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

• Published in: ChemistrySelect (Weinheim) 2020-03, Vol.5 (11), p.3445-3453
• Main Authors: El Sayed, Mardia T., Sarhan, Alaadin E., Ahmed, Entsar, Khattab, Reham R., Elnaggar, Mohamed, El‐Messery, Shahenda M., Shaldam, Moataz A., Hassan, Ghada S.
• Format: Article
• Language: English
• Subjects: Antimicrobial agents, docking studies, MRSA, nitro compounds, pyruvate kinase
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.202000043

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. Methicillin‐resistant S. aurues (MRSA) represents a great challenge for all researchers to discover chemotherapeutic agent that is able to beat this organism. A new technique targeting pyruvate kinase enzyme that is crucial in glycolysis process was adopted. An efficient method for the synthesis of some novel Mannich bases was performed. Full characterization and biological screening were performed for the target compounds to ensure activity.