ANTIBACTERIAL, ANTI-BIOFIL AND ANTI-QUORUM-SENSING ACTIVITIES OF PYRIMIDINE-QUINOLONE HYBRIDS

FLORENCIA MARTINEZ; ADELA M. LUJAN; IVAN DÍAZ; JUSTO COBO; RICARDO DANIEL ENRIZ; MARÍA CECILIA CARPINELLA

Los cocos

Congreso; XVII Congreso Argentino de Microbiología General; 2022

Sociedad Argentina de Microbiología General

Antibacterial resistance is a growing concern in health care due to the lack of effective antibacterial therapeutic entities. One attractive strategy to tackle bacterial infections is to inhibit biofilm formation and the production of virulence factors that are regulated by the Quorum Sensing (QS) system. Among the potential entities showing effectiveness against these targets, molecular hybrids containing promising pharmacophores arise as encouraging agents. Under this scenario, the antibacterial, anti-biofilm and anti-QS activities of a series of 28 synthetic quinolone-pyrimidine hybrids were evaluated. These compounds contain a hydrophobic tail (p-chlorophenyl or naphthyl) attached to a pyrimidine, scaffold linked by 1-phenylpropenone, a piperazine ring or an aminophenyl fragment, to a polar head of a quinolone. The antibacterial activity was determined against the Gram-positive bacteria Staphylococcus aureus methicillin sensitive and resistant (MSSA and MRSA) and Bacillus subtilis; and the Gram-negative bacteria Pseudomonas aeruginosa and Escherichia coli. Compounds 43, 68, 73, 77, 78, and 79 showed to be effective against MSSA, MRSA and B. subtilis. Compound 78 was the most potent against MSSA (MIC= 4 µg/mL) and B. subtilis (MIC= 8 µg/mL). Compounds 68, 73 and 79 inhibited E. coli growth, being 68 the most active (MIC= 16 µg/mL). Since compounds with MIC values lower than 10 μg/mL are considered as very interesting, the here obtained results are encouraging. Preliminary structure-activity relationship analysis established that any of the compounds with antibacterial activity harbored the quinoline group or 1-phenylpropanone as a linker. In addition, it was found that the naphthalene ring as a substituent in the hydrophobic portion of the molecule showed advantages over p-chlorophenyl. A bactericidal effect was observed for compounds 68, 78 and 79 by time-kill curves in S. aureus. On the other hand, compounds 43, 68, 77, 78 and 79 showed anti-biofilm effects on MSSA, while compound 68 inhibited the formation of E. coli biofilm. Surprisingly, compounds 56, 95 and 113 inhibited MSSA biofilm formation; however these were not active on MSSA planktonic cells. The same was observed in compound 42 against E. coli. Compound 78 showed biofilm prevention concentration (BPC) of 8 µg/mL and a minimum biofilm eradication concentration (MBEC) of 16 µg/mL. For E. coli the most active anti-biofilm compound was 68 (BPC= 8 µg/mL). None of the compounds showed P. aeruginosa anti-biofilm activity. Interestingly, any of the 28 compounds showed anti-QS activity in S. aureus (QS regulated hemolysin production) and in P. aeruginosa (QS regulated pyocyanin production). Our results suggest that compounds 68, 78 and 79 could serve as promising leads for the development of new antibacterial agents to treat infections caused by planktonic and sessile S. aureus and E. coli cells. Further studies will be performed to elucidate the mechanism of action of each compound.