Synthesis and antiviral activity of 1-(1,3-disubstitutedimidazolidyn-2-ylidene)-3-ethoxycarbonylmethylurea derivatives

Abstract

Novel 1-(1,3-disubstituted-imidazolidyn-2-ylidene)-3-ethoxycarbonylmethylurea derivatives (3a-3j) were obtained from appropriate 1-aryl-3-arylsulfonyl-1H-imidazolidine-2-imines (1a-1j) and ethyl isocyanatoacetate (2), which were subjected to condensation. Seven compounds were tested for their antiviral activity against HSV-1 and CVB3 viruses. Among the tested compounds, 3c was found to be active against HSV-1, proving that 4-methoxy substituent as R and 4-methyl substituent as R1 are most beneficial for activity against this virus. Furthermore, 3e and 3g were active against CVB3, which demonstrated that both 4-methyl and 4-chloro substitution is tolerated as R1, whereas 4-chloro and 2-methoxy substituents are best as R. It was also shown that the active compounds are characterized by relatively big surface area, small ovality, and greatest HOMO and LUMO energies in comparison to the rest of the compounds.

Synthesis, antiviral activity and structure–activity relationship of 1-(1-aryl-4,5-dihydro-1H-imidazoline)-3-chlorosulfonylureas and products of their cyclization

“…Parameters to evaluate drug-likeness were calculated using VegaZZ version 3.0.1 21 (number of atoms), Discovery Studio version 3.1 22 (molar mass, number of rings, lipophilicity, number of rotatable bonds), ACDLabs (molar refractivity, number of hydrogen bond donors and acceptors) and the Schrödinger Suite (a number of rigid bonds) as described previously [23][24][25][26] . ADMET parameters were calculated with Discovery Studio 3.1 (solubility, blood-brain permeation) or Osiris Property Explorer 27 (toxicity risks) as previously described [23][24][25][26] . The prediction of toxicity is based on a pre-computed set of structural fragment that give rise to toxicity alerts in case they are encountered in the investigated compound 27 .…”

“…Drug-likeness was assessed using Lipinski's rule as well as the placement of the investigated compounds in the chemical space determined by the databases of the pharmacologically active compounds (CMC, Comprehensive Medicinal Chemistry Database, containing about 7000 compounds and MDDR, MACCS-II Drug Data Report, containing about 100 000 compounds) according to the methodology of PREADMET 31 service as described previously [23][24][25][26] . Regarding Lipinski's rule, all the compounds possess the molar mass below 500, the number of hydrogen bond donors below 5, the number of hydrogen bond acceptors below 10 and the lipophilicity below 5 32 .…”

“…Regarding subsequent criteria of drug-likeness, most compounds collected in the CMC database has lipophilicity from À0.4 to 5.6, molar refractivity in the range of 40-130 the number of atoms from 20 to 70 and molar mass from 160 to 480 [23][24][25][26]33 .…”

“…Concerning the compounds in MDDR database, the drug-like substances have the number of rings equal or greater than 3, the number of rigid bonds equal or greater than 18, and the number of rotatable bonds equal or greater than 6 [23][24][25][26]34 . Compounds 3a-3f have too few rings and all the compounds have too few rotatable bonds.…”

Anticandidal Effect of New Imidazole Derivatives Over Aspartic Protease Inhibition

“…Aspartic proteases (EC 2.4.23), also known as aspartic acid proteases or acid proteases, are endopeptidases that require aspartic acid residues to function catalytically [7,8] . In recent years, many other protease inhibitors have been researched and created to combat viruses and fungi [9–11] . Small molecules with antiviral properties based on imidazolidine have been reported and are continually being published [12–14] …”