Synthesis and α‐Mannosidase Inhibitory Evaluation of (2R,3R,4S)‐ and (2S,3R,4S)‐2‐(Aminomethyl)pyrrolidine‐3,4‐diol Derivatives

The synthesis of 46 derivatives of (2R,3R,4S)‐2‐(aminomethyl)pyrrolidine‐3,4‐diol is reported (Scheme 1 and Fig. 3), and their inhibitory activities toward α‐mannosidases from jack bean (B) and almonds (A) are evaluated (Table). The most‐potent inhibitors are (2R,3R,4S)‐2‐{[([1,1′‐biphenyl]‐4‐ylmethyl)amino]methyl}pyrrolidine‐3,4‐diol ( 3fs ; IC₅₀(B)=5 μM , K_i=2.5 μM ) and (2R,3R,4S)‐2‐{[(1R)‐2,3‐dihydro‐1H‐inden‐1‐ylamino]methyl}pyrrolidine‐3,4‐diol ( 3fu ; IC₅₀(B)=17 μM , K_i=2.3 μM ). (2S,3R,4S)‐2‐(Aminomethyl)pyrrolidine‐3,4‐diol ( 6 , R?H) and the three 2‐(N‐alkylamino)methyl derivatives 6fh, 6fs , and 6f are prepared (Scheme 2) and found to inhibit also α‐mannosidases from jack bean and almonds (Table). The best inhibitor of these series is (2S,3R,4S)‐2‐{[(2‐thienylmethyl)amino]methyl}pyrrolidine‐3,4‐diol ( 6o ; IC₅₀(B)=105 μM , K_i=40 μM ). As expected (see Fig. 4), diamines 3 with the configuration of α‐D ‐mannosides are better inhibitors of α‐mannosidases than their stereoisomers 6 with the configuration of β‐D ‐mannosides. The results show that an aromatic ring (benzyl, [1,1′‐biphenyl]‐4‐yl, 2‐thienyl) is essential for good inhibitory activity. If the C‐chain that separates the aromatic system from the 2‐(aminomethyl) substituent is longer than a methano group, the inhibitory activity decreases significantly (see Fig. 7). This study shows also that α‐mannosidases from jack bean and from almonds do not recognize substrate mimics that are bulky around the O‐glycosidic bond of the corresponding α‐D ‐mannopyranosides. These observations should be very useful in the design of better α‐mannosidase inhibitors.     

Syntheses of 5‐(3‐Arylsydnon‐4‐yl)Tetrazole Derivatives

3‐Arylsydnone‐4‐carbohydroximic acid chlorides ( 1 ) could react with sodium azide to produce the corresponding 3‐arylsydnone‐4‐carbazidoximes ( 2 ), but not 1‐hydroxytetrazoles 3 . Treatment of 3‐arylsydnone‐4‐carbazidoximes ( 2 ) with acid chlorides such as acetyl chloride ( 4a ), propionyl chloride ( 4b ) and benzoyl chloride ( 4c ) in the presence of excess triethylamine generated the derivatives of the azidoximes 5 . To obtain the desired tetrazoles, the azidoximes 2 should first cyclize directly with acetyl chloride ( 4a ) or propionyl chloride ( 4b ) to afford the acetyl or propionyl derivatives 6 . The cyclized tetrazole derivatives 6 underwent deacylation upon heating in ethanol to give 1‐hydroxy‐5‐(3‐arylsydnon‐4‐yl)tetrazoles ( 3 ).     

Synthesis and Herbicidal Activities of Novel 3‐(α‐Hydroxymethylene) pyrrolidine‐2,4‐dione Derivatives Containing a Cyclopropane Moiety

A variety of novel 3‐(α‐hydroxymethylene)pyrrolidine‐2,4‐dione derivatives containing a cyclopropane moiety were designed and synthesized in satisfactory yields. Their structures were confirmed by ¹H NMR and HRMS. The bioassays indicated that most of the title compounds displayed some extent herbicidal activities at 100 mg/mL.     

Antibacterial and Antifungal Activities of 2‐(substituted ether)‐5‐(1‐phenyl‐5‐(trifluoromethyl)‐1H‐pyrazol‐4‐yl)‐1,3,4‐oxadiazole Derivatives

By replacing the amide bond into 1,3,4‐oxadiazole moiety, a series of 1‐phenyl‐5‐(trifluoromethyl)‐1H‐pyrazole derivatives bearing 1,3,4‐oxadiazole were synthesized and evaluated their antibacterial and antifungal activity. The bioassay results revealed that compounds 7a and 7b showed the strongest antibacterial activity toward pathogen Xanthomonas oryzae pv. oryzae with the EC50 values of 15.0 and 6.4 µg/mL, respectively; compound 6a exhibited comprehensive antifungal activity toward six kinds of fungi; compound 6f could selectively inhibit the growth of Sclertinia sclerotiorum and Rhizoctonia solani with the inhibition rates of 82.5 and 80.3% at the concentrate of 100 µg/mL, respectively; compound 7b exerted good antifungal activity toward Fusarium oxysporum, Cytospora mandshurica, and Rhizoctonia solani with the inhibition rates of 70.8, 69.5, and 71.5%, respectively. The results suggested that this kind of compounds could be further studied as promising antimicrobial agents.     

An Efficient Synthesis of Novel 2‐(5‐indolyl)‐1H‐benzimidazole Derivatives and Evaluation of Their Antimicrobial Activities

In this paper, we report the synthesis of novel 2‐(5‐indolyl)‐1H‐benzimidazole derivatives. The methodology involves the Sonogashira reaction of 4‐(1H‐benzimidazol‐2‐yl)‐2‐bromo‐N,N‐dimethylaniline ( 3 ) with variety of terminal alkynes to get corresponding novel 4‐(1H‐benzimidazol‐2‐yl)‐2‐alkynyl‐N,N‐dimethylaniline derivatives ( 4 ). These compounds on iodocyclization afforded novel iodoindolylbenzimidazole derivatives ( 5 ). The resulting compounds were functionalized further via palladium‐mediated carbon–carbon bond formation for generating novel structurally diversified heterocyclic compounds. All these newly synthesized compounds were evaluated for antimicrobial activity.     

Synthesis and Antimicrobial Activities of Novel Series of 3‐(4‐(2‐substituted thiazol‐4‐yl)phenyl)‐2‐(4‐methyl‐2‐substituted thiazol‐5‐yl)thiazolidin‐4‐one Derivatives

In the present investigation, a novel series of 3‐(4‐(2‐substituted thiazol‐4‐yl)phenyl)‐2‐(4‐methyl‐2‐substituted thiazol‐5‐yl)thiazolidin‐4‐one derivatives were synthesized by condensation of 2‐substituted‐4‐methylthiazole‐5‐carbaldehyde with 4‐(2‐substituted thiazol‐4‐yl)benzenamine followed by cyclo‐condensation with thioglycolic acid in toluene. All the newly synthesized compounds were characterized by spectral (IR, ¹H NMR, ¹³C NMR, and Mass) methods. The title compounds were screened for quantitative antibacterial activity (minimal inhibitory concentration). All compounds 7a , 7b , 7c , 7d , 7e , 7f , 7g , 7h and 8a , 8b , 8c , 8d , 8e , 8f , 8g , 8h show moderate to good antimicrobial activity, whereas compounds ( 7a , 7b , 7c , 7d , 7e , 7f , 7g , 7h ) also show moderate antifungal activity.     

Asymmetric Syntheses of 2‐(1‐Aminoethyl)phenols

Three different routes were probed for the synthesis of enantiomerically enriched 2‐(1‐aminoethyl)phenols and their methyl ethers. The first route centers on diastereoselective nucleophile addition to chiral imines. The second route has as key steps the enantioselective reduction of a ketone followed by nucleophilic substitution, and the third route involves a diastereoselective imine reduction. The efficiency of the approach depends on the substrate substitution pattern. All three methods work well for the parent compound 2‐(1‐aminoethyl)phenol ( 1 ) but the third route is the most efficient, providing the compound with >96% enantiomer excess in three steps with an overall yield of 71%. Conversely, for the ortho‐methyl analogue 2 , the first method is best. For the t‐Bu‐substituted analogue 3 , only moderate enantiomeric enrichment was achieved.     

Synthesis of Novel 1‐(5‐(Benzylsulfinyl)‐3‐methyl‐1,3,4‐thiadiazol‐2(3H)‐ylidene)‐thiourea/urea Derivatives and Evaluation of Their Antimicrobial Activities

A new series of 1‐(5‐(benzylsulfinyl)‐3‐methyl‐1,3,4‐thiadiazol‐2(3H)‐ylidene)‐thiourea/urea derivatives ( 1a – j ) were designed and synthesized. For the first time, (i) a new process was developed for N‐methylation of 1,3,4‐thiadiazole moiety using dimethyl carbonate an environmentally benign reagent in presence of N,N,N′,N′‐tetramethylethylenediamine and (ii) the sulfide was selectively oxidized to sulfoxide in higher yield by using chlorine (g) in aqueous acetic acid media under mild reaction condition. The synthesized compounds ( 1a – j ) were investigated for their antimicrobial activities. The tested compounds ( 1a – j ) were exhibited moderate to excellent antibacterial activities against both Gram‐positive and Gram‐negative bacterial strains. The same compounds exhibited good antifungal activities against selected fungal strains. Particularly, the compounds 1b , 1d , 1h , and 1i were proved to be promising leads exhibiting both antibacterial and antifungal activities compared with standard drugs, ciprofloxacin, and fluconazole. The presence of 1,3,4‐thiadiazole moiety has a significant role in the display of antimicrobial activity. In addition, the presence of both sulfinyl and thiourea or urea functionalities has enhanced the activity as per obtained antimicrobial activity data.     

Synthesis of 9‐[2‐(2‐hydroxymethyl‐2‐methyl‐, ‐(2‐acetoxymethyl‐2‐methyl‐, ‐(2,2‐di(hydroxymethyl)‐, and ‐(2,2‐Di(acetoxymethyl)‐1,3‐dioxan‐5‐yl)ethyl] derivatives of guanine and 2‐aminopurine

Synthesis of 9‐[2‐(2‐hydroxymethyl‐2‐methyl‐, ‐(2‐acetoxymethyl‐2‐methyl‐, ‐(2,2‐di(hydroxymethyl)‐, and ‐(2,2‐di(acetoxymethyl)‐1,3‐dioxan‐5‐yl)ethyl] derivatives of guanine and 2‐aminopurine, 2–9 , has been accomplished in seven to eight step sequences from readily available 1‐(tert‐butyldiphenylsilyloxy)‐acetone, 1,3‐di(tert‐butyldiphenylsilyloxy)acetone, and the diol 10 . Formation of cyclic ketals 11 and 12 was carried out successfully under an acidic condition using a catalytic amount of methanesulfonic acid along with excess anhydrous copper(II) sulfate in toluene. Subsequent reactions of desilylation, acetylation, hydrogenolysis, and bromination afforded the key intermediates 19 and 20 , which were coupled with 2‐amino‐6‐chloropurine to produce the purine compounds 21 and 22 in good yields. Guanine derivatives 2–5 were obtained from 21 and 22 by hydrolysis and acetylation, while the dechlorination and hydrolysis of 21 and 22 yielded the 2‐aminopurine compounds 6–9 .     

Synthesis of 3‐(5‐Methylthiophen‐2‐yl)coumarins and Their Photochromic Dihetarylethene Derivatives

Novel unsymmetrical di(thienyl)maleic acid anhydride, including coumarin moiety, has been designed and synthesized. Its photochromism study and fatigue resistance estimation are reported. Microwave‐assisted procedure has been successfully used for synthesis of 3‐(5‐methylthiophen‐2‐yl)coumarins.     

Syntheses of substituted 2‐(2‐alkylthio‐1‐benzyl‐5‐imidazolyl)‐1,3,4‐oxadiazoles

Starting from the readily available benzylamine hydrochloride a series of 2‐(2‐alkylthio‐1‐benzyl‐5imida‐zolyl)‐1,3,4‐oxadiazoles were prepared.     

Efficient Domino Approach to Polysubstituted 2‐Hydroxyindole‐3,4‐(2H,5H)‐diones

Concise and efficient domino [3 + 2] heterocyclization promoted by HCOOH has been established for unprecedented synthesis of 15 examples of 2‐hydroxyindole‐3,4‐(2H,5H)‐diones in good yields. The present methodology shows attractive properties such as mild reaction conditions, concise one‐pot operation, short reaction periods of 15–20 min, and easy purification. The resulting 2‐hydroxyindole‐3,4(2H,5H)‐diones are of importance for organic and medicinal research.     

Synthesis and Antibacterial Activities of 2‐(1‐Aryl‐5‐Methyl‐1,2,3‐triazol‐4‐yl)‐1,3,4‐Oxadiazole Derivatives

Eighteen novel 2‐(1‐aryl‐5‐methyl‐1,2,3‐triazol‐4‐yl)‐1,3,4‐oxadiazole derivatives and two acylhydrazone intermediate compounds were synthesized by various pathways starting from 1‐aryl‐5‐methyl‐1,2,3‐triazol‐4‐formhydrazide ( 1 ). All products were identified by spectroscopic analysis, and 2‐(1‐aryl‐5‐methyl‐1,2,3‐triazol‐4‐yl)‐5‐benzalthio‐1,3,4‐oxadiazole was further validated by X‐ray crystallography. Results from primary antibacterial activity tests indicated that most of the compounds were effective against E. coli, P. aeruginosa, B. subtilis and S. aureus.     

Synthesis of 3,4‐Dialkyl‐5‐(1‐oxo‐ethyl)‐3H‐thiazole‐2‐thiones Derivatives and Their Pesticidal Activity

By interaction of N‐methyl(ethyl)‐dithiocarbamate sodium salt with 3‐chloro‐pentane‐2,4‐dion the 1‐(3‐alkyl‐4‐methyl‐2‐thioxo‐2,3‐dihydro‐thiazol‐5‐yl)‐ethanones 1 , 2 and corresponding oximes 7 , 8 were synthesized. On the basis of the mentioned compounds hydrazono ( 3 , 4 ), ureayl and thioureayl ( 5 , 6 ) derivatives, substituted oximes ( 9 , 10 ) and azinyl oximes ( 11 , 12 ) were obtained. The structures of synthesized compounds were confirmed by proton nuclear magnetic resonance spectroscopy and elemental analysis. The pesticidal activities of synthesized compounds were studied. Some of the synthesized compounds simultaneously have shown growth stimulant and fungicidal activity.     

Synthesis and Bioactivities of Novel 1‐(3‐Chloropyridin‐2‐yl)‐N‐Substituted‐5‐(Trifluoromethyl)‐Pyrazole Carboxamide Derivatives

A series of novel 1‐(3‐chloropyridin‐2‐yl)‐N‐substituted‐5‐(trifluoromethyl)‐pyrazole carboxamide derivatives TC₁ , TC₂ , TC₃ , TC₄ , TC₅ , TC₆ , TC₇ , TC₈ , TC₉ , TC₁₀ , TC₁₁ were synthesized and characterized by IR, ¹H NMR, ¹³C NMR, MS, and elemental analysis. All the target compounds were tested in vitro for their antibacterial activities and antifungal activities. The preliminary bioassays indicated that compound TC₆ exhibited excellent activity against Xanthomonas oryzae (94.9% and 84.9%) at different concentrations (200 µg/mL and 100 µg/mL), which was higher than that of Bismerthiazol (94.6% and 64.0%), respectively. At the same time, most of the compounds exhibited moderate antifungal activities against four kinds of phytopathogenic fungi     

Syntheses and characterization of 2‐hydroxy‐N‐(2′‐hydroxyalkyl)acetamides

The reaction of glycolic acid 1 with some β‐aminoalcohols 2–8 without solvent, with temperature and time controlled, led to the syntheses of2‐hydroxy‐N‐(2′‐hydroxyalkyl)acetamides 9–15. All compounds studied in this work were characterized by ¹H, ¹³C, and ¹⁵N NMR, infrared, and mass spectroscopy. The structure of compound 13 was established by a single‐crystal X‐ray diffraction study. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 153–158, 1999     

Ultrasonic and Grinding Aptitudes of One‐Pot Synthesis of 5‐(4‐Chlorophenyl)‐7‐(3,4‐Dimethyl Phenyl)‐2‐oxo‐2H‐Pyrano[2,3‐b]Pyridine Derivatives as Antibacterial Agents

A simple facile “one‐pot” synthesis of 5‐(4‐chlorophenyl)‐7‐(3,4‐dimethyl phenyl)‐2‐oxo‐2H‐pyrano[2,3‐b]pyridine derivatives via three‐component reaction of chalcone, ethyl‐2‐substituted acetate, and ammonium acetate under ultrasonic irradiation and grinding tools. The newly synthesized compounds were evaluated for their antibacterial activity against ATCC 25923, ATCC 10987, ATCC 274, and SM514. All the synthesized compounds have been characterized on the basis of their elemental analyses and spectral data.     

One‐Pot Syntheses of 2‐(2‐Sulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetic Acid Derivatives via Reactions of 3‐(2‐Isothiocyanatophenyl)prop‐2‐enoic Acid Derivatives with Thiols or Sodium Sulfide

Two efficient methods for the preparation of 2‐(2‐sulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetic acid derivatives 3 under mild conditions have been developed. The first method is based on the reaction of 3‐(2‐isothiocyanatophenyl)prop‐2‐enoates 1a – 1c with thiols in the presence of Et₃N in THF at room temperature, leading to the corresponding dithiocarbamate intermediates 2 , which underwent spontaneous cyclization at the same temperature by an attack of the S‐atom at the prop‐2‐enoyl moiety in a 1,4‐addition manner (Michael addition) to give 2‐(2‐sulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetates in one pot. The second method involves treatment of 3‐(2‐isothiocyanatophenyl)prop‐2‐enoic acid derivatives 1b – 1d with Na₂S leading to the formation of 2‐(2‐sodiosulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetic acid intermediates 5 by a similar addition/cyclization sequence, which are then allowed to react with alkyl or aryl halides to afford derivatives 3 . 2‐(2‐Thioxo‐4H‐3,1‐benzothiazin‐4‐yl)acetic acid derivatives 6 can be obtained by omitting the addition of halides.