Mustafa M. El-Abadelah

Heterocycles from Nitrile Imines. Part IV. Chiral 4,5-Dihydro-1,2,4-triazin-6-ones

The reaction of nitrile imines (II) with α-amino esters (III) proceeds with no detectable racemization and constitutes a convenient synthetic route to 4,5-dihydro-1,2,4-triazin-6-ones (IV). Permanganate oxidation of the heterocycles (IV) affords the corresponding 1,2,4-triazin-6-ones (V). The reaction of (II) with β-amino esters gives the respective acyclic amidrazone adducts (VI)

Synthesis, and antitumor activity of some N1-(coumarin-7-yl) amidrazones and related congeners.

A series of new N1-(coumarin-7-yl)amidrazones incorporating N-piperazines and related congeners were synthesized by reacting the hydrazonoyl chloride derived from 7-amino-4-methylcoumarin with the appropriate piperazines. The chemical structures of the newly prepared compounds were supported by elemental analyses, 1H-NMR, 13C-NMR, and ESI-HRMS spectral data. The antitumor activity of the newly synthesized compounds was evaluated. Among all the compounds tested, 7-{2-[1-(4-(1-benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)piperazin-1-yl)-2-oxopropylidene]hydrazinyl}-4-methyl-2H-chromen-2-one (3n) was the most potent against MCF-7 and K562 cells, with IC50 values of 20.2 and 9.3 μM, respectively.

Thienopyridinone antibacterials : Synthesis and antibacterial activity of some 7-aryl-2-chloro-4,7-dihydro-4-oxothieno[2,3-b]pyridine-5-carboxylic acids

Abstract A series of 7-aryl-4-oxothieno[2,3- b ]pyridine-5-carboxylic acids 8 and their methyl esters 7 were synthesized by intramolecular cyclization of the respective 3- N -arylamino-2-(2,5-dichloro-3-thenoyl) acrylates 6 . The latter are accessible from methyl 3-ethoxy-2-(2,5-dichloro-3-thenoyl) acrylate 5 which, in turn, is obtained via the parent β-keto ester 4 . Of the present series, the 7-( p -hydroxyphenyl) and 7-(2′,4′-difluorophenyl) derivatives 8e,i possess the highest activity especially against Klebsiella pneumoniae, Escherichia coli and Staphylacoccus aureus (MICs of 8e/8i ∩ 0.06:0.25, 0.5:1.0 and 1.0:2.0 μg/mL, respectively).

New Synthesis and Antiparasitic Activity of Model 5-Aryl-1- methyl-4-nitroimidazoles

A number of 5-aryl-1-methyl-4-nitroimidazoles 5a-f have been synthesized in good yields by the Suzuki coupling reaction between 5-chloro-1-methyl-4-nitroimidazole (3) and arylboronic acids 4a-f, aided by dichlorobis-(triphenylphosphine)palladium(II), K2CO3, and tetrabutylammonium bromide in water at 70-80 °C. Compounds 5a-f were characterized by elemental analysis, NMR and MS spectral data. On the basis of in vitro screening data, 5-(3-chlorophenyl)-1-methyl-4-nitro-1H-imidazole (5f) exhibited potent lethal activity against Entamoeba histolytica and Giardia intestinalis with IC50 = 1.47 µM/mL, a value lower by a factor of two than that of the standard drug, metronidazole. The boosted activity of 5f was not accompanied by any increased cytotoxicity. The rest of the series also exhibited potent antiparasitic activity with IC50 values in the 1.72-4.43 µM/mL range. The cytotoxicity of the derivatives 5c and 5e was increased compared to the precursor compound, metronidazole, although they remain non-cytotoxic at concentrations much higher than the antiparasitic concentration of the two derivatives.

Synthesis of new optically active α-alkoxypropionanilides

Abstract Two promising routes towards synthesis of the hitherto unknown α-alkoxypropionanilides were explored with success. As expected, facile displacement of the bromide in l (−)α-bromopropionanilide by alkoxide lead to inversion of configuration with considerable racemization, whereas substitution of the chloride in l (−) α-alkoxypropionyl chloride by arylamine proceeded with little or no racemization. α-Ethoxypropionanilide and the higher alkoxy homologues appear as low-melting noncrystallizable gum. Optical properties and other physical data for few model compounds of this new anilide series are reported.

Circular dichroism—LVII : Chiroptical properties of some α-halo- propionanilides

Abstract The CD of the anilides of α-halo-propionic acids depends on solvent and substitution of the aromatic ring. Changes of the CD with solvent can be explained by taking into account three conformers (G, A + and A − of Fig 1). The CD band around 250 nm is negative for derivatives of the l -acids in all solvents except hydrocarbons in which it is positive. The 1 L b band Cotton effects are very weak or not observed. The 1 L a —CD band is much stronger in the m - and o- substituted anilides than in-the p - or unsubstituted anilides.

Cleavage of 2-acetyl-2-phenylazopropionanilide and related compounds by boron trifluoride. New Japp–Klingemann reactions

2-Acetyl, 2-cyano-, and 2-nitro-2-phenylazopropionic acid derivatives suffer cleavage of the phenylazo-grouping on treatment with boron trifluoride, giving benzenediazonium tetrafluoroborate and the corresponding difluoroboron propionic acid derivative; 2-cyano- or 2-nitro-2-phenylazoisobutyronitrile and the corresponding amides behave similarly, but 1-phenylazo-2-naphthol gives a difluoroboron salt, and 2-phenylazo(diphenylmethyl)acetate is cyclised to 1,3-diphenylindazole on treatment with boron trifluoride. Acyl-2-phenylazopropionates suffer loss of the acyl grouping during attempted ketonic carbonyl condensation reactions, with conversion into corresponding phenylhydrazones; new examples, broadening the scope of the Japp–Klingemann reaction, are described.

Synthesis and biological activity assays of some new N1-(flavon-7-yl)amidrazone derivatives and related congeners.

A series of new N1-(flavon-7-yl)amidrazones incorporating N-piperazines and related congeners were synthesized by reacting the hydrazonoyl chloride derived from 7-aminoflavone and 7-amino-2-methylchromen-4-one with the appropriate piperazine. The chemical structures of the newly prepared compounds were confirmed by elemental analyses, (1)H NMR, (13)C NMR, and ESI-HRMS spectral data. The antitumor activity of these compounds was evaluated on breast cancer (MCF-7 and T47D) and Leukemic (K562) cell lines by a cell viability assay utilizing the tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Although with varying degrees, a significant growth inhibitory and cytotoxic effect was observed on all three cancer cell lines. Among the compounds tested compounds, 5a, 15a, and 18b, were the most active against T47D cell line with IC(50) values of 1.42, 1.92, and 2.92 μM, respectively. By using other cancer cell lines and with further characterization of their biological mechanism of action, these compounds could prove to be useful candidates as anticancer drugs.

HETEROCYCLES (H)-FUSED TO 4-OXOQUINOLINE-3-CARBOXYLIC ACID. PART IX. 1 SYNTHESIS OF 2,6-DIOXOTETRAHYDRO-1H- PYRROLO(3,2-H)QUINOLINE-7-CARBOXYLIC ACID

Interaction of deprotonated malonic esters with 7-chloro-8-nitro-4- oxoquinoline-3-carboxylate (1) gave the respective 7-(bis(alkoxycarbonyl)- methyl) derivatives (2, 3) which were converted into the corresponding 7-(carboxymethyl)-8-nitro-4-oxoquinoline-3-carboxylic acid (4). Reductive lactamization of the latter furnished the target tetrahydro-2,6-dioxo-1H-pyrrolo- (3,2-h)quinoline-7-carboxylic acid (5). Both compounds 4 and 5 exhibited broad spectrum of high antibacterial activity against representatives of Gram-negative and Gram-positive bacteria classes, but were less potent than the reference ciprofloxacin.

Heterocycles [h]-fused onto 4-oxoquinoline-3-carboxylic acid, part VIII [1]. Convenient synthesis and antimicrobial properties of substituted hexahydro[1,4]diazepino[2,3-h]quinoline-9-carboxylic acid and its tetrahydroquino[7,8-b]benzodiazepine analog.

[1,4]Diazepino[2,3-h]quinolone carboxylic acid 3 and its benzo-homolog tetrahydroquino[7,8-b]benzodiazepine-3-carboxylic acid 5 were prepared via PPA-catalyzed thermal lactamization of the respective 8-amino-7-substituted-1,4-dihydro-quinoline-3-carboxylic acid derivatives 8, 10. The latter compounds were obtained by reduction of their 8-nitro-7-substituted-1,4-dihydroquinoline-3-carboxylic acid precursors 7, 9 which, in turn, were prepared by reaction of 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-1,4-dihydroquinoline-3-carboxylic acid (6) with each of β-alanine and anthranilic acid. All intermediates and target compounds were characterized using elemental analysis, NMR, IR and MS spectral data. The prepared targets and the intermediates have shown interesting antibacterial activity mainly against Gram positive strains. In particular, compound 8 showed good activity against S. aureus (MIC = 0.39 µg/mL) and B. subtilis (MIC = 0.78 µg/mL). Compounds 5a and 9 have also displayed good antifungal activity against C. albicans (MIC = 1.56 µg/mL and 0.78 µg/mL, respectively). None of the compounds tested showed any anticancer activity against solid breast cancer cell line MCF-7 cells or a human breast adenocarcinoma cell line.