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...
In silico
research was executed on forty unsymmetrical aromatic disulfide derivatives as inhibitors of the SARS Coronavirus (SARS-CoV-1). Density functional theory (DFT) calculation with B3LYP functional employing 6-311+G(d,p) basis set was used to calculate quantum chemical descriptors. Topological, physicochemical and thermodynamic parameters were calculated using ChemOffice software. The dataset was divided randomly into training and test sets consisting of 32 and 8 compounds, respectively. In attempt to explore the structural requirements for bioactives molecules with significant anti-SARS-CoV-2 activity, we have built valid and robust statistics models using QSAR approach. Hundred linear pentavariate and quadrivariate models were established by changing training set compounds and further applied in test set to calculate predicted IC
50
values of compounds. Both built models were individually validated internally as well as externally along with Y-Randomization according to the OECD principles for the validation of QSAR model and the model acceptance criteria of Golbraikh and Tropsha’s. Model 34 is chosen with higher values of R
2
, R
2
test
and Q
2
cv (R
2
= 0.838, R
2
test
= 0.735, Q
2
cv
= 0.757).
It is very important to notice that anti-SARS-CoV main protease of these compounds appear to be mainly governed by five descriptors, i.e. highest occupied molecular orbital energy (E
HOMO
), energy of molecular orbital below HOMO energy (E
HOMO-1
), Balaban index (BI), bond length between the two sulfur atoms (S1S2) and bond length between sulfur atom and benzene ring (S2Bnz). Here the possible action mechanism of these compounds was analyzed and discussed, in particular, important structural requirements for great SARS-CoV main protease inhibitor will be by substituting disulfides with smaller size electron withdrawing groups. Based on the best proposed QSAR model, some new compounds with higher SARS-CoV inhibitors activities have been designed. Further,
in silico
prediction studies on ADMET pharmacokinetics properties were conducted.
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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