Antimicrobial Pyridazines: Synthesis, Characterization, Cytotoxicity, Substrate Promiscuity, and Molecular Docking

Abstract

A facile and convenient synthesis of new pyridazines suitable for use as antimicrobial agents was reported. The hydrazide intermediate was coupled with various benzaldehydes and/or acetophenones and cyclized instantaneously to afford target pyridazine derivatives. The structures of new pyridazines were confirmed by IR, 1H‐ and 13C‐NMR, elemental analysis in addition to representative LC/MS. Antimicrobial activity was screened against 10 bacterial and fungal strains. The new pyridazines showed strong to very strong antibacterial activity against Gram‐negative (GNB) bacteria, while none of them showed significant antifungal activity at the same concentration range. Chloro derivatives exhibited the highest antibacterial activity with MICs (0.892–3.744 μg/mL) lower than that of chloramphenicol (2.019–8.078 μg/mL) against E. coli, P. aeruginosa, and S. marcescens. Prediction of ADME parameters, pharmacokinetics, and substrate promiscuity revealed that these new pyridazines could be promising drug candidates. Cytotoxic studies on rat hepatocytes showed how much safe these new pyridazines on living organisms (IC50>64 μg/mL). MOE docking studies showed a good overlay of these new pyridazines with co‐crystallized ligand within an E. coli DNA gyrase subunit B active sites (4KFG).

In vitro inhibition and molecular docking of a new ciprofloxacin‐chalcone against SARS‐CoV‐2 main protease

“…Lipinski rule parameters and drug-likeness properties were calculated by the Swiss ADME predictor (http:// www.swiss adme.ch/) and PreADMET server (https:// pread met.bmdrc.kr/adme). [39][40][41][42] The entry of the structures of the ciprofloxacin and its chalcone was through their smiles. These properties comprise molecular weight (MW), number of hydrogen-bond acceptors (HBA) and donors (HBD), rotatable bonds (nrotb), lipophilicity (ilogP) and topological polar surface area (TPSA).…”

Base Promoted Three-Component Annulation of 4-Diazoisochroman-3-imines with Dimethylsulfonium Ylides: Synthesis of Highly Functionalized Isochromeno[4,3-c]pyridazines

“…They have numerous applications as chemo-luminescent materials, photovoltaic materials, ligands for heterogeneous catalysis, nonlinear optical materials, and in supramolecular chemistry . Moreover, the pyridazine ring system has been considered as one of the best for drug design by GlaxoSmithKline, as incorporation of pyridazine ring into medically active drugs leads to the formation of new diazines having promising pharmacological activities . Some examples of medicinally important pyridazine derivatives with various biological activities like anticancer, anti-inflammatory, anticonvulsant, antimicrobial, cytotoxic, and antifungal are shown in Figure …”

TBAI/K2S2O8-Promoted [4 + 2] Annulation of Ketene N,S-Acetals and N-Tosylhydrazones toward Pyridazines

“…The pyridazine ring is a special six-membered heterocycle similar to a phenyl ring with two nitrogen atoms at the adjacent positions, and about 50% of medicinally active drugs display a wide range of pharmacological activities. Replacing a phenyl ring with a pyridazine ring offers a new method to synthesize different drugs with potential biological and medicinal activities . In addition, the pyridazine ring has been ranked by many pharmaceutical companies as one of the best potential heterocycles for designing new drugs .…”

“…Replacing a phenyl ring with a pyridazine ring offers a new method to synthesize different drugs with potential biological and medicinal activities. 2 In addition, the pyridazine ring has been ranked by many pharmaceutical companies as one of the best potential heterocycles for designing new drugs. 3 Nowadays, many functional molecules employ pyridazine rings as the main component of their structures (Figure 1).…”

“…13 Recently, Zhai's group synthesized pyridazines from a ring-contractive extrusion reaction of thiadiazepine S-oxides. 14 He, 15 Volkova, 4b Mostafa, 2 and Nikolaev et al 16 also described colorful procedures to pyridazines. Although numerous efforts have been documented to synthesize pyridazines, most of these methods are limited to employing prefunctionalized substrates, utilizing toxic and unstable reagents, and multistep sequences.…”