Antitarget interaction, acute toxicity and protein binding studies of quinazolinedione sulphonamides as GABA<sub>1</sub>antagonists

Ajeet,; Verma, Mansi; Rani, Sangeeta; Kumar, Ajay

doi:10.4103/0250-474x.180249

Cited by 3 publications

(1 citation statement)

References 12 publications

(14 reference statements)

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“…[7] In an effort towards new drug design and development, the improvement of molecules by the combination of diverse pharmacophores could lead to compounds with interesting biological profiles [8] sulfonamide is one such pharmacophore to hybridize with heterocyclic units. [9] Few recent examples of such hybrid clinical agents derived with sulfonamide unit are depicted in Figure 2. The favorable influence of sulfonamide substituents on the antitumor potential of designed compounds has been recognized and demonstrated.…”

Section: Introductionmentioning

confidence: 99%

Anticancer Potential of N‐Sulfonyl Noscapinoids: Synthesis and Evaluation

et al. 2020

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Noscapine is an alkaloid with a basic phthalideisoquinoline moiety and is well recognized as an antitussive drug. It is obtained from opium poppy Papaver somniferum and demonstrates a rather safe toxicity profile in vitro. Recent studies found noscapine and its analogues to have anticancer activity against mammalian cancer cell lines by modulating microtubule assembly. In the present study, we report the synthesis and evaluation of cytotoxicity of a series of N‐sulfonyl noscapinoids 6 a–n obtained by reaction of nornoscapine with various aryl/heteroaryl sulfonyl chlorides. To assess the antiproliferative activity of the novel derivatives 6 a–n, SRB assay was performed in four different human cancer cell lines, MIAPaCa‐2 (pancreatic), HeLa (cervical), SK−N−SH (neuroblastoma) and DU145 (prostate cancer). The study identified four compounds 6 e–g and 6 j ability to arrest cell‐cycle at the G2/M phase and cytotoxic potential against the human pancreatic cancer cell line MIAPaCa‐2. We observed that these compounds 6 e–g and 6 j induce microtubule depolymerisation and cause cell cycle arrest at the G2/M phase thereby resulting in caspase‐3 and PARP activation leading to cell death. In silico molecular docking studies of these compounds showed non‐covalent interactions like Van der Waals and hydrogen‐bonding with tubulin protein and with good binding energy.

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Section: Introductionmentioning

confidence: 99%

Anticancer Potential of N‐Sulfonyl Noscapinoids: Synthesis and Evaluation

et al. 2020

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Computer-aided prediction of biological activity spectra for chemical compounds: opportunities and limitation

Филимонов

Druzhilovskiy

Lagunin

et al. 2018

BMCRM

135

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An essential characteristic of chemical compounds is their biological activity since its presence can become the basis for the use of the substance for therapeutic purposes, or, on the contrary, limit the possibilities of its practical application due to the manifestation of side action and toxic effects. Computer assessment of the biological activity spectra makes it possible to determine the most promising directions for the study of the pharmacological action of particular substances, and to filter out potentially dangerous molecules at the early stages of research. For more than 25 years, we have been developing and improving the computer program PASS (Prediction of Activity Spectra for Substances), designed to predict the biological activity spectrum of substance based on the structural formula of its molecules. The prediction is carried out by the analysis of structure-activity relationships for the training set, which currently contains information on structures and known biological activities for more than one million molecules. The structure of the organic compound is represented in PASS using Multilevel Neighborhoods of Atoms descriptors; the activity prediction for new compounds is performed by the naive Bayes classifier and the structure-activity relationships determined by the analysis of the training set. We have created and improved both local versions of the PASS program and freely available web resources based on PASS (http://www.way2drug.com). They predict several thousand biological activities (pharmacological effects, molecular mechanisms of action, specific toxicity and adverse effects, interaction with the unwanted targets, metabolism and action on molecular transport), cytotoxicity for tumor and non-tumor cell lines, carcinogenicity, induced changes of gene expression profiles, metabolic sites of the major enzymes of the first and second phases of xenobiotics biotransformation, and belonging to substrates and/or metabolites of metabolic enzymes. The web resource Way2Drug is used by over 18,000 researchers from more than 90 countries around the world, which allowed them to obtain over 600,000 predictions and publish about 500 papers describing the obtained results. The analysis of the published works shows that in some cases the interpretation of the prediction results presented by the authors of these publications requires an adjustment. In this work, we provide the theoretical basis and consider, on particular examples, the opportunities and limitations of computer-aided prediction of biological activity spectra.

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Synthesis, Molecular Docking and ADME-TOX Studies of New Tacrine Analogs as Promising for Alzheimer's Disease Therapy

Kibou

Baba-Ahmed

Daoud

et al. 2022

COC

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The modification of drug delivery routes can be used as a promising strategy to improve the therapeutic profile of various drug agents. Herein, the synthesis and molecular modeling of a series of 6,7,8,9-tetrahydrobenzo [b] [1,8] naphthyridines derivatives were reported to explore potent and less toxic scaffolds. The tacrine analogs 6–10 were obtained by an efficient strategy using Friedlander's condensation between 2-aminopyridine-3-carbonitriles 1–5 and cyclohexanone under microwave irradiations without catalysts and solvents. The synthesized compounds were identified through 1H NMR, 13C NMR, IR. Their inhibition activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were focused as probable drug targets for Alzheimer’s disease (AD). The pharmaco-kinetic properties, the risk of probable hepato-toxic metabolites, and the toxicological properties were predicted using computational methods. The prediction of the toxicity risks via the GUSAR software allowed us to resolve the best approach for drug delivery, namely the subcutaneous, intravenous, or oral route., Also, the GUSAR software was used to reveal all possible adverse effects. All these techniques were tested for the L1-6 compounds by choosing tacrine as a template compound. Among these compounds, the optimal compound L1 was the most potent inhibitor and had the best score binding affinity compared to the reference drug (Tacrine) -7.926 and -7.007 kcal/mol for AChE and BuChE, respectively. Moreover, this same compound presented a satisfying pharmaceutical profile. In the present study, subcutaneous delivery is considered a promising administration of reference drug and their derivatives against AD.

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Antitarget interaction, acute toxicity and protein binding studies of quinazolinedione sulphonamides as GABA₁antagonists

Cited by 3 publications

References 12 publications

Anticancer Potential of N‐Sulfonyl Noscapinoids: Synthesis and Evaluation

Anticancer Potential of N‐Sulfonyl Noscapinoids: Synthesis and Evaluation

Computer-aided prediction of biological activity spectra for chemical compounds: opportunities and limitation

Synthesis, Molecular Docking and ADME-TOX Studies of New Tacrine Analogs as Promising for Alzheimer's Disease Therapy

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Antitarget interaction, acute toxicity and protein binding studies of quinazolinedione sulphonamides as GABA1antagonists

Cited by 3 publications

References 12 publications

Anticancer Potential of N‐Sulfonyl Noscapinoids: Synthesis and Evaluation

Anticancer Potential of N‐Sulfonyl Noscapinoids: Synthesis and Evaluation

Computer-aided prediction of biological activity spectra for chemical compounds: opportunities and limitation

Synthesis, Molecular Docking and ADME-TOX Studies of New Tacrine Analogs as Promising for Alzheimer's Disease Therapy

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Antitarget interaction, acute toxicity and protein binding studies of quinazolinedione sulphonamides as GABA₁antagonists