Stereoselective total syntheses of (+)-exo- and (−)-exo-brevicomins, (+)-endo- and (−)-endo-brevicomins, (+)- and (−)-cardiobutanolides, (+)-goniofufurone

Stereoselective total syntheses of aggregation pheromones (+)-exo-brevicomin (9a), (−)-exo-brevicomin (9b), (+)-endo-brevicomin (9c), (−)-endo-brevicomin (9d) and styryllactones (+)-cardiobutanolide (14a), (−)-cardiobutanolide (14b), and (+)-goniofufurone (19a) were achieved in good yields from enantiomerically pure highly functionalized furanoid glycal building blocks (1a-d) involving similar synthetic strategies, thus making these furanoid glycals highly useful building blocks in diversity-oriented synthesis (DOS).     

Bioactive meroditerpenes and indole alkaloids from the soil fungus Neosartorya fischeri (KUFC 6344), and the marine-derived fungi Neosartorya laciniosa (KUFC 7896) and Neosartorya tsunodae (KUFC 9213)

Two new metabolites including a new aszonalenin analogue (1c) and a new meroditerpene (3) were isolated, together with aszonalenin (1a), acetylaszonalenin (1b), 13-oxofumitremorgin B (2), aszonapyrone A (4b) and helvolic acid, from the culture of the soil fungus Neosartorya fischeri (KUFC 6344). While the ethyl acetate extract of the culture of the diseased coral-derived fungus Neosartorya laciniosa (KUFC 7896) furnished aszonapyrone B (4a), aszonapyrone A (4b), tryptoquivaline L and 3′-(4-oxoquinazolin-3-yl) spiro[1H-indole-3,5′-oxolane]-2,2′-dione, the ethyl acetate extract of the culture of the marine sponge-associated fungus Neosartorya tsunodae (KUFC 9213) yielded a new analogue of chevalone C (5) and helvolic acid. The structures of the new compounds were established based on 1D and 2D NMR spectral analysis as well as HR-ESIMS. Compounds 1a–c, 2, 3, 4a, 4b and 5 were evaluated for their in vitro growth inhibitory activity on the MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and A375-C5 (melanoma) cell lines by the protein binding dye SRB method.     

Determination of the absolute structure of albaconol

The concise synthesis of (8aR)-(−)-albaconol (1) from (8aR)-albicanol (2) obtained from the lipase-assisted asymmetric acetylation of rac-2, was achieved in 45% overall yield (eight steps). By comparison of the sign of specific rotation of between synthetic (8aR)-(−)-albaconol (1) and natural (+)-albaconol (1), the absolute structure of natural (+)-1 was determined to be 1R,2R,4aS,8aS configuration.     

Synthesis, properties, and oxidizing function of 6-substituted 7,9-dimethylcyclohepta[b]pyrimido[5,4-d]pyrrole-8(7H),10(9H)-dionylium tetrafluoroborates

Uracil-annulated heteroazulenes, 6-substituted 7,9-dimethylcyclohepta[b]pyrimido[5,4-d]pyrrole-8(7H),10(9H)-dionylium tetrafluoroborates 7a,b·BF₄⁻, which are the isoelectronic compounds of 5-dezazaflavin, were synthesized. X-Ray crystal analysis and MO calculations were carried out to clarify the structural characteristics of 7a,b·BF₄⁻. The stability of cations 7a,b is expressed by the pK_R+ values which were determined spectrophotometrically to be 10.9 and 11.2, respectively. The electrochemical reduction of 7a,b exhibited high reduction potentials at −0.84 and −0.87 (V vs Ag/AgNO₃) upon cyclic voltammetry (CV). A good linear correlation between the pK_R+ values and reduction potentials (E1_red) of 7a,b·BF₄⁻ and reference compounds 4·BF₄⁻ and 5·BF₄⁻ was obtained. In a search of the reactivity, reactions of 7a,b·BF₄⁻ with some nucleophiles, hydride and diethylamine, were carried out to clarify that the introduction of nucleophiles to give regio-isomers is dependent on the nucleophile. The photo-induced oxidation reactions of 7a,b·BF₄⁻ toward some alcohols under aerobic conditions were carried out to give the corresponding carbonyl compounds in more than 100% yield [based on compounds 7a,b·BF₄⁻], suggesting the oxidizing function of 7a,b·BF₄⁻ toward alcohols in the autorecycling process.     

Solvent-free reactions of N,N′-thiocarbonyldiimidazole with ferrocenylcarbinols

The efficient and simple routes for the synthesis of various ferrocenyl derivatives from ferrocenylcarbinols and N,N′-thiocarbonyldiimidazole (TCDI) are described. It involves grinding the two substrates in a Pyrex tube with a glass rod at room temperature. The reaction of ferrocenylmethanol (1a) provided S,S-bis(ferrocenylmethyl)dithiocarbonate (1b), whose crystal structure and a plausible mechanism for its formation are also reported. The reaction of 1-ferrocenyl-1-phenylmethanol (2a) and 1-ferrocenylbutanol (2b) gave the products 2c and 2d, respectively. The reaction of ω-ferrocenyl alcohols 4-ferrocenylphenol (3a) and 6-ferrocenylhexan-1-ol (3b) yielded the products 3c and 3d, respectively. Reaction of 1,1′-ferrocenedimethanol (3e) afforded 3f in moderate yield, and by contrast, it was not similar to 1b. Reaction of [4-(trifluoromethyl)phenyl]methanol (4a) provided the thiocarbonate 4b in good yield.     

Synthesis and properties of novel 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-triones: methodology for synthesizing cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates

Novel condensation reaction of tropone with N-substituted and N,N′-disubstitued barbituric acids in Ac₂O afforded 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (8a-f) in moderate to good yields. The ¹³C NMR spectral study of 8a-f revealed that the contribution of zwitterionic resonance structures is less important as compared with that of 8,8-dicyanoheptafulvene. The rotational barriers (ΔG^‡) around the exocyclic double bond of mono-substituted derivatives 8a-c were obtained to be 14.51-15.03 kcal mol⁻¹ by the variable temperature ¹H NMR measurements. The electrochemical properties of 8a-f were also studied by CV measurement. Upon treatment with DDQ, 8a-c underwent oxidative cyclization to give two products, 7 and 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates (11a-c·BF₄⁻ and 12a-c·BF₄⁻) in various ratios, while that of disubstituted derivatives 8d-f afforded 7,9-disubstituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborate (11d-f·BF₄⁻) in good yields. Similarly, preparation of known 5-(1′-oxocycloheptatrien-2′-yl)-pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (14a-d) and novel derivatives 14e,f was carried out. Treatment of 14a-c with aq. HBF₄/Ac₂O afforded two kinds of novel products 11a-c·BF₄⁻ and 12a,c·BF₄⁻ in various ratios, respectively, while that of 14d-f afforded 11d-f. The product ratios of 11a-c·BF₄⁻ and 12a-c·BF₄⁻ observed in two kinds of cyclization reactions were rationalized on the basis of MO calculations of model compounds 20a and 21a. The spectroscopic and electrochemical properties of 11a-f·BF₄⁻ and 12a-c·BF₄⁻ were studied, and structural characterization of 11c·BF₄⁻ based on the X-ray crystal analysis and MO calculation was also performed.     

Structural and stereochemical investigations into bromotyrosine-derived metabolites from southern Australian marine sponges, Pseudoceratina spp.

Chemical investigation of a southern Australian sponge, Pseudoceratina sp., resulted in the isolation of twelve bromotyrosine-derived alkaloids, comprising four new metabolites, aplysamine-7 (1), (−)-purealin B (2), purealin C (3) and purealin D (4); two new spiroisoxazole enantiomers, (−)-purealidin R (5) and (−)-aerophobin-2 (6); five known metabolites (−)-pseudoceratinine A (7), (−)-aeroplysinin-1 (8), aplysamine-2 (9), purpuramine G (10) and purpuramine J (11); and an artifact 12 derived from ethanolysis of 5. Structures for 1-12 were assigned on the basis of detailed spectroscopic analysis. A second southern Australian Pseudoceratina sp. afforded the first recorded account of a racemic bromotyrosine-derived spiroisoxazole, (±)-purealin (13b), together with the known achiral precursor purealidin A (15). A literature review of marine bromotyrosine-derived spiroisoxazoles reaffirmed the published dominance of (+)-spiroisoxazoles, acknowledging several accounts of (−)-spiroisoxazoles, while also revealing a wide range of chiroptical measurements suggestive of variable optical purity. The Pseudoceratina sp. metabolites 1-12, 13b and 15 were assessed for antibiotic properties, with the new metabolites 3 and 13b exhibiting broad spectrum activity against several Gram-positive bacteria.     

Synthesis and antibacterial activity of chalcones bearing prenyl or geranyl groups from Angelica keiskei

Chalcones bearing prenyl or geranyl groups from Angelica keiskei, such as 4-hydroxyderricin (1a), xanthoangelol (1e), xanthoangelol F (1f), xanthoangelol H (2), deoxyxanthoangelol H (3), and deoxydihydroxanthoangelol H (4) and their derivatives were synthesized. From the evaluation of antibacterial activity of the synthesized chalcones, 1a, isobavachalcone (1b), 1e, 1f, bavachalcone (5a), and broussochalcone B (5b) were found to inhibit Gram-positive bacteria.     

An efficient approach to 2-substituted N-tosylpiperdines: asymmetric synthesis of 2-(2-hydroxy substituted)piperidine alkaloids

We have developed an efficient and a general approach to chiral 2-substituted N-tosylpiperidines starting from chiral α-substituted-N-tosylaziridines. Using this approach, we have synthesized (+)-coniine. The synthesis of chiral N-tosyl-2-piperidinylethanol 15 and ent-15, was achieved from l- and d-aspartic acids, respectively in few steps. Piperidine 15 was converted into 2-(2-hydroxysubstituted)piperidines of type 2 in optically active form. By applying this strategy, asymmetric syntheses of halosaline (R,R)-2a, (+)- and (−)-sedamine 2b, (+)- and (−)-allosedamine 2c, (+)- and (−)-sedridine 2d, (+)- and (−)-allosedridine 2e, (+)-tetraponerine T-3 3a, T-4 3c, T-7 3b, and T-8 3d have been achieved in high yields. These stereoisomers can be interconverted via Mitsunobu inversion in excellent yields.     

Preparation of new pyrido[3,4-b]thienopyrroles and pyrido[4,3-e]thienopyridazines

Two new types of pyrido-fused tris-heterocycles (1a,b and 2a,b) have been prepared from 3-aminopyridine in five/six steps. A synthetic strategy for the preparation of the novel pyrido[3,4-b]thieno[2,3- and 3,2-d]pyrroles (1a,b) and pyrido[4,3-e]thieno[2,3- and 3,2-c]pyridazines (2a,b) has been studied. The Suzuki cross coupling of the appropriate 2- and 3-thienoboronic acids (3,4) and 4-bromo-3-pyridylpivaloylamide (9) afforded the biaryl coupling products (10,11) in high yields (85%). Diazotization of the hydrolysed (2-thienyl)-coupling product (12) and azide substitution gave the 3-azido-4-(2-thienyl)pyridine intermediate (72%, 14). 3-Azido-4-(3-thienyl)pyridine (15) was prepared by exchanging the previous order of reactions. The desired β-carboline thiophene analogues (1a,b) were obtained via the nitrene by thermal decomposition of the azido precursors (14,15). By optimising conditions for intramolecular diazocoupling, the corresponding pyridazine products (72-83%, 2a,b) were afforded.     

Synthesis and properties of 4,9-methanoundecafulvenes and their transformation to 3-substituted 7,12-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1H,3H)-diones: photo-induced autorecycling oxidizing reaction toward amines

The synthesis and properties of 4,9-methanoundecafulvene [5-(4,9-methanocycloundeca-2′,4′,6′,8′,10′-pentaenylidene)pyrimidine-2,4,6(1,3,5H)-trione] derivatives 8a,b were studied. Their structural characteristics were investigated on the basis of the ¹H and ¹³C NMR and UV-vis spectra. The rotational barrier (ΔG^‡) around the exocyclic double bond of 8a was found to be 12.55 kcal mol⁻¹ by the variable temperature ¹H NMR measurement. The electrochemical properties of 8a,b were also studied by CV measurement. Furthermore, the transformation of 8a,b to 3-substituted 7,12-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1H,3H)-diones 16a,b was accomplished by oxidative cyclization using DDQ and subsequent ring-opening and ring-closure. The structural details and chemical properties of 16a,b were clarified. Reaction of 16a with deuteride afforded C13-adduct 19 as the single product, and thus, the methano-bridge controls the nucleophilic attack to prefer endo-selectivity. The photo-induced oxidation reaction of 16a and a vinylogous compound, 3-methylcyclohepta[4,5]furo[2,3-d]pyrimidine-2,4(3H)-dione 2a, toward some amines under aerobic conditions were carried out to give the corresponding imines (isolated by converting to the corresponding 2,4-dinitrophenylhydrazones) with the recycling number of 6.1-64.0 (for 16a) and 2.7-17.2 (for 2a), respectively.     

Half-sandwich η-arene–ruthenium(II) complexes bearing 1-alkyl(benzyl)-imidazo[4,5-f][1,10]-phenanthroline (IP) derivatives: the effect of alkyl chain length of ligands to catalytic activity

The reaction of bromoalkanes (R–Br; (3), R=C_nH_2n+1, n=4 (a), 8 (b), 12 (c),18 (d)) and bromobenzyl derivatives (R′–Br; (4), R′=CH₂C₆H₂(CH₃)₃-2,4,6 (a); CH₂C₆H(CH₃)₄-2,3,5,6 (b); CH₂C₆(CH₃)₅ (c)) with 1H-imidazo[4,5-f][1,10]-phenanthroline (IP)(L₂) gave the corresponding 1-R-imidazo[4,5-f][1,10]-phenanthroline (IPR)(L_3a–d) and 1-R′-imidazo[4,5-f][1,10]-phenanthroline(IPR')(L_4a–c) ligands, respectively. Treatment of L_3a–d and L_4a–d with [Ru(p-cymene)Cl₂]₂ led to the formation of [Ru(p-cymene)(IPR)Cl]Cl (RuL_3a–d) and [Ru(p-cymene)(IPR′)Cl]Cl (RuL_4a–c). New ruthenium(II) complexes RuL_3a–d and RuL_4a–c were characterized by elemental analysis, FTIR, UV–visible and NMR spectroscopy. In order to understand effects of these changes on the N-substituent of imidazol on IP and how they translate to catalytic activity, these new RuL₂, RuL_3a–d and RuL_4a–c were applied in the transfer hydrogenation of ketones by 2-propanol in presence of potassium hydroxide. The activities of the catalysts were monitored by NMR and GC analysis.     

A synthetic strategy using Witkop's pyrroloindole for (−)-debromoflustramine B, (+)-ent-debromoflustramine B and (+)-ent-debromoflustramide B

While prenylation of (−)-Witkop's pyrroloindole (2), secured from l-tryptophan under standard N-alkylation conditions, led to a ca. 1:1 diastereoisomeric mixture of two C^3a-alkylated indolenines 3 and 4, use of phase-transfer conditions altered this to ca. 1:2. Reduction followed by N-prenylation of the resulting secondary amines gave C,N-dialkylated products. The derived separable diastereoisomeric (−)- and (+)-Barton esters 19a and 19b were then converted into (−)-debromoflustramine B and (+)-ent-debromoflustramine B, respectively. A novel reaction involving oxygen and the carbanion derived from Barton ester 19b led to (+)-ent-debromoflustramide B. Treatment of N⁸-prenylated Witkop's pyrroloindole 5 with Lewis acid (BF₃·Et₂O) uncovered a new clean intramolecular cyclisation involving the prenyl unit.     

Isolation and synthesis of N-acyladenine and adenosine alkaloids from a southern Australian marine sponge, Phoriospongia sp.

Chemical fractionation of the southern Australian marine sponge Phoriospongia sp. (CMB-03107) yielded phorioadenine A (1) as a nematocidal agent and the first reported example of a 6-N-acyladenine natural product. The structure of 1 was confirmed by spectroscopic analysis and the chemical synthesis of racemic (1a) and enantiomeric (1b) analogues. HPLC–ESIMS analysis of the crude sponge extract with comparisons to the synthetic 6-N-acyladenosine 2a provided evidence that the biosynthetically related adenosine, phorioadenosine A (2), was present as a trace co-metabolite. The rare starfish metabolite asterubine (3) was also isolated as a co-metabolite, and its structure confirmed by spectroscopic analysis and chemical synthesis. Biological investigations confirmed that natural products 1–3 and synthetic analogues 1a–e and 2a were not cytotoxic to multiple mammalian cancer cell lines, or Gram-positive or -negative bacteria. Nematocidal activity (inhibition of larval development of Haemonchus contortus) detected in the Phoriospongia sp. extract was attributed to 1 (LD₉₉ 31 μg/mL), with preliminary structure–activity relationship investigations confirming the importance of the N-acyl side chain.     

Substituted six-membered ring carbenes: the effects of amino and cyclopropyl groups through DFT calculations

DFT calculations are employed to compare and contrast six-membered ring carbenes including 1,3-dimethyltetrahydropyrimidin-2-ylidene (1a), 1-methyl-3-cyclopropyltetrahydropyridine-2-ylidene (2a), and 1,3-dicyclopropylcyclohexane-2-ylidene (3a) as well as their unsaturated analogues 1b, 2b, 3b, and 2c. The amino groups exert singlet-triplet energy separation (?E_s−t) of 60.9 kcal/mol to 1a while cyclopropyls induce a ?E_s−t of 14.8 kcal/mol to 3a. The simultaneous presence of amino and cyclopropyl in 2a leads to a ?E_s−t of 43.3 kcal/mol. Unsaturation slightly increases the ?E_s−t of 1a and 3a but not that of 2a. Our thermodynamic, kinetic, and reactivity results are compared with those of synthetic five-membered ring N-heterocyclic carbenes.     

New α-substituted alkylbenzene- and dialkylbenzene-1,2-diphosphonates: side-chain metalation of tetraethyl 4-methyl- and 4,5-dimethylbenzene-1,2-diphosphonates

Carbocyclic 1,2-diphosphonates (1a, 1b) are prepared by the Diels-Alder reaction of classical donor alka-1,3-dienes (isoprene and 2,3-dimethyl-1,3-butadiene) with tetraethyl acetylene bisphosphonate. Their aromatization by the KMnO₄-Al₂O₃ system affords 4-methyl and 4,5-dimethylbenzene-1,2-diphosphonates (2a, 2b), used as precursor for the generation of benzyl-type carbanions (3a, 3b) by lithiation with lithium isopropylamide in THF at −80 °C. The carbanions react with electrophilic reagents (chlorotrimethylsilane, p-fluorobenzaldehyde, and ethyl trifluoroacetate) in situ to form corresponding α-substituted monoalkyl- and dialkylbenzenediphosphonates in good yields.     

Stabilization of (N-methyleneamino)imidoylketenes: synthesis of dipyrazolo[1,2-a;1′,2′-d][1,2,4,5]tetrazines

Thermolysis of substituted methyl 1-methyleneamino-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates 2a,b led to substituted dimethyl 3,9-dioxo-1,5,7,11-tetrahydro-1H,7H-dipyrazolo[1,2-a;1′,2′-d][1,2,4,5]tetrazine-1,7-dicarboxylates 4a,b and methyl 2,5-dihydro-5-oxo-1H-pyrazole-3-carboxylates 5a,b as minor products. The structure of compound 4a was determined by X-ray crystallography. The proposed mechanism of this conversion includes generation of (N-methyleneamino)imidoylketenes 6a,b and its intramolecular transformation to azomethine imines—5-oxo-2,5-dihydropyrazole-1-methylium-2-ides 7a,b, which undergo dimerization in head-to-tail manner yielding products 4a,b and partially hydrolyse to compounds 5a,b.     

Synthesis of arylated highly congested indans using a domino sequence

A novel and efficient regioselective synthesis of various arylated highly congested 7-aryl-5-methylsulfanylindan-4-carbonitriles (3a-f), methyl 7-aryl-5-methylsulfanylindan-4-carboxylates (10a-e) and 7-aryl-5-methylsulfanylindan-4-carboxylic acids (11a-e) through base-catalyzed reaction of 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles (1a-f) and methyl 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carboxylates (9a-e) by cyclopentanone (2) has been delineated. The synthetic potential of 2-pyranone was explored further to generate molecular diversity using 6-aryl-4-sec-amino-2-oxo-2H-pyran-3-carbonitriles (7a-h), 5,6-diaryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles (5a,b) and methyl 5,6-diaryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carboxylates (12a,b) as precursors for the ring transformation by cyclopentanone to assess the effects of substituents on the course of the reaction to obtain highly congested indans, 6,7-diaryl-5-methylsulfanylindan-4-carbonitriles (6a,b), 7-aryl-5-(piperidin-1-yl)indan-4-carbonitriles (8a-h) and methyl 6,7-diaryl-5-methylsulfanylindan-4-carboxylates (13a,b).     

Chemoenzymatic resolution of epimeric cis 3-carboxycyclopentylglycine derivatives

Epimeric 3-carboxycyclopentylglycines (+)-10/(−)-10 and (+)-11/(−)-11 were efficiently prepared by the way of a sequence of Diels-Alder and retro-Claisen reactions. The synthesis incorporates a concise and inexpensive chemoenzymatic resolution of racemic compounds 4,5a, the N,O-protected derivatives of amino acids 10,11. Systematic screening with different enzymes and microorganisms was performed to select a very efficient catalyst for the separation of the racemic mixtures. The reaction conditions allowing deprotection of both ester and amino functions and to avoiding epimerization processes were studied. Enantiomers (i.e., (+)-10/(−)-10 and (+)-11/(−)-11) were obtained in high enantiopurity. The absolute configuration of all stereocenters was unequivocally assigned.     

Phosphorus–nitrogen compounds: Part 19. Syntheses,structural and electrochemical investigations,biological activities,and DNA interactions of new spirocyclic monoferrocenylcyclotriphosphazenes

The reactions of hexachlorocyclotriphosphazatriene, N₃P₃Cl₆, with N-alkyl-N-ferrocenylmethylethylene diamines, FcCH₂NH(CH₂)₂NHR₁ [R₁ = Me (1) and Et (2)], and sodium [3-(N-ferrocenylmethylamino)-1-propanoxide] (3) produce spirocyclic monoferrocenyl tetrachlorophosphazenes (1a–3a). The tetrapyrrolidinophosphazenes (1b–3b) are prepared from the reactions of corresponding phosphazenes (1a–3a) with excess pyrrolidine. The reaction of 1a with excess morpholine affords geminal-morpholino phosphazene (1c), whilst the reactions of 2a and 3a give diethylaminotrimorpholino (2c) and fully substituted morpholino products (3c), respectively. The structural investigations of the compounds are examined by Fourier transform IR, MS, ¹H, ¹³C, ³¹P NMR, DEPT, HETCOR, and HMBC techniques. The crystal structures of 3b and 3c are determined using X-ray crystallography. Cyclic voltammetric and chronoamperometric data show that compounds 1a–3a, 1b–3b, and 1c–3c exhibit electrochemically reversible one-electron oxidation of Fc redox centers which are hardly affected by the substituents on the phosphazene ring. The compounds 1b, 2b, 3b, and 3c are screened for antibacterial activities against Gram-positive and Gram-negative bacteria and for antifungal activities against yeast strains. In addition, the antituberculosis activities (in vitro) of these compounds are evaluated against INH-susceptible reference strain M. tuberculosis H37Rv, and six multi-drug resistant clinical M. tuberculosis isolates. Compound 2b is found to be the most active against the susceptible the reference strain. In addition, 1b, 2b, and 3c are active against all the multidrug-resistant clinical isolates at the highest concentrations. Gel electrophoresis data indicate that the compounds promote the formation of strand breaks in plasmid DNA. Almost all the concentrations lost of supercoiled DNA suggests that the compound 3b is very efficient plasmid-modifier. The compounds inhibit BamHI cleavage of pUC18 DNA while restricting HindIII.