Synthesis, Characterization, and Biological Evaluation of Meldrum's Acid Derivatives: Dual Activity and Molecular Docking Study

Syed Nasir Abbas Bukhari; Mohamed Abdelwahab Abdelgawad; Naveed Ahmed; Muhammad Wahab Amjad; Muhammad Ajaz Hussain; Mervat A Elsherif; Hasan Ejaz; Nasser H Alotaibi; Ignjat Filipović; Nenad Janković

doi:10.3390/ph16020281

Synthesis, Characterization, and Biological Evaluation of Meldrum's Acid Derivatives: Dual Activity and Molecular Docking Study

Pharmaceuticals (Basel). 2023 Feb 13;16(2):281. doi: 10.3390/ph16020281.

Affiliations

¹ Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72388, Al Jouf, Saudi Arabia.
² Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka 72388, Al Jouf, Saudi Arabia.
³ Center for Ultrasound Molecular Imaging and Therapeutics, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15260, USA.
⁴ Centre for Organic Chemistry, School of Chemistry, University of the Punjab, Lahore 54590, Pakistan.
⁵ Chemistry Department, College of Science, Jouf University, Sakaka 72388, Al Jouf, Saudi Arabia.
⁶ Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Al Jouf, Saudi Arabia.
⁷ Department of Clinical Pharmacy, College of Pharmacy, Jouf University, Sakaka 72388, Al Jouf, Saudi Arabia.
⁸ University of Kragujevac, Faculty of Science, Radoja Domanovića 12, 34000 Kragujevac, Serbia.
⁹ University of Kragujevac, Department of Science, Institute for Information Technologies Kragujevac, Jovana Cvijića bb, 34000 Kragujevac, Serbia.

Abstract

In the presented study, eight novel Meldrum's acid derivatives containing various vanillic groups were synthesized. Vanillidene Meldrum's acid compounds were tested against different cancer cell lines and microbes. Out of nine, three showed very good biological activity against E. coli, and HeLa and A549 cell lines. It is shown that the O-alkyl substituted derivatives possessed better antimicrobial and anticancer activities in comparison with the O-acyl ones. The decyl substituted molecule (3i) has the highest activity against E. coli (MIC = 12.4 μM) and cancer cell lines (HeLa, A549, and LS174 = 15.7, 21.8, and 30.5 μM, respectively). The selectivity index of 3i is 4.8 (HeLa). The molecular docking study indicates that compound 3i showed good binding affinity to DNA, E. coli Gyrase B, and topoisomerase II beta. The covalent docking showed that 3i was a Michael acceptor for the nucleophiles Lys and Ser. The best E_b was noted for the topoisomerase II beta-LYS482-3i cluster.

Keywords: Meldrum’s acid; anticancer activity; antimicrobial activity; gyrase B; topoisomerase II; vanillin.

Grants and funding

DSR2022-RG-0148/Deanship of Scientific Research at Jouf University