Design, synthesis and biological evaluation of novel aryldiketo acids with enhanced antibacterial activity against multidrug resistant bacterial strains

Abstract

Antimicrobial resistance (AMR) is a major health problem worldwide, because of ability of bacteria, fungi and viruses to evade known therapeutic agents used in treatment of infections. Aryldiketo acids (ADK) have shown antimicrobial activity against several resistant strains including Gram-positive Staphylococcus aureus bacteria. Our previous studies revealed that ADK analogues having bulky alkyl group in ortho position on a phenyl ring have up to ten times better activity than norfloxacin against the same strains. Rational modifications of analogues by introduction of hydrophobic substituents on the aromatic ring has led to more than tenfold increase in antibacterial activity against multidrug resistant Gram positive strains. To elucidate a potential mechanism of action for this potentially novel class of antimicrobials, several bacterial enzymes were identified as putative targets according to literature data and pharmacophoric similarity searches for potent ADK analogues. Among the seven bacterial targets chosen, the strongest favorable binding interactions were observed between most active analogue and S. aureus dehydrosqualene synthase and DNA gyrase. Furthermore, the docking results in combination with literature data suggest that these novel molecules could also target several other bacterial enzymes, including prenyl-transferases and methionine aminopeptidase. These results and our statistically significant 3D QSAR model could be used to guide the further design of more potent derivatives as well as in virtual screening for novel antibacterial agents.

High-Throughput Experimentation and Continuous Flow Evaluation of Nucleophilic Aromatic Substitution Reactions

“…Nucleophilic aromatic substitution (S N Ar) reactions are versatile transformations in the organic chemistry arsenal, and one of the important reactions used for making pharmacologically , and biologically active molecules. − The reaction mechanism of this transformation , involves a stepwise addition–elimination sequence, − wherein the first step involves a nucleophilic attack of the substrate to provide a Meisenheimer complex, followed by the loss of the leaving group through either catalyzed or noncatalyzed pathways. − The reaction typically involves an amine as the nucleophile, although a wide variety of non-nitrogenous nucleophiles may be used. This study reports HTE evaluation of S N Ar reactions performed in both droplets/thin film and bulk microtiter formats with analysis by DESI-MS. After HTE evaluation, validation of the reaction hotspots were performed in flow to increase confidence in the HTE findings (Scheme ).…”

Antibacterial Discovery: 21st Century Challenges

“…Crystal structure of the enzyme is crucial in this process and in silico screening of chemical libraries becomes an early first step in finding developable leads. A number of recent examples can be used to guide this process [17,37,38]. The power of computational biology and chem-informatics has yet to be fully exploited, so this area has room to grow.…”

Synthesis, recyclization under the action of methanol and analgetic activity of N'-(5-aryl-2-oxofuran-3(2H)-ylidene)furan-2-carbohydrazides

“…For example, the reactions of 3-imino-(hydrazinylidene)-furan-2(3H)-ones derivatives with various nucleophilic reagents lead to the attack on the carbonyl group of the lactone fragment and to the for-mation of acyclic or heterocyclic structures [16][17][18][19][20][21] that retain the pharmacophore fragment of 2,4-dioxobutanoic acid [22][23][24][25][26][27][28][29][30][31][32]. This fragment was found in the structure of various biologically active and natural compounds [33,34], which indicates that this idea is worth developing. Previously, we proposed a simple method for the preparation of 3-hydrazinylidenefuran-2(3H)-one derivatives by intramolecular cyclization of substituted 2-[2-(4-Rbenzoyl)hydrazinylidene]-4-oxobutanoic acids in the presence of acetic or propionic anhydride [35,36].…”