Novel Pyruvate Kinase (PK) Inhibitors: New Target to Overcome Bacterial Resistance

Abstract

In the present investigation, some novel nitro Mannich bases derived from Michael type addition of activated nitro olefin, β‐nitrostyrene with various amines either primary or secondary including some amino sugars were designed and synthesized. The produced Mannich bases have been full characterized through different spectroscopic techniques. Antimicrobial evaluation has been performed against the Gram positive S. aureus and methicillin‐resistant S. aurues (MRSA) infections. 5 of the synthesized compounds represent the best candidates in the biological screening, they have exhibited good activity with MIC values range from 100 to 250 μg/ml. The active agents have been tested for pyruvate kinase inhibition activity with % of inhibition range from 30 to 79 % with IC50 in a nano molar range. They also exhibited significant Pyruvate kinase inhibition in nanomolar range with IC50 of 1066, 662, 1887, 418 and 1128 ng/ml, respectively (versus 196 ng/ml for AZD7545). Molecular docking calculations for active agents were performed. A complete conformational analysis molecular modeling utilizing Gaussian 09 program (HF/DFT) was used to verify the mode of bonding through the optimized geometries as well as essential quantum parameters were calculated using frontier energies (EHOMO & ELUMO) for the active candidates indicating the overall stability of the structure.

Bacterial Pyruvate Kinase: A New Potential Target to Combat Drug‐Resistant Staphylococcus aureus Infections

“…Compound 13 e demonstrated PK independent bacteriostatic and PK dependent bactericidal properties. [50] Other chemotypes such as 1,3-di(1H-indol-3-yl)-1,2,3,4tetrahydrocycloalka[b]indoles, [52] indole carboxamides, [51] phenyl indoles, [51] 2-heteryl indoles, [51] (4-(1H-indol-3-yl)thiazol-2-yl)(1Hindol-3-yl)methanones, [53] N-benzylbenzo[d]thiazol-2-amine, [51] and nitro mannich bases [55] demonstrated good to moderate inhibition against SAPK and whole S. aureus bacterial cells. ChemistrySelect…”

“…Sayed et al [55] reported synthesis of new mannich bases from βnitrostyrene through Michael type addition with different type of amines/amino sugars (Figure 16). Among them, nitro mannich bases 22 a and 22 b displayed moderate inhibition against bacterial PK with IC 50 662.98 ng/mL and 418.72 ng/mL, respectively.…”

“…Sayed et al [55] . reported synthesis of new mannich bases from β‐nitrostyrene through Michael type addition with different type of amines/amino sugars (Figure 16).…”

Synthesis, Antibacterial, and Antioxidant Activities of Thiazolyl-Pyrazoline Schiff Base Hybrids: A Combined Experimental and Computational Study

“…e synthesized compounds (16)(17)(18)(19)(20)(21)(22)(23)(24) were subjected to a molecular docking analysis to determine their binding affinity towards pyruvate kinase in a complex containing the natural bisindole alkaloid, and the results were compared to amoxicillin (SI Appendix D Figure S5(c), 1-10, and Table S9) [59,60]. It was found that the synthesized compounds have minimum binding energy in the range of is suggests that these compounds are effective antibacterial agents against S. aureus.…”

The Interference Mechanism of Basil Essential Oil on the Cell Membrane Barrier and Respiratory Metabolism of Listeria monocytogenes

“…At the same time, the ligand is hydrogenated, charged, and protonated. The active site of pyruvate kinase was prepared according to the study of El Sayed et al (2020). The platform is used to identify the binding site of phosphofructokinase.…”