Acetophenone-Based 3,4-Dihydropyrimidine-2(1H)-Thione as Potential Inhibitor of Tyrosinase and Ribonucleotide Reductase: Facile Synthesis, Crystal Structure, In-Vitro and In-Silico Investigations


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Saeed A., Ejaz S. A. , Khalid A., Channar P. A. , Aziz M., Abbas Q., ...More

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol.23, no.21, 2022 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 23 Issue: 21
  • Publication Date: 2022
  • Doi Number: 10.3390/ijms232113164
  • Journal Name: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, CAB Abstracts, EMBASE, Food Science & Technology Abstracts, MEDLINE, Veterinary Science Database, Directory of Open Access Journals
  • Keywords: thione, dihydropyrimidine, single crystal analysis, DFT, molecular docking, ONE-POT SYNTHESIS, CALCIUM-CHANNEL BLOCKERS, INTERMOLECULAR INTERACTIONS, ANTICANCER ACTIVITY, HIRSHFELD SURFACES, ACID-ESTERS, HOMO-LUMO, FT-RAMAN, DOCKING, NBO
  • Hacettepe University Affiliated: Yes

Abstract

The acetophenone-based 3,4-dihydropyrimidine-2(1H)-thione was synthesized by the reaction of 4-methylpent-3-en-2-one (1), 4-acetyl aniline (2) and potassium thiocyanate. The spectroscopic analysis including: FTIR, H-1-NMR, and single crystal analysis proved the structure of synthesized compound (4), with the six-membered nonplanar ring in envelope conformation. In crystal structure, the intermolecular N-H MIDLINE HORIZONTAL ELLIPSIS S and C-H MIDLINE HORIZONTAL ELLIPSIS O hydrogen bonds link the molecule in a two-dimensional manner which is parallel to (010) the plane enclosing R-2(2) (8) and R-2(2) (10) ring motifs. After that, the Hirshfeld surfaces and their related two-dimensional fingerprint plots were used for thorough investigation of intermolecular interactions. According to Hirshfeld surface analysis, the most substantial contributions to the crystal packing are from H MIDLINE HORIZONTAL ELLIPSIS H (59.5%), H MIDLINE HORIZONTAL ELLIPSIS S/S MIDLINE HORIZONTAL ELLIPSIS H (16.1%), and H MIDLINE HORIZONTAL ELLIPSIS C/C MIDLINE HORIZONTAL ELLIPSIS H (13.1%) interactions. The electronic properties and stability of the compound were investigated through density functional theory (DFT) studies using B3LYP functional and 6-31G* as a basis set. The compound 4 displayed the high chemical reactivity with chemical softness of 2.48. In comparison to the already reported known tyrosinase inhibitor, the newly synthesized derivatives exhibited almost seven-fold better inhibition of tyrosinase (IC50 = 1.97 mu M), which was further supported by molecular docking studies. The compound 4 inside the active pocket of ribonucleotide reductase (RNR) exhibited a binding energy of -19.68 kJ/mol, and with mammalian deoxy ribonucleic acid (DNA) it acts as an effective DNA groove binder with a binding energy of -21.32 kJ/mol. The results suggested further exploration of this compound at molecular level to synthesize more potential leads for the treatment of cancer.