Novel Guanidine Compound against Multidrug-Resistant Cystic Fibrosis-Associated Bacterial Species

Abstract

Chronic pulmonary infection is a hallmark of lung disease in cystic fibrosis (CF). Infections dominated by non-fermentative Gram-negative bacilli are particularly difficult to treat and highlight an urgent need for the development of new class of agents to combat these infections. In this work, a small library comprising thiourea and guanidine derivatives with low molecular weight was designed; these derivatives were studied as antimicrobial agents against Gram-positive, Gram-negative, and a panel of drug-resistant clinical isolates recovered from patients with CF. One novel compound, a guanidine derivative bearing adamantane-1-carbonyl and 2-bromo-4,6-difluouro-phenyl substituents (H-BDF), showed potent bactericidal activity against the strains tested, at levels generally higher than those exhibited by tobramycin, ceftazimide and meropenem. The role that different substituents exert in the antimicrobial activity has been determined, highlighting the importance of the halo-phenyl group in the guanidine moiety. The new compound displays low levels of cytotoxicity against THP-1 and A549 cells with a selective index (SI) > 8 (patent application PCT/IB2017/054870, August 2017). Taken together, our results indicate that H-BDF can be considered as a promising antimicrobial agent.

Densely substituted piperidines as a new class of elastase inhibitors: Synthesis and molecular modeling studies

“…Previous research showed that lipophilicity is a fundamental property to improve compound efficacy and leads to new potential drug candidates . The lipophilicity prediction of LE, LLE, and LELP and their proposed acceptable standard values were reported for LE (>~0.30 Kcal/mole/HA) and LLE (>~0.5 Kcal/mol) . The predicted LE values of synthesized compounds showed comparable results with the standard value.…”

“…A single π–π bond was observed between the benzene of the ligand and His57 having a bond length of 4.50 Å (Figure ). Literature data also ensured the importance of these residues in bonding with other elastase inhibitors, which strengthens our docking results . The comparative binding energy and SAR analysis showed the significance of 4i ,which may be considered as a potent inhibitor by targeting porcine pancreatic elastase.…”

“…Literature data also ensured the importance of these residues in bonding with other elastase inhibitors, which strengthens our docking results. [34,35] The comparative binding energy and SAR analysis showed the significance of 4i, which may be considered as a potent inhibitor by targeting porcine pancreatic elastase. Ethyl 2,6-bis(4-trifluoromethyl)phenyl)-1,2,5,6-tetrahydro-1-phenyl-…”

“…Radical scavenging activity was carried out using a 2,2-DPPH assay. [34] 4.3 | In silico methodology 4.3.1 | Retrieval of porcine pancreatic elastase structure…”

Synthesis, Characterization, Anticancer and Antimicrobial Activity Studies of Novel Isomeric 2,4‐Disubstituted Ureide Derivatives of Pyrimidinopiperidines

“…Similarly, the compounds 5B, 5E, 5H, 5 J, 5 K, 5 L exhibited maximum activity on all bacterial strains which may be due to the presence of halo groups on the phenyl ring. Recently, Lamberti et al . designed a small library of molecules comprising thiourea and guanidine derivatives and studied their antimicrobial activities against Gram‐positive and Gram‐negative bacteria along with a panel of drug‐resistant clinical isolates, but these compounds did not showed significant activity, but only one guanidine derivative having adamantane‐1‐carbonyl and a phenyl group substitution at ‘S’ with 2‐bromo‐4,6‐difluoro substituents showed comparable activity with standard drugs.…”