Synthesis, characterization and biological profile of some new dihydropyrimidinone derivaties

Objective: The rise of drug-resistant bacteria, viruses, and fungi has prompted the search for new drugs without cross-resistance to current treatments. As a result, the aim of this research was to synthesize various types of dihydropyrimidinones heterocyclic compounds and screened them for their antibiotic properties.

Methodology: Newly synthesized dihydropyrimidinone derivatives were characterized spectroscopically using proton NMR (¹HNMR), and FT-IR. These substances were then subjected to molecular docking studies via Auto dock Vina software to determine their affinity for binding to proteins from different bacterial strains including (Staphylococcus epidermidis (S. epidermidis), Staphylococcus aureus (S. aureus), Mycobacterium luteus (M. luteus), Salmonella typhi (S.typhi), Bacillus subtilis (B. subtilis), and Escherichia coli (E. coli) and fungal (Candida glabrata (C. glabrata), Candida albicans (C. albicans), and Saccharomyces cerevisiae (S. cerevisiae) strains. Also in-vitro anti-fungal, anti-bacterial and anti-oxidant activity was performed by using ager well diffusion method and DPPH assay respectively. Moreover, the In-vivo biological evaluation of these derivatives was conducted by using carrageenan-induced hind paw model. The cytotoxicity profile of the synthesized derivatives was done via in-vitro MTT assay.

Results: All newly synthesized derivatives were confirmed via the multiple spectroscopic analysis techniques. All derivatives showed good binding affinities against the multiple targeted protein with. Compound 4c exhibited hightest potential with -10 kcal/mol against bacterial strains. 4b showed best antifungal potential with -10.8 kcal/mol binding affinities. For Bacillus subtilis compound 4b and 4c performed best with 17 mm ± 2.21. for anti-fungal activity against Candida glabrata, amongst the five newly formed compounds, 4a showed best activity with 19 mm ± 1.22 The analogue 4b exhibited best anti-oxidant potential with 63.85 ± 1.39. Compound 4a and 4b showed highest anti-inflammatory potential with 1.011 mm ± 0.247 mg/kg and 1.447 ± 0.212 mg/kg in countering inflammation by targeting toll-like receptor activation and reduce the inflammation in hind paw edema. The selected derivatives exhibited no toxicity profile with 99 % and 98 % cell survival rate using compound 4a and 4b.

Conclusion: Research has been done on the multiple biological activities of dihydropyrimidinones derivatives but the innovation on MDR is still pending. New dihydropyrimidinone derivatives were developed as agents to combat drug resistance. The results of these studies showed that newly synthesized dihydropyrimidinone derivatives are remarkably effective not only as anti-biotic agents but also counter inflammation caused by carrageenan resulting from the activation of the Toll-like receptors (TLRs) signaling pathway along with the non-toxic effect. So it is concluded that the recently synthesized new dihyropyrimidinone derivatives are highly effective antimicrobial derivatives with non-toxic effects on human cell lines.