Novel 2,4-Dichloro-5-sulfamoylbenzoic Acid Oxime Esters: First Studies as Potential Human Carbonic Anhydrase Inhibitors.

In this study, a focused library of oxime ester derivatives of 2,4-dichloro-5-sulfamoylbenzoic acid (lasamide) containing Schiff bases was synthesized and tested in vitro for their ability to inhibit the cytosolic human carbonic anhydrases (hCAs) I and II, as well as the transmembrane and tumor-associated IX and XII isoforms. As a result, we obtained a first line of knowledge on lasamide derivatives potentially useful for development as CA inhibitors (CAIs). In particular, we focused our attention on the derivative 11, which was selective toward hCAs IX and XII over the cytosolic isoenzymes. An in silico study was conducted to assess the binding mode of 11 within hCAs IX and XII. Also, antiproliferative assays highlighted promising derivatives. The data obtained in this study are currently in use for the development of better-performing compounds on the tumor-associated isoforms.

High-throughput computational screening for identification of potential hits against bacterial Acriflavine resistance protein B (AcrB) efflux pump.

Antibiotic resistance is a pressing global health challenge, driven in part by the remarkable efflux capabilities of efflux pump in AcrB (Acriflavine Resistance Protein B) protein in Gram-negative bacteria. In this study, a multi-approached computational screening strategy encompassing molecular docking, In silico absorption, distribution, metabolism, excretion and toxicity (ADMET) analysis, druglikeness assessment, molecular dynamics simulations and density functional theory studies was employed to identify novel hits capable of acting against AcrB-mediated antibiotic resistance. Ligand library was acquired from the COCONUT database. Performed computational analyses unveiled four promising hit molecules (CNP0298667, CNP0399927, CNP0321542 and CNP0269513). Notably, CNP0298667 exhibited the highest negative binding affinity of -11.5 kcal/mol, indicating a possibility of strong potential to disrupt AcrB function. Importantly, all four hits met stringent druglikeness criteria and demonstrated favorable in silico ADMET profiles, underscoring their potential for further development. MD simulations over 100 ns revealed that the CNP0321542-4DX5 and CNP0269513-4DX5 complexes formed robust and stable interactions with the AcrB efflux pump. The identified hits represent a promising starting point for the design and optimization of novel therapeutics aimed at combating AcrB-mediated antibiotic resistance in Gram-negative bacteria.Communicated by Ramaswamy H. Sarma.

Synthesis of Novel Hydrazones of Levofloxacin Related Molecule and their In Vitro Evaluation as Antioxidant, and Molecular Docking Studies.

OBJECTIVE: The research work aims to synthesize novel series of hydrazones and antioxidant screening. It also aims to evaluate the binding affinities and in silico methods for identifying possible drug targets of synthesized compounds. METHODS: This report briefly explains the synthesis of a novel series of hydrazones. It was synthesized via. hydrazinolysis of esters to obtain hydrazide, treated with aldehyde and acetophenone to get hydrazones. The spectral confirmed hydrazones exhibited excellent to comparable anti-oxidant as compared to the standard drugs Butylated hydroxytoluene (BHT) and Ascorbic acid. Molecular docking on myeloperoxidase (MPO) demonstrated the ability of this scaffold to correctly recognize the target and engage in significant bonded and non-bonded interactions with key residues therein. RESULTS AND DISCUSSION: In this study, we report effectively synthesized compounds BK-35, BK- 41, BK-26, BK-28, and BK-39 that showed the best DPPH radical scavenging activity. The docking results clearly showed the binding mode of hydrazones into the active site of Myeloperoxidase (MPO). In in-silico results, none of the synthesized compounds, BK-24 to BK- 41, violated Lipinski's rule of five (miLog P ≤ 5). CONCLUSIONS: In vitro preliminary anti-oxidant screening results in support by in Silico binding affinity data of novel hydrazones of levofloxacin related molecules BK-24 to BK-41 reported here have emerged as excellent anti-oxidant agents. The inference derived from the in vitro anti-oxidant screening data and the quantitative insights derived from the per-residue interaction analysis with MPO enzyme are now being fruitfully utilized for site-specific mutation around the nucleus to identify selective and potent anti-oxidants.

Efficient Synthesis of Potential Impurities in Levonadifloxacin (WCK 771).

Levonadifloxacin (WCK 771) is a novel broad-spectrum anti-methicillin-resistant Staphylococcus aureus (MRSA) agent recently launched in India. Five process impurities and one degradation impurity were synthesized as reference standards for their quantification by high-performance liquid chromatography (HPLC) methodology in drug substance and drug product. These compounds are not easily commercially available. The synthesis and characterization of these impurities are discussed in detail.