Synthesis, characterization, in silico molecular docking, and antibacterial activities of some new nitrogen-heterocyclic analogues based on a p-phenolic unit.

Nitrogen-containing heterocycles have shown pharmacological properties against various diseases. Herein, in our study, flavoHB enzyme is a highly promising well-validated target for identification of antibacterial inhibitors using in silico and in vitro techniques. To identify a new class of antimicrobial agents, N-(4-hydroxyphenyl)-3-oxobutanamide was utilized as a precursor in the synthesis of several nitrogen-based heterocycles (pyridine, pyrimidine, and pyrazole) attached to p-phenolic substrates 2-8. Treatment of 3-oxobutanimide 1 with malononitrile and/or ethyl cyanoacetate in ethanolic piperidine afforded the pyridinone analogues 2a,b. On the other hand, treatment of 1 with arylidene cyanothioacetamide furnished the pyridinthione derivative 3. The reaction of starting material 1 with salicylaldehyde and/or dimethyl formamide dimethyl acetal (DMF-DMA) yielded the pyridinones 4 and 5, respectively. Reaction of 1 with terephthalaldehyde and urea or thiourea gave bis structures 6a,b. The reaction of compound 1 with ethyl isothiocyanate and hydrazine hydrate afforded pyrimidine and pyrazole derivatives 7 and 8, respectively. The structures of newly prepared compounds 2-8 were elucidated using elemental data and spectral analyses such as IR, 1H NMR, 13C NMR, and MS. In addition, an in-house nitrogen-containing heterocycle analogues library 2-8 was examined and screened in vitro for their antibacterial effects against Gram-negative bacteria, Escherichia coli and Gram-positive bacteria, Staphylococcus haemolyticus, Kocuria kristinae, Enterococcus casseliflavus, and Bacillus cereus. Compounds 6a and 6b have also shown the highest antibacterial activity against all types of bacteria strains tested except Kocuria kristinae. Further, the molecular docking study of the newly prepared compounds with the target enzyme flavohemoglobin (flavoHB) was undertaken to explore their potential inhibitory activities. The results of the docking study indicated that compounds 6a and 6b have exerted the highest docking scores against the active site of flavoHB. As a result, the in vitro and molecular docking study findings suggested that the compounds 6a and 6b (with pyrimidine moiety, amide linkage, and phenolic substrate) might be potent bacterial flavohemoglobin (flavoHB) inhibitors and they could set a promising starting point for future design of antibacterial agents.

Eco-Friendly Synthesis, Biological Evaluation, and In Silico Molecular Docking Approach of Some New Quinoline Derivatives as Potential Antioxidant and Antibacterial Agents.

A new series of quinoline derivatives 5-12 were efficiently synthesized via one-pot multicomponent reaction (MCR) of resorcinol, aromatic aldehydes, ß-ketoesters, and aliphatic/aromatic amines under solvent-free conditions. All products were obtained in excellent yields, pure at low-cost processing, and short time. The structures of all compounds were characterized by means of spectral and elemental analyses. In addition, all the synthesized compounds 5-12 were in vitro screened for their antioxidant and antibacterial activity. Moreover, in silico molecular docking studies of the new quinoline derivatives with the target enzymes, human NAD (P)H dehydrogenase (quinone 1) and DNA gyrase, were achieved to endorse their binding affinities and to understand ligand-enzyme possible intermolecular interactions. Compound 9 displayed promising antioxidant and antibacterial activity, as well as it was found to have the highest negative binding energy of -9.1 and -9.3 kcal/mol for human NAD (P)H dehydrogenase (quinone 1) and DNA gyrase, respectively. Further, it complied with the Lipinski's rule of five, Veber, and Ghose. Therefore, the quinoline analogue 9 could be promising chemical scaffold for the development of future drug candidates as antioxidant and antibacterial agents.

Multifunctional Isosteric Pyridine Analogs-Based 2-Aminothiazole: Design, Synthesis, and Potential Phosphodiesterase-5 Inhibitory Activity.

The elaboration of new small molecules that target phosphodiesterase enzymes (PDEs), especially those of type 5 (PDE5), is an interesting and emerging topic nowadays. A new series of heterocycle-based aminothiazoles were designed and synthesized from the key intermediate, 3-oxo-N-(thiazol-2-yl)butanamide (a PDE5 inhibitor that retains its amidic function), as an essential pharmacophoric moiety. The PDE5 inhibitors prevent the degradation of cyclic guanosine monophosphate, thereby causing severe hypotension as a marked side effect. Hence, an in vivo testing of the target compounds was conducted to verify its relation with arterial blood pressure. Utilizing sildenafil as the reference drug, Compounds 5, 10a, and 11b achieved 100% inhibitions of PDE5 without significantly lowering the mean arterial blood pressures (115.95 ± 2.91, 110.3 ± 2.84, and 78.3 ± 2.57, respectively). The molecular docking study revealed that the tested compounds exhibited docking poses that were similar to that of sildenafil (exploiting the amide functionality that interacted with GLN:817:A). The molecular shape and electrostatic similarity revealed a comparable physically achievable electrostatic potential with the reference drug, sildenafil. Therefore, these concomitant results revealed that the tested compounds exerted sildenafil-like inhibitory effects (although without its known drawbacks) on blood circulation, thus suggesting that the tested compounds might represent a cornerstone of beneficial drug candidates for the safe treatment for erectile dysfunction.

Design, synthesis and biological evaluation of new 2-aminothiazole scaffolds as phosphodiesterase type 5 regulators and COX-1/COX-2 inhibitors.

A new series of 2-aminothiazole derivatives was designed and prepared as phosphodiesterase type 5 (PDE5) regulators and COX-1/COX-2 inhibitors. The screening of the synthesized compounds for PDE5 activity was carried out using sildenafil as a reference drug. Strikingly, compounds 23a and 23c were found to have a complete inhibitory effect on PDE5 (100%) at 10 µM without causing hypotension and the limited side effect of PDE5 inhibitors, suggest a distinctive therapeutic role of these derivatives in erectile dysfunction. On the other hand, compounds 5a, 17, 21 and 23b increased the PDE5 activity (PDE5 enhancers) at 10 µM. In addition, the study includes the screening of the COX-1/COX-2 inhibition induced by the synthesized compounds. All tested compounds have an inhibitory effect against COX-1 activity (IC50 = 1.00-6.34 µM range) and COX-2 activity (IC50 = 0.09-0.71 µM range). Moreover, a molecular docking study was implemented to reveal the binding interactions of potent compounds in the binding sites of PDE5 (PDB ID 2H42), COX-1 and COX-2 (PDB ID 3LN1) enzymes. For the interaction with the PDE5 enzyme, activator compounds had a strong binding mode (HB with Gln817:A) than inhibitory derivatives. Both types of compounds are considered as PDE5 regulators. This novel finding will encourage us to discover a new pharmacological application of small chemical entities as the PDE5 enhancer, or will lower side effects as PDE5 inhibitors. All active compounds adopted the Y-shape along the COX-2 active site.