A Novel Ambroxol-Derived Tetrahydroquinazoline with a Potency against SARS-CoV-2 Proteins

Abstract

We report synthesis of a novel 1,2,3,4-tetrahydroquinazoline derivative, named 2-(6,8-dibromo-3-(4-hydroxycyclohexyl)-1,2,3,4-tetrahydroquinazolin-2-yl)phenol (1), which was obtained from the hydrochloride of 4-((2-amino-3,5-dibromobenzyl)amino)cyclohexan-1-ol (ambroxol hydrochloride) and salicylaldehyde in EtOH. The resulting compound was produced in the form of colorless crystals of the composition 1∙0.5EtOH. The formation of the single product was confirmed by the IR and 1H spectroscopy, single-crystal and powder X-ray diffraction, and elemental analysis. The molecule of 1 contains a chiral tertiary carbon of the 1,2,3,4-tetrahydropyrimidine fragment and the crystal structure of 1∙0.5EtOH is a racemate. Optical properties of 1∙0.5EtOH were revealed by UV-vis spectroscopy in MeOH and it was established that the compound absorbs exclusively in the UV region up to about 350 nm. 1∙0.5EtOH in MeOH exhibits dual emission and the emission spectra contains bands at about 340 and 446 nm upon excitation at 300 and 360 nm, respectively. The DFT calculations were performed to verify the structure as well as electronic and optical properties of 1. ADMET properties of the R-isomer of 1 were evaluated using the SwissADME, BOILED-Egg, and ProTox-II tools. As evidenced from the blue dot position in the BOILED-Egg plot, both human blood–brain barrier penetration and gastrointestinal absorption properties are positive with the positive PGP effect on the molecule. Molecular docking was applied to examine the influence of the structures of both R-isomer and S-isomer of 1 on a series of the SARS-CoV-2 proteins. According to the docking analysis results, both isomers of 1 were found to be active against all the applied SARS-CoV-2 proteins with the best binding affinities with Papain-like protease (PLpro) and nonstructural protein 3 (Nsp3_range 207–379-AMP). Ligand efficiency scores for both isomers of 1 inside the binding sites of the applied proteins were also revealed and compared with the initial ligands. Molecular dynamics simulations were also applied to evaluate the stability of complexes of both isomers with Papain-like protease (PLpro) and nonstructural protein 3 (Nsp3_range 207–379-AMP). The complex of the S-isomer with Papain-like protease (PLpro) was found to be highly unstable, while the other complexes are stable.

The Inhibitory Properties of the Ambroxol Derivative on the Corrosion of Mild Steel in Hydrochloric Acid Medium

“…The first two bands also exhibit a hyperchromic shift, whereas the third band exhibits a slight hypochromic shift. The absorption maxima coincide with those presented in the literature (214, 244, and 308 nm for ambroxol hydrochloride [13] and 216, 256, and 316 nm for ambroxol derivative [11]). The IR and Raman spectra are presented in Figure 3.…”

“…The recorded UV and IR spectra of the ambroxol derivative coincide with those from the study [11]. Moreover, the position and multiplicity of the bands in the experimental and predicted [14] NMR spectra also generally coincide.…”

“…In the range from 2800 to 3090 cm −1 , there are bands corresponding to the vibrations of the C-H bonds in aromatic rings and at the saturated carbon atoms. In the "fingerprint" range from 1460 to 1700 cm −1 , there are bands corresponding to the vibrations of C=C, NH (1535-1700), ОН (1482), and NH (1460) bonds [11]. The similar bands, taking into account the intensity change of the symmetric and asymmetric vibrations, are present at the Raman spectrum of the ambroxol derivative (4 in Figure 3).…”

“…In the literature, there are several pieces of evidence [10] that the products of condensation of aromatic primary amines with aromatic aldehydes exhibit excellent inhibitory properties. Recently, a synthesis of the new derivative of ambroxol and salicylaldehyde [11], namely, 2-(6,8dibromo-3-(4-hydroxycyclohexyl)-1,2,3,4-tetrahydroquinazolin-2-yl)phenol (Figure 1), was reported. The toxicity of the reported compound was also estimated [11] using the ProTox-II web application [12], and it was found that the compound is nontoxic, with the predicted LD 50 equal to 12 g/kg.…”

“…Recently, a synthesis of the new derivative of ambroxol and salicylaldehyde [11], namely, 2-(6,8dibromo-3-(4-hydroxycyclohexyl)-1,2,3,4-tetrahydroquinazolin-2-yl)phenol (Figure 1), was reported. The toxicity of the reported compound was also estimated [11] using the ProTox-II web application [12], and it was found that the compound is nontoxic, with the predicted LD 50 equal to 12 g/kg. In the present study, the aim is to investigate the inhibitory properties of this compound on the corrosion of mild stainless steel EN Fe37-3FN in 0.5 M hydrochloric acid medium.…”