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Different classes of antimicrobial compounds such as β-lactams, sulfonamides, aminoglycosides, tetracyclines, quinolines and others have been developed during the 20th century to control the growing antimicrobial resistance. Therefore, there is an urgent need to build up new and effective antimicrobial agents with different working mechanisms to suppress this resistance. Accordingly, the judicious design of antimicrobial organic compounds with antiquorum-sensing activities could be a major solution for this global challenge. Herein, the versatile precursor 6-allyl-3-formyl-4H-benzo[h]chromen-4-one (2) was used for the synthesis of various isolated and condensed naphthoyl or (chromenyl) nicotinonitriles, azalactone, thiazolidinone, xanthene, indenopyridine, Schiff bases, diazepine, imidazole and triazolopyrimidine derivatives 5-21via its reactions with several active carbon nucleophiles in addition to amines, benzil and hydrazine. Some of the newly synthesized compounds showed moderately and good antimicrobial activities. The compounds 2 and 14 were the best concerning effects. In addition, the antiquorum-sensing activities of the newly prepared compounds were assessed against Chromobacterium violaceum. Specifically, pharmaceutical evaluation, antimicrobial prediction, and molecular docking using computational tools illustrated that the complexes of the latter compounds may show substantial antimicrobial activity in comparison with the other derivatives.

Thesis AbstractBackground: Heterocyclic are known to have multiple applications in particular biomedical settings. Aim: The present study reports a convenient protocol for the design and synthesis of new heterocyclic compounds incorporating 1- hydroxy-naphthyl and new angular chromones bearing allylnaphthyl fragments. Materials and Methods: The versatile precursor 2-acetyl-4- allyl-1-hydroxy naphthalene was subjected to Claisen-Schmidt condensation but the precursor 6-allyl-3-formyl-4H-benzo[h]chromone was prepared via Vilsmeier–Haack reaction of 4-allyl-1- hydroxy-2-acetonaphthone. Results: Some new compounds are considered as promising leads with dual biological activity as antibacterial and antioxidant. The isoalloxazine ring of the cofactor FAD is essential to the recognition of the compound that has proper antioxidant activity. Benzocoumarin ring is essential for the recognition of the amino acid residues. Allyl chain improves the p stacking interaction while the n-propyl chain attenuates the overall interaction. Naphthyl ring needs to be substituted with a short bridge to avid the ring extended away from the pocket. The antimicrobial and antiquorum-sensing activities of the newly synthesized compounds showed that many compounds have good and promising activities in comparison with the reference drugs. Conclusion: Based on the computational prediction of pharmacokinetics, drug-likeness properties, biological activity, and molecular docking suggested that formyl chromone and tetracarbonyl may be potent antimicrobial drugs

The present study reports a convenient protocol for the design and synthesis of new heterocyclic compounds incorporating 1- hydroxy-naphthyl and new angular chromones bearing allylnaphthyl fragments. The versatile precursor 2-acetyl-4- allyl-1-hydroxy naphthalene was subjected to Claisen-Schmidt condensation but The precursor 6-allyl-3-formyl-4H-benzo[h]chromone was prepared via Vilsmeier–Haack reaction of 4-allyl-1- hydroxy-2-acetonaphthone.Some new compounds are considered as promising leads with dual biological activity as antibacterial and antioxidant. The isoalloxazine ring of the cofactor FAD is essential to the recognition of the compound that has proper antioxidant activity. Benzocoumarin ring is essential for the recognition of the amino acid residues. Allyl chain improves the p stacking interaction while the n-propyl chain attenuates the overall interaction. Naphthyl ring needs to be substituted with a short bridge to avid the ring extended away from the pocket.The antimicrobial and antiquorum-sensing activities of the newly synthesized compounds showed that many compounds have good and promising activities in comparison with the reference drugs. Computational prediction of pharmacokinetics, drug-likeness properties, biological activity, and molecular docking suggested that formyl chromone and tetracarbonyl may be potent antimicrobial drugs.

Multitarget-directed drugs (hybrid drugs) constitute an efficient avenue for the treatment of multifactorial diseases. In this work, novel naphthalene hybrids with different heterocyclic scaffolds such as nicotinonitrile, pyran, pyranopyrazole, pyrazole, pyrazolopyridine, and azepine were efficiently synthesized via tandem reactions of 3-formyl-4H-benzo[h]chromen-4-one 1 with different nucleophilic reagents. Analysis of these hybrids using PASS online software indicated different predicted biological activities such as anticancer, antimicrobial, antiviral, antiprotozoal, anti-inflammatory, etc. By focusing on antitumor, anti-inflammatory, and antituberculosis activities, many compounds revealed remarkable activities. While 3c, 3e, and 3h were more potent than doxorubicin in the case of HepG-2 cell lines, 3a–e, 3i, 6, 8, 10, 11, and 12b were more potent in the case of MCF-7. Moreover, compounds 3c, 3h, 8, 10, 3d, and 12b manifested superior activity and COX-2 selectivity to the reference anti-inflammatory Celecoxib. Regarding antituberculosis activity, 3c, 3d, and 3i were found to be the most promising with MIC less than 1 μg mL−1. The molecular docking studies showed strong polar and hydrophobic interactions with the novel naphthalene-heterocycle hybrids that were compatible with experimental evaluations to a great extent.

The versatile precursor 2-acetyl-4-allyl-1-hydroxy naphthalene was synthesized efficiently via Claisen rearrangement 2-acetyl-1-allyloxynaphthalene. The Claisen-Schmidt condensation of latter precursor afforded the corresponding chalcones which were exploited to synthesize a series of potential heterocycles such as pyrazoline, isoxazoline, benzocoumarin and benzoflavone. The synthesized products showed potent antioxidant and antimicrobial activities. Chalcone 3c, naphthyl pyrazoline 6b and hydroxycoumarin 13 exhibited the highest activity as antioxidants. Their binding mode showed specialized recognition of hydroxycoumarin 13 with the triad key amino acids at the active site of the oxidoreductase enzyme (PDB code 1DXO). 1-Hydroxynaphth-2-yl pyrazoline (6b) revealed the highest efficacy against both Gram positive and negative bacterial species. In silico molecular docking of pyrazoline 6b endorsed its proper binding at the active site of the 2EX6 enzyme which explains its potent antibacterial activity in comparison with standard ampicillin. Keywords: Hydroxyacetyl, heterocycle, Naphthyl, Biological, Docking, 1DXO active site

A new promising protocol has been developed for the synthesis of scarce oxocine derivatives 3a–e and 6 through addition of amine-based nucleophiles such as hydroxylamine hydrochloride, primary amine and hydrazide to chromonylidene benzothiazol-2-ylacetonitrile 2 in refluxing dioxane under metal free reaction conditions in moderate to good yields. Other nitrogen nucleophiles such as piperidine, hydrazine and thiosemicarbazide failed to afford the corresponding oxocinols, and instead pyridine derivatives 7, 8 and 10 were obtained exclusively. Predictive study for the biological activities using PASS (prediction of activity spectra for biologically active substances) online software showed optimistic activities for oxocinols 3a–e in the treatment of cancer, influenza A and microbial infections. Additionally, DFT studies of oxocine derivatives 3a–e and 6 indicated the presence of required thermodynamics parameters for the application in dye-sensitized solar cells (DSSCs).