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(1) Background: A molecular hybridization docking approach was employed to develop and detect a new category of naturally activated compounds against Culex pipiens as acetylcholinesterase inhibitors via designing a one-pot multicomponent nano-delivery system. (2) Methods: A nanostructure lipid carrier (NLC), as a second generation of solid lipid nanoparticles, was used as a carrier to deliver the active components of curcumin (Cur), geraniol (G), and linalool (L) in one nanoformulation after studying their applicability in replacing the co-crystallized ligand imidacloprid. (3) Results: The prepared nanostructure showed spherical-shaped, polydisperse particles ranging in size from 50 nm to 300 nm, as found using a transmission electron microscope. Additionally, dynamic light scattering confirmed an average size of 169 nm and a highly stable dispersed solution, as indicated by the zeta potential (−38 mV). The prepared NLC-Cur-LG displayed competitive, high-malignancy insecticidal activity against fourth instar C. pipiens with an elevated rate of death of 0.649 µg/mL. The treatment, due to the prepared nanostructure, affects oxidative stress enzymes, e.g., hydrogen peroxide (4 ppm), superoxide dismutase (SOD) (0.03 OD/mg), and protein carbonyl (0.08 OD/mg), and there are observable upward and downward fluctuations when using different concentrations of NLC-Cur-LG, suggesting significant problems in its foreseeable insecticidal activity. The acetylcholinesterase activity was assessed by an enzyme inhibition assay, and strengthened inhibition occurred due to the encapsulated NLCs (IC50 = 1.95 µg/mL). An investigation of the gene expression by Western blotting, due to treatment with NLC-Cur-LG, revealed a severe reduction of nearly a quarter of what was seen in the untreated group. As a preliminary safety step, the nanoformulation's toxicity against normal cell lines was tested, and a reassuring result was obtained of IC50 = 158.1 µg/mL for the normal lung fibroblast cell line. (4) Conclusions: the synthesized nanoformulation, NLC-Cur-LG, is a useful insecticide in field conditions. [ABSTRACT FROM AUTHOR]

3-Bromoacetyl-4-(2-naphthoyl)-1-phenyl-1H-pyrazole (6) was synthesized from 2-acetylnaphthalene and was used as a new key building block for constructing the title targets. Thus, the reaction of 6 with the thiosemicarbazones 7a–d and 9–11 afforded the corresponding simple naphthoyl-(3-pyrazolyl)thiazole hybrids 8a–d and 12 ~ 14. The symmetric bis-(2-naphthoyl-pyrazol-3-yl)thiazol-2-yl)hydrazono)methyl)phenoxy)alkanes 18a-c and 21a-c were similarly synthesized from reaction of 6 with the appropriate bis-thiosemicarbazones 17a-c and 19a-c, respectively. The synthesized two series of simple and symmetrical bis-molecular hybrid merging naphthalene, thiazole, and pyrazole were evaluated for their cytotoxicity. Compounds 18b,c and 21a showed the most potent cytotoxicity (IC50 = 0.97–3.57 µM) compared to Lapatinib (IC50 = 7.45 µM). Additionally, they were safe (non-cytotoxic) against the THLE2 cells with higher IC50 values. Compounds 18c exhibited promising EGFR and HER-2 inhibitory activities with IC50 = 4.98 and 9.85 nM, respectively, compared to Lapatinib (IC50 = 6.1 and 17.2 nM). Apoptosis investigation revealed that 18c significantly activated apoptotic cell death in HepG2 cells, increasing the death rate by 63.6-fold and arresting cell proliferation at the S-phase. Compound 18c upregulated P53 by 8.6-fold, Bax by 8.9-fold, caspase-3,8,9 by 9, 2.3, and 7.6-fold, while it inhibited the Bcl-2 expression by 0.34-fold. Thereby, compound 18c exhibited promising cytotoxicity against EGFR/HER2 inhibition against liver cancer. [ABSTRACT FROM AUTHOR]

The reaction of the appropriate α-haloketones or α-keto-hydrazonoyl chlorides with the corresponding bis(hydrazinecarbothioamide) in EtOH at reflux in the presence of a few drops of TEA produced good yields of novel bis-thiazoles linked to diphenyl ether as novel hybrid molecules. Furthermore, some novel bis-thiazoles were obtained in high yields by reacting 1,1′-(oxybis(4,1-phenylene))bis(2-bromoethanone) with the appropriate thioamide. Furthermore, by reacting bis(2-bromoethanone) with the appropriate 4-amino-3-mercapto-1,2,4-triazole derivatives in ethanol in the presence of TEA, novel bis(5,6-dihydro-s-triazolo[3,4-b]thiadiazines) linked to diphenyl ether moiety were obtained in good yields. Moreover, by reacting bis(2-bromoethanone) with the appropriate pyridinethiones in ethanolic sodium ethoxide at reflux, good yields of bis(thienopyridines) linked to diphenyl ether moiety were obtained. The structures of new compounds were confirmed using elements and spectral data. [ABSTRACT FROM AUTHOR]

A synthesis of novel bis-thiazoles, linked to quinoxaline as novel hybrid molecules, was accomplished in good yields by the reaction of the appropriate α-haloketones or α-keto-hydrazonoyl chlorides with the corresponding bis(hydrazinecarbothioamide) in ethanol/dimethylformamide (EtOH/DMF) at reflux in the presence of a few drops of triethylamine (TEA). The reaction of the appropriate thioamide with the corresponding bis(2-bromoethanone) yielded novel bis-thiazoles. Furthermore, by reacting bis(2-bromoethanone) with the appropriate 4-amino-3-mercapto-1,2,4-triazole derivatives, novel bis(5,6-dihydro-s-triazolo[3,4-b]thiadiazines) linked to quinoxaline moiety were obtained in good yields. The starting bis-thiosemicarbazone was obtained by reacting 1,1'-((quinoxaline-2,3-diylbis(oxy))bis(4,1-phenylene))diethanone with thiosemicarbazide in EtOH containing a few drops of acetic acid (AcOH) at reflux. On the other hand, the 1,1'-((quinoxaline-2,3-diylbis(oxy))bis(4,1-phenylene))bis(2-bromoethanone) was obtained from the corresponding bis(acetyl) derivative upon treatment with N-bromosuccinimide (NBS) in the presence of p-toluenesulfonic acid (p-TsOH), respectively. Structures of new compounds were confirmed using elemental analyses and spectral data. [ABSTRACT FROM AUTHOR]

A new series of bis(4H‐chromene), bis (pyrano[3,2‐c]chromene), and bis (pyrano[2,3‐c]pyrazole) each linked to the piperazine core via ether linkages was synthesized. The target compounds are probably formed through a three‐component reaction involving two equivalents of each malononitrile and the corresponding active methylene compounds, such as dimedone, 4‐hydroxycoumarine, or 5‐methyl‐2,4‐dihydro‐3H‐pyrazol‐3‐one. Several spectral methods and elemental analyses were used to deduce the chemical structures of the novel compounds. Furthermore, all synthesized compounds were tested for antimicrobial activity, which revealed promising inhibitory results against a variety of multidrug‐resistant microbial strains. These findings were compared to those obtained in the in silico molecular docking study. The docking results improved the activity of new derivatives as potentially effective antimicrobial agents. [ABSTRACT FROM AUTHOR]

The molecular hybridization of various compounds with known pharmacological activity is a particularly popular approach for the development of potential drugs with improved pharmacokinetic profiles. In this respect, a novel series of bis(1,4-dihydropyridine-3,5-dicarbonitrile), bis(decahydroacridine), bis(tetrahydrodipyrazolo[3,4-b:4′,3′-e]pyridin), and bis(tetrahydropyrimido[4,5-b]quinoline-2,4,6-trione) derivatives linked to piperazine core via phenoxyethanone linkages were prepared via Hantzsch like reaction of the ((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(oxy))dibenzaldehydes, with the appropriate active methylene containing reagents. Attempted synthesis of the target products via bis-alkylation of the appropriate phenol with 1,1′-(piperazine-1,4-diyl)bis(2-chloroethan-1-one) in different basic conditions were unsuccessful. [ABSTRACT FROM AUTHOR]

A synthesis of novel bis(sulfanediyl)bis(tetrahydropyrimido[4,5-b]quinoline-4,6-diones), linked to aryl, heteroaryl, and spirocyclic-oxindole moieties at position-5, as novel hybrid molecules was reported. 2,2'-(Butane-1,4-diylbis(sulfanediyl))bis(6-aminopyrimidin-4(1H)-one) was utilized as a precursor to our target compounds via a multicomponent reaction with two equivalents of both of the appropriate aldehyde and dimedone. The target compounds were alternatively obtained by bis-(alkylation) of the appropriate 5-aryl-2-thioxohexahydropyrimido[4,5-b]quinoline-4,6-dione with 1,4-dibromobutane in moderate basic medium. [ABSTRACT FROM AUTHOR]

Heterocycles, particularly pyrimidine derivatives, which are present in many natural products and many interesting synthetic compounds, are the most diverse class of organic compounds and have significant chemical, biomedical and industrial applications. Uracil, a pyrimidine derivative, constitutes a promising structure in widespread natural products and many of its derivatives exhibited significant pharmacological properties. They have been widely used as starting materials for the synthesis of a huge number of biologically important nitrogen-containing heterocycles. This review casts light on various methods for the construction of different heterocyclic systems utilizing aminouracil and aminothiouracil as versatile precursors. The heterocyclic systems mentioned in this review are categorized according to the type of the heterocyclic systems. [ABSTRACT FROM AUTHOR]

A synthesis of novel bis(benzo[4,5]imidazo[1,2-a]pyridines) via the reaction of the appropriate bis(aldehyde) with 2-(1H-benzo[d]imidazol-2-yl)acetonitrile and malononitrile in ethanol at reflux in the presence of piperidine was reported. On the other hand, attempted synthesis of bis(benzo[4,5]thiazolo[3,2-a]pyridines) by a three-component reaction of the appropriate bis-aldehyde with malononitrile and (benzo[d]thiazol-2-yl)acetonitrile under similar reaction conditions was unsuccessful. The reactions gave instead the corresponding novel bis(benzo[d]thiazol-2-yl)acrylonitriles. [ABSTRACT FROM AUTHOR]

A synthesis of novel hybrid molecules containing thiazole or bis(thiazoles) each bearing benzofuran and/or benzo[d]thiazole moieties by the reaction of the appropriate thioamide derivatives with the corresponding bis-bromoacetyl derivatives is reported. Mono- and bis(triazolothiadiazine) derivatives based on benzofuran or benzo[d]thiazole moieties were also synthesized in good yields by the reaction of the appropriate bis(bromoacetyl) derivatives with each of 4-amino-5-mercapto-1,2,4-triazoles and their corresponding bis-derivatives. [ABSTRACT FROM AUTHOR]

A novel series of bis- and poly(arydiazenyl)thiazoles were prepared in good yields by the reaction of the appropriate α-keto-hydrazonoyl chlorides with the corresponding bis- and poly(hydrazinecarbothioamide) in refluxing EtOH/DMF in the presence of few drops of TEA. Based on elemental analyses as well as spectral data, the structures of the new compounds were confirmed. [ABSTRACT FROM AUTHOR]

A novel series of bis(thiazolylchromen‐2‐one) derivatives 8 were prepared in good yields by the reaction of the appropriate bis(α‐bromoketones) 7 with 2‐(1‐(2‐oxo‐2H‐chromen‐3‐yl)ethylidene) hydrazinecarbothioamide (6) in refluxing EtOH in the presence of few drops of TEA. Some other isomeric derivatives of bis(thiazolylchromen‐2‐one) 11 and 13 were also successfully obtained by the reaction of bromoacetylcoumarin 9 with the corresponding bis(ethan‐1‐yl‐1‐ylidene))bis(hydrazinecarbothioamides) 10 and 12. The structures of the new compounds were established based on elemental analyses as well as spectral data. [ABSTRACT FROM AUTHOR]

A series of novel thieno[2,3-b]pyridines were prepared from the reaction of the appropriate bromoacetylbenzofurans or bromoacetylbenzothiazole with the corresponding pyridinethione derivatives in ethanolic sodium ethoxide at reflux. Moreover, new bis(thieno[2,3-b]pyridine) derivatives have also been synthesized by the reaction of the appropriate bis-bromoacetyl derivatives with the corresponding pyridinethiones in the presence of sodium ethoxide. Attempts to synthesize the target bis(thieno[2,3-b]pyridine) derivatives by bis-alkylation of the corresponding (thieno[2,3-b]pyridin-2-yl)(hydroxyphenyl)methanone with the appropriate dihaloalkanes using a mild base were unsuccessful. [ABSTRACT FROM AUTHOR]

The synthesis of novel bis(thiazoles) 20a, 20b, 20c and 23a, 23b, 23c is reported. Thus, reaction of 2-bromo-1-(5-methyl-1-phenyl-1 H-pyrazol-4-yl)ethanone ( 6) with the corresponding thioamide derivatives 7a, 7b, in refluxing EtOH in the presence of triethylamine, afforded 4-pyrazolylthiazoles 8a, 8b in good yields. On the other hand, the novel bis(thiazoles) 20a, 20b, 20c and 23a, 23b, 23c were obtained from the reaction of 6 with the corresponding benzaldehyde thiosemicarbazones 19a, 19b, 19c, 22a, 22b, 22c in refluxing EtOH. Compounds 19a, 19b, 19c and 22a, 22b, 22c were obtained by condensation of the corresponding bis(aldehydes) 18a, 18b, 18c and 21a, 21b, 21c with thiosemicarbazide. [ABSTRACT FROM AUTHOR]

A synthesis of novel three-, four-, and sixfold branched 4-phenylthiazolylhydrazones, 4-pyrazolylthiazolyl hydrazones, and thiadiazoles which are linked to a benzene core via phenoxymethyl spacers was reported. The synthetic methodology includes initially formation of poly(aldehyde thiosemicarbazones) 9, 14, and 15 by acid catalyzed condensation of thiosemicarbazide ( 8) with the appropriate poly(aldehydes) 3, 5, and 7, respectively. Subsequent reaction of 9, 14, and 15 with each of 2-bromo-1-phenylethanone ( 10a) and 2-bromo-1-( 4-chlorophenyl)ethanone ( 10b) in refluxing ethanol in the presence of few drops of TEA afforded 11, 16, and 18, respectively, in good yields. On the other hand, the synthesis of the novel poly(4,5-dihydro-1,3,4-thiadiazolyl) derivatives 20, 21a, 21b, and 22 was performed by of 9b, 14a, 14b, and 15a, respectively, in refluxing . [ABSTRACT FROM AUTHOR]

Pyrazolo[1,5- a ]pyrimidine, triazolo[1,5- a ]pyrimidine, and pyrimido[1,2- a ]benzimidazole, pyrido[1,2- a ]benzimidazole ring systems incorporating phenylsulfonyl moiety were synthesized via the reaction of 3-( N , N -dimethylamino)-1-(thiophen-2-yl)-2-(phenylsulfonyl)prop-2-en-1-one derivatives with the appropriate aminoazoles as 1,3-binucleophiles and 1 H -benzimidazol-2-ylacetonitrile using conventional methods as well as microwave irradiation. The regioselectivity of the cyclocondensation reactions was confirmed both experimentally by alternative synthesis of reaction products and theoretically using ab initio quantum chemical calculations namely the Density Functional Theory (DFT). The theoretical work was carried out using the Becke, three parameter, Lee–Yang–Parr hybrid functional (B3LYP) combined with the 6-311++G(d,p) basis set. It was found that the final cyclocondensation reaction product depends mainly on the initial addition to the activated double bond by the nitrogen atom of the 1,3-binucleophiles that has the higher electron density. [ABSTRACT FROM AUTHOR]

Novel 9-aminoimidazo[1,2-a:5,4-b']dipyridine-6,8-dicarbonitriles were prepared via the Michael addition reaction of readily accessible 2-(3H-imidazo[4,5-b]pyrid-2-yl)acetonitrile with arylidenemalononitriles. The regioselectivity of the reaction was supported by theoretical calculations at the DFT level. In contrast, the reaction of the appropriate bis-arylidenemalononitrile with 2-(3H-imidazo[4,5-b]pyrid-2-yl)acetonitrile under similar reaction conditions gave the corresponding bis[2-(3H-imidazo[4,5-b]pyrid-2-yl)acrylonitriles]. [ABSTRACT FROM AUTHOR]

The target mono- and bis-(6-pyrazolyltriazolo-thiadiazine) derivatives 4a-c and 6a-d were synthesized using a straightforward protocol via reaction of 3-bromoacetylpyrazole 2 with 4-amino- s -triazole-3-thiols 3a-c and bis(4-amino-5-mercapto- s -triazol-3-yl)alkanes 5a-d , respectively. The bis(6-pyrazolyl- s -triazolo[3,4- b ][1,3,4]thiadiazine) derivatives 8a , b and 10 were also constructed by reaction of the triazolo[3,4- b ][1,3,4]thiadiazine-3-thiol 4c with the proper dibromo compounds 7a , b and 9 , respectively. Structures of the new substances were determined by spectroscopic and analytical data. Compounds 4b , 4c , and 6a showed potent cytotoxicity against MCF-7 (IC 50 = 3.16, 2.74, and 0.39 μM, respectively) and were safe against the MCF-10A cells. Compounds 4b , 4c , and 6a also showed promising dual EGFR and CDK-2 inhibition activities, particularly 6a was the most effective (IC 50 = 19.6 and 87.9 nM, respectively), better than Erlotinib and Roscovitine. Compound 6a treatment induced EGFR and CDK-2 enzyme inhibition by 97.18% and 94.11%, respectively, at 10 μM (the highest concentration). Compound 6a notably induced cell apoptosis in MCF-7 cells, increasing the cell population by total apoptosis 43.3% compared to 1.29% for the untreated control group, increasing the cell population at the S-phase by 39.2% compared to 18.6% (control)., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)