Preliminary Insight of Pyrrolylated-Chalcones as New Anti-Methicillin-Resistant Staphylococcus aureus (Anti-MRSA) Agents

Abstract

Bacterial infections are regarded as one of the leading causes of fatal morbidity and death in patients infected with diseases. The ability of microorganisms, particularly methicillin-resistant Staphylococcus aureus (MRSA), to develop resistance to current drugs has evoked the need for a continuous search for new drugs with better efficacies. Hence, a series of non-PAINS associated pyrrolylated-chalcones (1–15) were synthesized and evaluated for their potency against MRSA. The hydroxyl-containing compounds (8, 9, and 10) showed the most significant anti-MRSA efficiency, with the MIC and MBC values ranging from 0.08 to 0.70 mg/mL and 0.16 to 1.88 mg/mL, respectively. The time-kill curve and SEM analyses exhibited bacterial cell death within four hours after exposure to 9, suggesting its bactericidal properties. Furthermore, the docking simulation between 9 and penicillin-binding protein 2a (PBP2a, PDB ID: 6Q9N) suggests a relatively similar bonding interaction to the standard drug with a binding affinity score of −7.0 kcal/mol. Moreover, the zebrafish model showed no toxic effects in the normal embryonic development, blood vessel formation, and apoptosis when exposed to up to 40 µM of compound 9. The overall results suggest that the pyrrolylated-chalcones may be considered as a potential inhibitor in the design of new anti-MRSA agents.

In silico studies, X-ray diffraction analysis and biological investigation of fluorinated pyrrolylated-chalcones in zebrafish epilepsy models

“…To further validate the in-silico results, ( E )-3-(3,5-difluorophenyl)-1-(1 H -pyrrol-2-yl)prop-2-en-1-one (compound 8 ) was selected for synthesis. Compound 8 was chemically prepared by a one-pot base-catalyzed Claisen-Schmidt condensation reaction [ 21 ] and structurally characterized using X-ray crystallography technique.…”

“…The synthesis was adapted based on [ 21 ], where the predicted active antiepileptic chalcone, compound 8 , was synthesized by a one-pot Claisen-Schmidt condensation reaction, purified and structurally characterized single crystal X-ray diffraction technique. Synthetically, 2 mmol of 2-acetylpyrrole (0.22 g) and 3,5-difluorobenzaldehyde (218 μL) were dissolved in 5 mL of 95% ethanol and the mixture was stirred for 5 min, followed by the dropwise addition of 1 mL of NaOH (6 M).…”

A Review on Five and Six-Membered Heterocyclic Compounds Targeting the Penicillin-Binding Protein 2 (PBP2A) of Methicillin-Resistant Staphylococcus aureus (MRSA)

“…ADMET investigation revealed that these compounds are non-toxic and exhibit a high rate of oral absorption. Although allosteric site inhibition against doubly mutant PBP2a was explored using quinazolinone (QNZ) pharmacophore screening, it exhibited lower binding affinity compared to the reported molecules mentioned below [148][149][150].…”

“…Figure 11. (A) Novel structure of 1,2,4-Oxadiazole-containing derivatives[150]. (B) Synthesis route for 1,2,4-oxadiazole-containing derivatives.…”

Crystal structure and Hirshfeld surface analysis of 3-(3-hydroxyphenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-one hemihydrate

“…Chalcone analogues have been reported with a wide range of biological activities, including anti-inflammatory, antimicrobial, and anticancer properties (Kar Mahapatra et al, 2019;Lin et al, 2002;Nowakowska, 2007). Recently, we discovered a new promising anti-microbial candidate, 3-(3hydroxyphenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-one (3HPPP), which showed remarkable inhibitory activity on methicillin-resistant Staphylococcus aureus (MRSA, ATCC 700699) with MIC and MBC values of 0.23 mg ml À1 and 0.47 mg ml À1 , respectively (Gunasekharan et al, 2021). However, as yet the crystal structure of this compound has remained elusive.…”