Influence of Open Chain and Cyclic Structure of Peptidomimetics on Antibacterial Activity in E. coli Strains

Abstract

An efficient method for the synthesis of functionalized peptidomimetics via multicomponent Ugi reaction has been developed. The application of trifluoroethanol (TFE) as a reaction medium provided desired products with good yields. Further, using the developed cyclisation reaction, the obtained peptidomimetics were transformed into the cyclic analogues (diketopiperazines, DKPs). The goal of the performed studies was to revised and compare whether the structure of the obtained structurally flexible acyclic peptidomimetics and their rigid cycling analogue DKPs affect antimicrobial activity. We studied the potential of synthesized peptidomimetics, both cyclic and acyclic, as antimicrobial drugs on model E. coli bacteria strains (k12, R2–R4). The biological assays reveal that DKPs hold more potential as antimicrobial drugs compared to open chain Ugi peptidomimetics. We believe that it can be due to the rigid cyclic structure of DKPs which promotes the membrane penetration in the cell of studied pathogens. The obtained data clearly indicate the high antibiotic potential of synthesized diketopiperazine derivatives over tested antibiotics.

Promiscuous Lipase-Catalyzed Knoevenagel–Phospha–Michael Reaction for the Synthesis of Antimicrobial β-Phosphono Malonates

“…All selected analyzed β-phosphonate derivatives ( Figure 3 ) with different substituents located at the phenyl ring are responsible for the change of the topology of bacterial DNA. After digestion with Fpg, approximately 3.5% of oxidative damage was identified, which very strongly indicates oxidative damage in bacterial DNA, similar to the previous observations [ 71 , 72 , 73 , 74 ].…”

“…All selected analyzed derivatives of β-phosphonate derivatives, including various types of alkoxy groups, substituents located at aromatic rings, and the length of the alkyl chain, can strongly change the bacterial DNA topology. After Fpg digestion, approximately 3.5% of the oxidative damage was identified, which, similar to previous observations, indicates very strong oxidative damage in bacterial DNA [ 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ]. Different types of alkoxy groups, substituents located on the aromatic ring and the length of the alkyl chain, may determine the toxicity of the analyzed E. coli strains, including, in particular, R4, as evidenced by the obtained MIC, MBC, and MTT values.…”

The Synthesis and Evaluation of Diethyl Benzylphosphonates as Potential Antimicrobial Agents

“…Based on the observed results in the MIC and MBC tests, it was found that the analyzed compounds significantly influenced the defragmentation of the membrane and the structure of the cell wall of bacteria containing LPS of various lengths [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 28 , 29 , 30 , 31 ], causing oxidative stress to damage and modification of bacterial DNA. This was further confirmed by the digestion with a specific enzyme Fpg of modified bacterial DNA (Labjot, New England Biolabs, UK), recognizing oxidized guanine and adenine.…”

“…This was further confirmed by the digestion with a specific enzyme Fpg of modified bacterial DNA (Labjot, New England Biolabs, UK), recognizing oxidized guanine and adenine. The obtained values of oxidative damage, after digestion with the Fpg protein in the bacterial DNA, were compared with the modifications of the bacterial DNA after treatment with antibiotics such as ciprofloxacin, bleomycin and cloxacillin [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 28 , 29 , 30 , 31 ] ( Figure 6 ). The presented research shows that diethyl benzylphosphonate derivatives can be used in the future as typical “substitutes” for new drugs in relation to the antibiotics used in hospital infections.…”

“…Recently, we have focused our attention on the development of new potent antimicrobial drugs [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ] including organophosphonates [ 17 , 18 ]. We have developed several efficient protocols toward the synthesis of this class of compounds, including selective esterification of phosphonic acids [ 19 , 20 ], lipase-catalyzed Kabachnik-Fields [ 18 ] and Pudovik reactions [ 17 , 21 ].…”