth of strains. In this regard, these ionic liquids considered as promising antibacterial agents when compared with standard antibiotics. By encouraging in vitro antimicrobial screening, in silico ADMET evaluation has been performed and found excellent pharmacokinetic, bioavailability and toxicity profiles. Synthesized ionic liquids has found to be safe and non-toxic according to calculated in vivo computed LD50 values (2.49-2.80 mg/kg) for rat acute toxicity.

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Molecular Modeling Approaches for the Prediction of Selected Pharmacokinetic Properties

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666181220105726 ◽

2019 ◽

Vol 18 (26) ◽

pp. 2230-2238 ◽

Cited By ~ 1

Author(s):

Emilio S. Petito ◽

David J.R. Foster ◽

Michael B. Ward ◽

Matthew J. Sykes

Keyword(s):

Molecular Modeling ◽

In Silico ◽

Volume Of Distribution ◽

Future Directions ◽

Unbound Fraction ◽

Drug Candidates ◽

New Methods ◽

Pharmacokinetic Properties

Poor profiles of potential drug candidates, including pharmacokinetic properties, have been acknowledged as a significant hindrance to the development of modern therapeutics. Contemporary drug discovery and development would be incomplete without the aid of molecular modeling (in-silico) techniques, allowing the prediction of pharmacokinetic properties such as clearance, unbound fraction, volume of distribution and bioavailability. As with all models, in-silico approaches are subject to their interpretability, a trait that must be balanced with accuracy when considering the development of new methods. The best models will always require reliable data to inform them, presenting significant challenges, particularly when appropriate in-vitro or in-vivo data may be difficult or time-consuming to obtain. This article seeks to review some of the key in-silico techniques used to predict key pharmacokinetic properties and give commentary on the current and future directions of the field.

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Synthesis and studies of thiazolidinedione–isatin hybrids as α-glucosidase inhibitors for management of diabetes

Future Medicinal Chemistry ◽

10.4155/fmc-2020-0022 ◽

2021 ◽

Vol 13 (5) ◽

pp. 457-485

Author(s):

Ramandeep Kaur ◽

Rajnish Kumar ◽

Nilambra Dogra ◽

Ashok Kumar ◽

Ashok Kumar Yadav ◽

...

Keyword(s):

In Silico ◽

Binding Free Energy ◽

Biological Evaluation ◽

Free Energy Calculations ◽

Standard Drug ◽

Glucosidase Inhibitors ◽

Cytotoxicity Studies ◽

Cytotoxicity Assessment

Aim: Keeping in view the side effects associated with clinically used α-glucosidase inhibitors, novel thiazolidinedione–isatin hybrids were synthesized and evaluated by in vitro, in vivo and in silico procedures. Materials & methods: Biological evaluation, cytotoxicity assessment, molecular docking, binding free energy calculations and molecular dynamics studies were performed for hybrids. Results: The most potent inhibitor A-10 (IC50 = 24.73 ± 0.93 μM) was competitive in manner and observed as non-cytotoxic. A-10 possessed higher efficacy than the standard drug (acarbose) during in vivo biological testing. Conclusion: The enzyme inhibitory potential and safety profile of synthetic molecules was recognized after in vitro, in vivo, in silico and cytotoxicity studies. Further structural optimization of A-10 can offer potential hit molecules suitable for future investigations.

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ADMET Profiling in Drug Discovery and Development: Perspectives of in silico, in vitro and integrated approaches

Current Drug Metabolism ◽

10.2174/1389200222666210705122913 ◽

2021 ◽

Vol 22 ◽

Author(s):

Nour El-Huda Daoud ◽

Pobitra Borah ◽

Pran Kishore Deb ◽

Katharigatta N. Venugopala ◽

Wafa Hourani ◽

...

Keyword(s):

Drug Discovery ◽

In Silico ◽

Predictive Power ◽

Early Stage ◽

In Vitro Models ◽

Prediction Ability ◽

Drug Discovery And Development ◽

In Silico Admet

: In the drug discovery setting, undesirable ADMET properties of a pharmacophore with good predictive power obtained after a tedious drug discovery and development process may lead to late-stage attrition. The early-stage ADMET profiling has introduced a new dimension to leading development. Although several high-throughput in vitro models are available for ADMET profiling, however, the in silico methods are gaining more importance because of their economic and faster prediction ability without the requirements of tedious and expensive laboratory resources. Nonetheless, in silico ADMET tools alone are not accurate and, therefore, ideally adopted along with in vitro and or in vivo methods in order to enhance predictability power. This review summarizes the significance and challenges associated with the application of in silico tools as well as the possible scope of in vitro models for integration to improve the ADMET predictability power of these tools.

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1,3,5-Pyrazoline Derivatives in CNS Disorders: Synthesis, Biological Evaluation and Structural Insights through Molecular Docking

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319999200818182249 ◽

2020 ◽

Vol 19 (6) ◽

pp. 448-465

Author(s):

Himanshi Sharma ◽

Pooja A. Chawla ◽

Rohit Bhatia

Keyword(s):

In Silico ◽

Antidepressant Activity ◽

Tail Suspension Test ◽

Docking Studies ◽

Biological Evaluation ◽

Hydroxyl Group ◽

Spectral Techniques ◽

Lipinski’S Rule

Background: Anxiety and oxidative stress are the common disorders prevailing in the modern age. Many new pyrazoline derivatives have been synthesized and patented, but there is still continuous research in progress to explore antidepressant and antioxidant potential of pyrazoline scaffold. Objective: The present work was carried out to synthesize, characterize and evaluate the pharmacological potential of 1,3,5-Pyrazoline derivatives. Methods: Ten new 1,3,5-Pyrazoline derivatives were synthesized and characterized by IR, 1HNMR and mass spectral techniques. The synthesized pyrazoline derivatives were investigated for their in vivo antidepressant activity by Tail Suspension Test (TST) and in vitro antioxidant activity by FRAP and DPPH assay methods. The docking studies and in silico ADME and toxicity characteristics were also evaluated. Results: Among the synthesized analogues, IVh showed the highest antidepressant activity with a significant reduction in the duration of immobility. The compound IVh emerged as the most potent antioxidant compound due to the presence of an electron releasing hydroxyl group. Docking studies of most potent compounds revealed good interaction points with the MAO-A enzyme. The compounds were found to obey Lipinski’s Rule of Five and displayed the least in silico toxicity profile. Conclusion: The synthesized compounds were found to possess great potential in decreasing the duration of immobility in Swiss albino mice and scavenging free radicals. These compounds may serve as new leads for further drug exploration.

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A Novel Series of Acylhydrazones as Potential Anti-Candida Agents: Design, Synthesis, Biological Evaluation and In Silico Studies

Molecules ◽

10.3390/molecules24010184 ◽

2019 ◽

Vol 24 (1) ◽

pp. 184 ◽

Cited By ~ 3

Author(s):

Anca-Maria Borcea ◽

Gabriel Marc ◽

Ioana Ionuț ◽

Dan C. Vodnar ◽

Laurian Vlase ◽

...

Keyword(s):

In Silico ◽

Docking Study ◽

Biological Evaluation ◽

Antifungal Drugs ◽

Biologically Active ◽

Molecular Docking Study ◽

Candida Spp ◽

In Silico Admet ◽

In Silico Studies

In the context of an increased incidence of invasive fungal diseases, there is an imperative need of new antifungal drugs with improved activity and safety profiles. A novel series of acylhydrazones bearing a 1,4-phenylene-bisthiazole scaffold was designed based on an analysis of structures known to possess anti-Candida activity obtained from a literature review. Nine final compounds were synthesized and evaluated in vitro for their inhibitory activity against various strains of Candida spp. The anti-Candida activity assay revealed that some of the new compounds are as active as fluconazole against most of the tested strains. A molecular docking study was conducted in order to evaluate the binding poses towards lanosterol 14α-demethylase. An in silico ADMET analysis showed that the compounds possess drug-like properties and represent a biologically active framework that should be further optimized as potential hits.

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Synthesis, Biological Evaluation and Molecular Docking Studies of Novel Di-hydropyridine Analogs as Potent Antioxidants

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666191105100959 ◽

2019 ◽

Vol 19 (29) ◽

pp. 2676-2686 ◽

Cited By ~ 1

Author(s):

Saddala Madhu Sudhana ◽

Pradeepkiran Jangampalli Adi

Keyword(s):

Molecular Docking ◽

In Silico ◽

Docking Studies ◽

Biological Evaluation ◽

Binding Energies ◽

Molecular Docking Studies ◽

Metal Chelating ◽

In Silico Admet ◽

Dpph Method

Aims: The aim of this study is to synthesize, characterize and biological evaluation of 3-ethyl 5- methyl2-(2-aminoethoxy)-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate derivatives. Background: An efficient synthesis of two series of novel carbamate and sulfonamide derivatives of amlodipine, 3-ethyl 5-methyl 2-(2-aminoethoxy)-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (amlodipine) 1 were chemical synthesized process. Materials & Methods: In this process, various chloroformates 2(a-e) and sulfonyl chlorides 4(a-e) on reaction with 1 in the presence of N,N–dimethylpiperazine as a base in THF at 50-550 oC, the corresponding title compounds 3(a-e) and 5(a-e) in high yields. Furthermore, the compounds 3(a-e) and 5(a-e) were evaluated for antioxidant activity (DPPH method), metal chelating activity, hemolytic activity, antioxidant assay (ABTS method), cytotoxicity, molecular docking and in silico ADMET properties. Result: Results revealed that 5a, 5e, 3d, 3a and 5c exhibited high antioxidant, metal chelating activities, but 5a, 5e and 3d exhibited low activity. The molecular docking studies and ADMET of suggested ligands showed the best binding energies and non-toxic properties. Conclusion: The present in silico and in vitro evaluations suggested that these dihydropyridine derivatives act as potent antioxidants and chelating agents which may be useful in treating metals induced oxidative stress associated diseases.

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