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

Chalkha, Mohammed; Akhazzane, Mohamed; Moussaid, Fatima Zahrae; Daoui, Ossama; Nakkabi, Asmae; Bakhouch, Mohamed; Chtita, Samir; Elkhattabi, Souad; Housseini, Abdelilah Iraqi; Yazidi, Mohamed El

doi:10.1039/d1nj05621b

Cited by 39 publications

(26 citation statements)

References 53 publications

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“…After selecting the ideal N and Q 2 for the 3D-QSAR modeling design, we evaluate the overall significance of the developed model by computing statistical parameters such as the coefficient of determination ( R 2 ), the standard error of estimates (SEE), and F -value (Fischer’s test). If the values of R 2 > 0.6 and F test > 0.3 and low SEE, the model 3D-QSAR will be able to provide an ideal description of pIC 50 values based on the structural properties of investigated molecules [ 52 ].…”

Section: Methodsmentioning

confidence: 99%

Rational identification of small molecules derived from 9,10-dihydrophenanthrene as potential inhibitors of 3CLpro enzyme for COVID-19 therapy: a computer-aided drug design approach

2022

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Small molecules such as 9,10-dihydrophenanthrene derivatives have remarkable activity toward inhibition of SARS-CoV-2 3CL pro and COVID-19 proliferation, which show a strong correlation between their structures and bioactivity. Therefore, these small compounds could be suitable for clinical pharmaceutical use against COVID-19. The objective of this study was to remodel the structures of 9,10-dihydrophenanthrene derivatives to achieve a powerful biological activity against 3CL pro and favorable pharmacokinetic properties for drug design and discovery. Therefore, by the use of bioinformatics techniques, we developed robust 3D-QSAR models that are capable of describing the structure–activity relationship for 46 molecules based on 9,10-dihydrophenanthrene derivatives using CoMFA/SE ( R 2 = 0.97, Q 2 = 0.81, R 2 pred = 0.95, c R 2 p = 0.71) and CoMSIA/SEHDA ( R 2 = 0.94, Q 2 = 0.76, R 2 pred = 0.91, c R 2 p = 0.65) techniques. Accordingly, 96 lead compounds were generated based on a template molecule that showed the highest observed activity in vitro (T40, pIC 50 = 5.81) and predicted their activities and bioavailability in silico. The rational screening outputs of 3D-QSAR, Molecular docking, ADMET, and MM-GBSA led to the identification of 9 novel modeled molecules as potent noncovalent drugs against SARS-CoV-2-3CL pro . Finally, by molecular dynamics simulations, the stability and structural dynamics of 3CL pro free and complex (PDB code: 6LU7) were discussed in the presence of samples of 9,10-dihydrophenanthrene derivative in an aqueous environment. Overall, the retrosynthesis of the proposed drug compounds in this study and the evaluation of their bioactivity in vitro and in vivo may be interesting for designing and discovering a new drug effective against COVID-19. Supplementary Information The online version contains supplementary material available at 10.1007/s11224-022-02004-z.

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Section: Methodsmentioning

confidence: 99%

Rational identification of small molecules derived from 9,10-dihydrophenanthrene as potential inhibitors of 3CLpro enzyme for COVID-19 therapy: a computer-aided drug design approach

2022

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“…The presence of heterocyclic compounds as the main structural motif in a variety of biologically active, natural and synthetic molecules has led to the development of new methodologies of their synthesis. In this context, we have been interested in the synthesis of various aza-heterocyclic derivatives with potential biological activities, using easy and reproducible synthesis strategies [32][33][34][35]. In the present work, we describe the synthesis of quinazolin-4(3H)-one-isoxazoline hybrids according to the pathway shown in Scheme 1.…”

Section: Synthesis and Characterizationmentioning

confidence: 99%

“…The synthesis of new heterocycle molecules based on the hybridization of quinazolinone and isoxazoline pharmacophores is a promising avenue in modern medicinal chemistry [31]. In this regard and in continuation of our ongoing research focused on the design of new bioactive compounds [32][33][34][35], we reported in this work, the synthesis and characterization of new quinazolinone-isoxazoline hybrids. The synthesis of the target compounds 4a-h was performed using 1,3-dipolar cycloaddition reaction between arylnitriloxides 3a-h and Nallylquinazolinone 2.…”

Section: Introductionmentioning

confidence: 98%

Novel quinazolinone-isoxazoline hybrids: synthesis, structural elucidation and theoretical DFT mechanistic study

Rhazi

Chalkha

Nakkabi

et al. 2022

Preprint

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Quinazolinone and isoxazoline systems have attracted more attention due to their interesting pharmacological properties. The association of these two pharmacophores in a single hybrid structure can boost the biological activity or bring a new one. Inspired by this new paradigm, we report in the present work, the synthesis and spectroscopic characterization of a new quinazolinone-isoxazoline hybrids. The target compounds were obtained via 1,3-dipolar cycloaddition reaction of arylnitriloxides and N-allylquinazolinone. The synthesized compounds were characterized using spectroscopic techniques such as: IR, 1D NMR (1H and 13C), 2D NMR (COSY and HSQC), and high-resolution mass spectrometry (HRMS). The spectral data show that this reaction leads only to the 3,5-disubstituted isoxazoline regioisomer and the observed regiochemistry is not affected by the nature of the substituents in the phenyl ring of the dipole. In addition, a theoretical study was performed using the density functional theory (DFT) to support the experimental results regarding the regiochemistry of the studied reactions. The computational mechanistic study is in perfect agreement with experimental data.

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“…In continuation of our previous efforts in the development of new aza-heterocyclic antimicrobial candidates, − we report in the present work the synthesis, structural identification, and biological activity assessment of new poly heterocyclic molecules incorporating both pyrazole and isoxazoline cores. The synthesis of these heterocycles is carried out from aza-aurones by N-alkylation and 1,3-dipolar cycloaddition reactions.…”

Section: Introductionmentioning

confidence: 98%

Synthesis, Characterization, DFT Mechanistic Study, Antimicrobial Activity, Molecular Modeling, and ADMET Properties of Novel Pyrazole-isoxazoline Hybrids

et al. 2022

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A series of new heterocycle hybrids incorporating pyrazole and isoxazoline rings was successfully synthesized, characterized, and evaluated for their antimicrobial responses. The synthesized compounds were obtained utilizing N-alkylation and 1,3-dipolar cycloaddition reactions, as well as their structures were established through spectroscopic methods and confirmed by mass spectrometry. To get more light on the regioselective synthesis of new hybrid compounds, mechanistic studies were performed using DFT calculations with B3LYP/6-31G(d,p) basis set. Additionally, the results of the preliminary screening indicate that some of the examined hybrids showed potent antimicrobial activity, compared to standard drugs. The results confirm that the antimicrobial activity is strongly dependent on the nature of the substituents linked pyrazole and isoxazoline rings. Furthermore, molecular docking studies were conducted to highlight the interaction modes between the investigated hybrid compounds and the Escherichia coli and Candida albicans receptors. Notably, the results demonstrate that the investigated compounds have strong protein binding affinities. The stability of the formed complexes by the binding between the hybrid compound 6c, and the target proteins was also confirmed using a 100 ns molecular dynamics simulation. Finally, the prediction of ADMET properties suggests that almost all hybrid compounds possess good pharmacokinetic profiles and no signs of observed toxicity, except for compounds 6e, 6f, and 6g.

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

Abstract: 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...

Cited by 39 publications

References 53 publications

Rational identification of small molecules derived from 9,10-dihydrophenanthrene as potential inhibitors of 3CLpro enzyme for COVID-19 therapy: a computer-aided drug design approach

Rational identification of small molecules derived from 9,10-dihydrophenanthrene as potential inhibitors of 3CLpro enzyme for COVID-19 therapy: a computer-aided drug design approach

Novel quinazolinone-isoxazoline hybrids: synthesis, structural elucidation and theoretical DFT mechanistic study

Synthesis, Characterization, DFT Mechanistic Study, Antimicrobial Activity, Molecular Modeling, and ADMET Properties of Novel Pyrazole-isoxazoline Hybrids

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