Monocyclic,Substituted Imidazoles as Glycosidase Inhibitors

A range of 4‐monosubstituted and 2,4‐disubstituted 1H‐imidazoles and 1H‐imidazole‐1‐ethanols (R C(4): CH₂CH₂Ph, CHOHCH₂Ph, Ph, or Me; R C(2): CH₂OH, CHOHCH₂OH, CN, or CH₂NHAc) were prepared and tested as inhibitors of α‐ and β‐glucosidases and of a β‐galactosidase. A new access to 4‐(2‐phenylethyl)‐1H‐imidazoles starting from 4‐phenylbutan‐1‐ol was elaborated. The strongest inhibitors are the 2‐substituted 4‐(2‐phenylethyl)‐1H‐imidazoles 24a and 26a (R C(2): CH₂OH and CHOHCH₂OH) and the 2‐phenylethanol 34 . They inhibit the β‐galactosidase from bovine liver and the β‐glucosidase from Caldocellum saccharolyticum with inhibition constants in the micromolar range, but do not inhibit the α‐glucosidase from brewer's yeast.     

Synthesis and Self‐Assembly of NCN‐Pincer Pd‐Complex‐Bound Norvalines

The NCN‐pincer Pd‐complex‐bound norvalines Boc‐D /L ‐[PdCl(dpb)]Nva‐OMe ( 1 ) were synthesized in multigram quantities. The molecular structure and absolute configuration of 1 were unequivocally determined by single‐crystal X‐ray structure analysis. The robustness of 1 under acidic/basic conditions provides a wide range of N‐/C‐terminus convertibility based on the related synthetic transformations. Installation of a variety of functional groups into the N‐/C‐terminus of 1 was readily carried out through N‐Boc‐ or C‐methyl ester deprotection and subsequent condensations with carboxylic acids, R¹COOH, or amines, R²NH₂, to give the corresponding N‐/C‐functionalized norvalines R¹‐D /L ‐[PdCl(dpb)]Nva‐R² 2 – 9 . The dipeptide bearing two Pd units 10 was successfully synthesized through the condensation of C‐free 1 with N‐free 1 . The robustness of these Pd‐bound norvalines was adequately demonstrated by the preservation of the optical purity and Pd unit during the synthetic transformations. The lipophilic Pd‐bound norvalines L ‐ 2 , Boc‐L ‐[PdCl(dpb)]Nva‐NH‐n‐C₁₁H₂₃, and L ‐ 4 , n‐C₄H₉CO‐L ‐[PdCl(dpb)]Nva‐NH‐n‐C₁₁H₂₃, self‐assembled in aromatic solvents to afford supramolecular gels. The assembled structures in a thermodynamically stable single crystal of L ‐ 2 and kinetically stable supramolecular aggregates of L ‐ 2 were precisely elucidated by cryo‐TEM, WAX, SAXS, UV/Vis, IR analyses, and single‐crystal X‐ray crystallography. An antiparallel β‐sheet‐type aggregate consisting of an infinite one‐dimensional hydrogen‐bonding network of amide groups and π‐stacking of PdCl(dpb) moieties was observed in the supramolecular gel fiber of L ‐ 2 , even though discrete dimers are assembled through hydrogen bonding in the thermodynamically stable single crystal of L ‐ 2 . The disparate DSC profiles of the single crystal and xerogel of L ‐ 2 indicate different thermodynamics of the molecular assembly process.     

Synthesis of C(2)‐Substituted manno‐Configured Tetrahydroimidazopyridines and Their Evaluation as Inhibitors of Snail β‐Mannosidase

It was shown that retaining β‐glucosidases and galactosidases of families 1–3 feature a strong interaction between C(2)OH of the substrate and the catalytic nucleophile. An analogous interaction can hardly take place for retaining β‐mannosidases. A structure? activity comparison between the inhibition of the β‐glucosidase from Caldocellum saccharolyticum (family 1) and β‐glucosidase from sweet almonds by the gluco‐imidazoles 1 – 6 , and the inhibition of snail β‐mannosidase by the corresponding manno‐imidazoles 8 – 13 does not show any significant difference, suggesting that also the mechanisms of action of these glycosidases do not differ significantly. For this comparison, we synthesized and tested the manno‐imidazoles 9 – 13, 28, 29, 32, 35, 40, 41, 43, 46, 47 , and 50 . Among these, the alkene 29 is the strongest known inhibitor of snail β‐mannosidase (K_i=6 nM , non‐competitive); the aniline 35 is the strongest competitive inhibitor (K_i=8 nM ).     

Synthesis of New C(2)‐Substituted gluco‐Configured Tetrahydroimidazopyridines and Their Evaluation as Glucosidase Inhibitors

The gluco‐configured C(2)‐substituted tetrahydroimidazopyridines 8 – 14 were prepared and tested as inhibitors of the β‐glucosidases from Caldocellum saccharolyticum and from sweet almonds, and of the α‐glucosidase from brewer's yeast. All new imidazopyridines are nanomolar inhibitors of the β‐glucosidases and micromolar inhibitors of the α‐glucosidase. The 3‐phenylpropyl derivative 14 proved the strongest inhibitor of the Caldocellum β‐glucosidase (K_i = 0.9 nM ), only slightly weaker than the known 2‐phenylethyl analogue 7 , and the propyl derivative 13 is the strongest inhibitor of the sweet almond β‐glucosidases (K_i = 3.2 nM ), again slightly weaker than 7 . There is no strong dependence of the inhibition on the nature of the C(2)‐substituent and no clear correlation between the inhibitory strength of the known manno‐configured imidazopyridines 2 – 6 and the gluco‐analogues 8 – 12 . While most manno‐imidazopyridines are competitive inhibitors, the gluco‐analogues proved non‐competitive inhibitors of the Caldocellum β‐glucosidase and mixed‐type or partial mixed‐type inhibitors of the sweet almond β‐glucosidases.     

Sugar‐Derived Di‐ and Tetrahydropyridazinones: Synthesis of New Glycosidase Inhibitors

The N‐unsubstituted D ‐arabino‐tetrahydropyridazinone 7 is a micromolar inhibitor of β‐glucosidases from sweet almonds (competitive), Caldocellum saccharolyticum (mixed), yeast α‐glucosidase (competitive), jack bean α‐mannosidase (competitive), and snail β‐mannosidase (competitive). The N‐substituted tetrahydropyridazinones 22 , 24 , and 26 are weak inhibitors of these glycosidases, and so are the dihydropyridazinones 8 and 17 – 19 , where the best inhibition was observed for 8 (K_i=56 μM for jack bean α‐mannosidase). The tetrahydropyridazinones were obtained by reduction of the corresponding dihydropyridazinones with NaCNBH₃, and the dihydropyridazinones were prepared by treatment with hydrazine or substituted hydrazines of the known and readily available D ‐threo‐pent‐2‐uluronate 11 .     

Probing the Interaction of the Hydroxy Group at C(4) of Lactone‐Type Inhibitors with β‐Glucosidases and β‐Galactosidases

The inhibition of the β‐glucosidases from sweet almonds and from Caldocellum saccharolyticum by the 4‐amino‐4‐deoxy lactam 11 , the 4‐deoxy lactam 12 , and the corresponding imidazoles 13 and 14 was compared to the inhibition by the hydroxy analogues 1 and 3 . Substitution of the OH group at C(4) by an amino group or by hydrogen weakened the inhibition by ΔΔG_diss = + 1.9 to + 3.1 kcal/mol. Similarly, the inhibition of the β‐galactosidase from bovine liver and from E. coli by the 4‐deoxy lactam 12 and the imidazole 14 , as compared to the one by the galacto‐configured lactam 9 and imidazole 10 , is weakened by deoxygenation at C(4) (ΔΔG_diss = + 2.6 and 4.5 kcal/mol, resp.). The effect of these substitutions on the inhibition of the C. saccharolyticum β‐glucosidase is slightly stronger than the one on the sweet almonds β‐glucosidases. The effect is also stronger on the inhibition by the imidazoles than by the lactams, and depends on the flexibility of the inhibitors. The amino and deoxy lactams 11 and 12 were prepared from the galactonolactam‐derived triflate 17 by substitution with azide and hydride, respectively, followed by hydrogenation. Azidation of the galacto‐configured imidazopyridine‐derived triflate 24 and hydrogenation gave the amino‐imidazole 13 . The deoxy lactam 20 was transformed to the manno‐ and gluco‐configured deoxy‐imidazoles 29 and 30 via the thionolactam 28 . Hydrogenolytic deprotection of 30 gave the deoxy‐imidazole 14 .     

New Triterpenoid Saponins from the Roots of Gypsophila paniculata L.

The seven new triterpenoid saponins 1 – 7 were isolated from the roots of Gypsophila paniculata L. Their structures were established by 1D ‐ and 2D‐NMR techniques, HR‐MS, and acid hydrolysis. The isolated compounds include 3,28‐O‐bidesmosides with or without a 4‐methoxycinnamoyl group (see 1 vs. 2 and 3 ), and 3‐O‐monoglucosides 4 – 7 . All isolated saponins 1 – 7 and their aglycones were evaluated for their α‐glucosidase inhibition activity. Compound 1 showed inhibitory activity against yeast α‐glucosidase with an IC₅₀ value of 100.9±3.3 μM , whereas compounds 2 – 7 were inactive.     

Synthesis and Evaluation as Glycosidase Inhibitors of Carbasugar‐Derived Spirodiaziridines,Spirodiazirines, and Spiroaziridines

The spirodiaziridines 6 and 9 , potential inhibitors of α‐ and β‐glucosidases, were prepared from the validoxylamine A‐derived cyclohexanone 5 . The trimethylsilyl protecting groups of 5 are crucial for the formation of 6 in good yields. Oxidation of 6 gave 7 . The diaziridine 6 (pK_HA=2.6) and the diazirine 7 did not inhibit the β‐glucosidases from almonds, the β‐glucosidase from Caldocellum saccharolyticum, and the α‐glucosidase from yeast. The N‐benzyl diaziridine 9 is a very weak inhibitor of the α‐glucosidase, but did not inhibit the β‐glucosidases. To see whether the weak inhibition is due to the low basicity of the diaziridines or to geometric factors, we prepared the spiro‐aziridines 21 and 25 and 1‐epivalidamine ( 32 ). The known cyclohexanone 10 was methylenated and epoxidised to 16 and 17 . Azide opening of 16 and 17 , mesylation, LiAlH₄ reduction, and deprotection gave the aziridines 21 and 25 respectively. 1‐Epivalidamine ( 32 ) was prepared from the known carba‐glucose 29 . The aziridine 25 (pK_HA=6.8) is a weak irreversible inhibitor of the β‐glucosidase from Caldocellum saccharolyticum and a weak reversible inhibitor of the α‐glucosidase from yeast, but did not inhibit the β‐glucosidases from almonds. The poorly stable aziridine 21 weakly inhibited the three enzymes. Similarly, 1‐epivalidamine (pK_HA=8.4) proved only a weak inhibitor. The known cyclopentylamine 34 (pK_HA=7.9), however, is a micromolar inhibitor of these enzymes. The much stronger inhibition by 34 is related to the pseudoaxial orientation of its amino group.     

Concise Synthesis and Antidiabetic Effect of Three Natural Triterpenoid Saponins Isolated from Fadogia ancylantha (Makoni tea)

The first concise synthesis of the bidesmosidic oleanolic acid saponins 1 – 3 isolated from Fadogia ancylantha (Makoni tea) have been accomplished through a ‘one‐pot sequential glycosylation’ strategy with two glycosyl 1‐(trichloroacetimidate)s as glycosyl donors. The synthesized natural products 1 – 3 were then evaluated for their inhibitory activities against α‐glucosidase, α‐amylase, and lipase. Among the assayed compounds 1 – 3 , compound 1 showed strong α‐glucosidase and α‐amylase inhibition, with IC₅₀ values of 160 and 180 μM , respectively. Moreover, compounds 2 and 3 showed strong inhibition against α‐glucosidase and lipase, with the respective IC₅₀ values of 170 and 190 μM , and 190 and 200 μM .     

Preparation of β2‐Amino Acid Derivatives (β2hThr, β2hTrp, β2hMet, β2hPro, β2hLys,Pyrrolidine‐3‐carboxylic Acid) by Using DIOZ as Chiral Auxiliary

The title compounds were prepared from valine‐derived N‐acylated oxazolidin‐2‐ones, 1 – 3, 7, 9 , by highly diastereoselective (≥ 90%) Mannich reaction (→ 4 – 6 ; Scheme 1) or aldol addition (→ 8 and 10 ; Scheme 2) of the corresponding Ti‐ or B‐enolates as the key step. The superiority of the ‘5,5‐diphenyl‐4‐isopropyl‐1,3‐oxazolidin‐2‐one’ (DIOZ) was demonstrated, once more, in these reactions and in subsequent transformations leading to various t‐Bu‐, Boc‐, Fmoc‐, and Cbz‐protected β²‐homoamino acid derivatives 11 – 23 (Schemes 3–6). The use of ω‐bromo‐acyl‐oxazolidinones 1 – 3 as starting materials turned out to open access to a variety of enantiomerically pure trifunctional and cyclic carboxylic‐acid derivatives.     

Synthesis of Novel Chromene,Pyridine, Pyrazole,Pyrimidine, and Imidazole Derivatives via One‐pot Multicomponent Reaction

New series of chromenes 2 – 4 , pyridines 5 – 8 , and pyranopyrazoles 9a,b were synthesized via one‐pot multicomponent reaction of 4‐tosyloxybenzaldehyde ( 1 ) and malononitrile with phenols, amines or hydrazines, and ethyl acetoacetate, respectively. Compound 9a was reacted with acetic anhydride, formic acid, or formamide to afford N ‐acetyl derivative 10 and pyrazolopyranopyrimidines 11 – 13 , respectively. Imidazole derivatives 14 and 15a – d were obtained by multicomponent reaction between compound 1 with ammonium acetate and benzil or aromatic amines in (1:2:1) or (1:1:1:1) ratio, respectively. The structures of new compounds were elucidated by elemental and spectral analyses.     

Regioselective 1,3‐Dipolar Cycloadditions of (1Z)‐1‐(Arylmethylidene)‐5,5‐dimethyl‐3‐oxopyrazolidin‐1‐ium‐2‐ide Azomethine Imines to Acetylenic Dipolarophiles

The 5,5‐dimethylpyrazolidin‐3‐one ( 4 ), prepared from ethyl 3‐methylbut‐2‐enoate ( 3 ) and hydrazine hydrate, was treated with various substituted benzaldehydes 5a – i to give the corresponding (1Z)‐1‐(arylmethylidene)‐5,5‐dimethyl‐3‐oxopyrazolidin‐1‐ium‐2‐ide azomethine imines 6a – i . The 1,3‐dipolar cycloaddition reactions of azomethine imines 6a – h with dimethyl acetylenedicarboxylate (=dimethyl but‐2‐ynedioate; 7 ) afforded the corresponding dimethyl pyrazolo[1,2‐a]pyrazoledicarboxylates 8a – h , while by cycloaddition of 6 with methyl propiolate (=methyl prop‐2‐ynoate; 9 ), regioisomeric methyl pyrazolo[1,2‐a]pyrazolemonocarboxylates 10 and 11 were obtained. The regioselectivity of cycloadditions of azomethine imines 6a – i with methyl propiolate ( 9 ) was influenced by the substituents on the aryl residue. Thus, azomethine imines 6a – e derived from benzaldehydes 5a – e with a single substituent or without a substituent at the ortho‐positions in the aryl residue, led to mixtures of regioisomers 10a – e and 11a – e . Azomethine imines 6f – i derived from 2,6‐disubstituted benzaldehydes 5f – i gave single regioisomers 10f – i .     

Assembly of Anionic Conjugated Polymer with 6‐O‐Modified PNP‐β‐Galactoside for Fluorescence Logic‐signal‐based Multiplex Detections of Enzymes

Anionic conjugated polymer (PFP‐SO) was assembled with a novel enzymatic substrate 6‐O‐modified PNP‐β‐galactoside ( 1 ) for sensitive multiplex enzyme detections. The PFP‐SO/ 1 /lipase/β‐galactosidase system has two chemical input signals which are Input 1 (lipase) and Input 2 (β‐galactosidase), and output optical signals such as fluorescence emission at 416 nm or 450 nm. Four types of logic gates, including YES, INH, NAND and AND, were successfully constructed and utilized for multiplex detections of lipase and β‐galactosidase in one tube.

     

Stereoselective Preparation of 3‐Amino‐2‐fluoro Carboxylic Acid Derivatives,and Their Incorporation in Tetrahydropyrimidin‐4(1H)‐ones,and in Open‐Chain and Cyclic β‐Peptides

The preparation of (2S,3S)‐ and (2R,3S)‐2‐fluoro and of (3S)‐2,2‐difluoro‐3‐amino carboxylic acid derivatives, 1 – 3 , from alanine, valine, leucine, threonine, and β³h‐alanine (Schemes 1 and 2, Table) is described. The stereochemical course of (diethylamino)sulfur trifluoride (DAST) reactions with N,N‐dibenzyl‐2‐amino‐3‐hydroxy and 3‐amino‐2‐hydroxy carboxylic acid esters is discussed (Fig. 1). The fluoro‐β‐amino acid residues have been incorporated into pyrimidinones ( 11 – 13 ; Fig. 2) and into cyclic β‐tri‐ and β‐tetrapeptides 17 – 19 and 21 – 23 (Scheme 3) with rigid skeletons, so that reliable structural data (bond lengths, bond angles, and Karplus parameters) can be obtained. β‐Hexapeptides Boc[(2S)‐β³hXaa(αF)]₆OBn and Boc[β³hXaa(α,αF₂)]₆‐OBn, 24 – 26 , with the side chains of Ala, Val, and Leu, have been synthesized (Scheme 4), and their CD spectra (Fig. 3) are discussed. Most compounds and many intermediates are fully characterized by IR‐ and ¹H‐, ¹³C‐ and ¹⁹F‐NMR spectroscopy, by MS spectrometry, and by elemental analyses, [α]_D and melting‐point values.     

Norbornane Mimics of Distorted β‐D‐Glucopyranosides – Inhibitors of β‐D‐Glucopyranosidases?

The racemic gluco‐configured norbornanes 4 and 16 were prepared and tested as inhibitors of β‐glucosidases. The known alcohol 5 was deprotected to provide the triol 6 . Silylation (→ 7 ), monobenzoylation (→ 8 / 9 ), and oxidation provided the regioisomeric ketones 10 and 11 . Reduction of 10 gave the desired endo‐alcohol 13 , albeit in low yield, while reduction of the isomeric ketone 11 provided mostly the altro‐configured endo‐alcohol 12 . The alcohol 13 was desilylated to 14 . Debenzoylation to 15 followed by hydrogenolytic deprotection gave the amino triol 4 that was reductively aminated to the benzylamine 16 . The amino triols 4 and 16 proved weak inhibitors of the β‐glucosidase from Caldocellum saccharolyticum ( 4 : IC₅₀ = 5.6 mm; 16 : IC₅₀ = 3.3 mm) and from sweet almonds ( 16 : IC₅₀ = 5.5 mm) . A comparison of 4 with the manno‐configured norbornane 3 shows that 3 is a better inhibitor of snail β‐mannosidase than 4 is of β‐glucosidases, in keeping with earlier results suggesting that these β‐glycosidases enforce a different conformational itinerary.     

Chiral sensing of Eu(III)‐containing achiral polymer complex from chiral amino acids coordination induction

The β‐diketonate‐based achiral polymer P‐1 could be synthesized by the polymerization of 3,7‐dibromo‐2,8‐dimethoxy‐5,5‐dioctyl‐5H‐dibenzo[b,d]silole ( M1 ) with (Z)?1,3‐bis(4‐ethynylphenyl)?3‐hydroxyprop‐en‐1‐one ( M2 ) via typical Sonogashira coupling reaction. The β‐diketonate unit in the main chain backbone of P‐1 can further coordinate with Eu(TTA)_x [TTA^? = 4,4,4‐trifluoro‐1‐(thiophen‐2‐yl)butane‐1,3‐dionate anion, X = 1, 2, 3] to afford corresponding Eu(III)‐containing polymer complexes. The resulting achiral polymer complex P‐2 (X = 2) can exhibit strong circular dichroism (CD) response toward both N‐Boc‐l and d‐ proline enantiomers. The CD signal was preliminarily attributed to coordination induction between chiral N‐Boc‐proline and the Eu(III) complex moiety. The linear regression analysis of CD sensing shows a good agreement between the magnitude of molar ellipticity and concentration of chiral N‐Boc‐l or d‐ proline, which indicates this kind Eu(III)‐containing achiral polymer complex can be used as a chiral probe for enantioselective recognition of N‐Boc‐l or d‐ proline enantiomers based on Cotton effect of CD spectra. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 3080–3086     

Photocycloisomerization of Boc‐Protected 5‐Alkenyl‐2,5‐dihydro‐1H‐ pyrrol‐2‐ones

On irradiation (254 nm), the newly synthesized Boc‐protected 5‐alkenyl‐2,5‐dihydro‐1H‐pyrrol‐2‐ones 13 undergo regioselective intramolecular [2+2] photocycloadditions. While the allyl derivatives 13a – 13c afford mainly azatricyclo[3.3.0.0^2,7]octanones, i.e., crossed cycloadducts, the butenyl‐ and pentenyl‐substituted compounds 13d and 13e isomerize preferentially to straight cycloadducts.     

Xanthones with α‐Glucosidase Inhibitory Activities from Aspergillus versicolor,a Fungal Endophyte of Huperzia serrata

Three new xanthones, namely huperxanthones A–C ( 1 – 3 , resp.), were obtained from the cultures of Aspergillus versicolor, a fungal endophyte of Huperzia serrata, together with 1,7‐dihydroxy‐8‐(methoxycarbonyl)xanthone‐3‐carboxylic acid ( 4 ), β‐diversonolic acid methyl ester ( 5 ), 4‐hydroxyvertixanthone ( 6 ), and sydowinin B ( 7 ). The structures of the new compounds were established by detailed NMR and MS analysis, especially by 2D‐NMR experiments. All xanthones were evaluated for their effects on α‐glucosidase. Compound 4 exhibited a potent inhibitory activity against α‐glucosidase with an IC₅₀ value of 0.24 mM (vs. 0.38 mM for acarbose). The rest of the compounds showed weak or no activity against α‐glucosidase.     

Lycopodium Alkaloids from Huperzia serrata

Three new lycopodium alkaloids, huperserramines A–C ( 1 – 3 , resp.), along with 15 known ones, lycopodine‐6α,11α‐diol ( 4 ), lycoposerramine H ( 5 ), lycoposerramine I ( 6 ), lycopodine‐6α‐ol ( 7 ), lycoposerramine M ( 8 ), diphaladine A ( 9 ), lycoposerramine K ( 10 ), lycoposerramine W ( 11 ), huperzine M ( 12 ), luciduline ( 13 ), phlegmariuine N ( 14 ), huperzine A ( 15 ), huperzine B ( 16 ), lycodine ( 17 ), and lycoposerramine R ( 18 ), were isolated from the whole plant of Huperzia serrata. Their structures were established by spectroscopic methods, including 2D‐NMR and MS analyses. All the isolates were evaluated for their inhibitory effects on acetylcholinesterase (AChE) and α‐glucosidase. As a result, lycopodine‐6α,11α‐diol ( 4 ) exhibited more potent α‐glucosidase inhibitory activity (IC₅₀ 148±5.5 μM ) than the positive control acarbose (IC₅₀ 376.3±2.7 μM ).     

A Simple and Convenient Strategy for the Synthesis of Novel Ten,Twelve, and Fourteen‐membered Phosphorus Macrocyclic Compounds

Synthesis of the title compounds 4(a – i) was accomplished through a two‐step process. The synthetic route involves the cyclization of equimolar quantities of 2,2′‐methylene(methyl)bis(4,6‐di‐tert‐butyl‐phenol) ( 1 ) with tris‐(2‐chloro‐ethyl) phosphite ( 2a ), tris‐(2‐bromo‐ethyl) phosphine ( 2b ), and tris‐bromo methyl phosphine ( 2c ) in the presence of sodium hydride in dry tetrahydrofuran at 45–50°C. They were further converted to the corresponding oxides, sulfides, and selenides under N₂ atmosphere by reacting them with hydrogen peroxide, sulfur, and selenium, respectively ( 4a – c , 4d – f, and 4g – i ). But the compounds 6a , b were prepared by the direct cyclocondensation of equimolar quantities of 1 with (2‐chloro‐ethyl)‐phosphonic acid dibromomethyl ester ( 5a ) and (2‐chloro‐ethyl)‐phosphonic acid bis(2‐bromo‐ethyl) ester ( 5b ) in the presence of sodium hydride in dry tetrahydrofuran at 45–50°C in moderate yields. All the newly synthesized compounds 4 ( a – i ) and 6 ( a – b ) exhibited moderate in vitro antibacterial and antifungal activities.