Acetylenic Replacement of Albicidin's Methacrylamide Residue Circumvents Detrimental E/Z Photoisomerization and Preserves Antibacterial Activity

The natural product albicidin is a highly potent inhibitor of bacterial DNA gyrase. Its outstanding activity, particularly against Gram-negative pathogens, qualifies it as a promising lead structure in the search for new antibacterial drugs. However, as we show here, the N-terminal cinnamoyl moiety of albicidin is susceptible to photochemical E/Z isomerization. Moreover, the newly formed Z isomer exhibits significantly reduced antibacterial activity, which hampers the development and biological evaluation of albicidin and potent derivatives thereof. Hence, we synthesized 13 different variants of albicidin in which the vulnerable para-coumaric acid moiety was replaced; this yielded photostable analogues. Biological activity assays revealed that diaryl alkyne analogues exhibited virtually undiminished antibacterial efficacy. This promising scaffold will therefore serve as a blueprint for the design of a potent albicidin-based drug.     

Surprising Antibacterial Activity and Selectivity of Hydrophilic Polyphosphoniums Featuring Sugar and Hydroxy Substituents

There is currently an urgent need for the development of new antibacterial agents to combat the spread of antibiotic‐resistant bacteria. We explored the synthesis and antibacterial activities of novel, sugar‐functionalized phosphonium polymers. While these compounds exhibited antibacterial activity, we unexpectedly found that the control polymer poly(tris(hydroxypropyl)vinylbenzylphosphonium chloride) showed very high activity against both Gram‐negative Escherichia coli and Gram‐positive Staphylococcus aureus and very low haemolytic activity against red blood cells. These results challenge the conventional wisdom in the field that lipophilic alkyl substituents are required for high antibacterial activity and opens prospects for new classes of antibacterial polymers.     

Oxidative Cyclization of Isoniazid with Fluoroquinolones: Synthesis,Antibacterial and Antitubercular Activity of New 2,5‐disubstituted‐1,3,4‐Oxadiazoles

We report herein one‐pot synthesis and the antibacterial and antitubercular activities of 2,5‐disubstituted‐1,3,4‐oxadiazole compounds obtained by hybridization of a well‐known antitubercular agent isoniazid (INH ) with four broad‐spectrum antibiotics belonging to fluoroquinolone (FQ ) class. The work is aimed at designing and developing potential antimicrobial agents having synergistic action due to the coupling of INH and FQ through the biologically active 1,3,4‐oxadiazole nucleus. The synthesized compounds are expected to have low toxicity as compared to INH due to the absence of free hydrazide group in the chemical structure of the prepared derivatives. The antibacterial activities of the 1,3,4 oxadiazole derivatives were also tested against several Gram‐positive and Gram‐negative pathogenic bacterial strains. The antitubercular activity was evaluated against M. tuberculosis H₃₇Rv strain, and the results were compared with that of the positive control INH . The title compounds showed excellent antimicrobial and promising antitubercular activity in comparison to the parent fluoroquinolones and INH , respectively.     

Microwave Assisted Green Synthesis of Pyrazole, 1, 2, 3‐ Triazole Based Novel Benzohydrazones and Their Antibacterial Activities

A series of novel pyrazole, triazole based benzohydrazones ( 7a‐l ) were synthesized via conventional and microwave methods in the presence of acetic acid catalyst. Microwave method provided green and economical approach towards the synthesis of novel Schiff bases ( 7a‐l ). Some intermediates and all the final compounds were characterized by NMR, mass, and elemental analysis. The compounds were screened for their in vitro antibacterial activity against Gram‐negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and Gram‐positive bacteria (Staphylococcus aureus and Bacillus cereus). Compounds 7e and 7g showed good antibacterial activity.     

Synthesis of Some 3‐(4‐Aryl‐benzofuro[3,2‐b]pyridin‐2‐yl)coumarins and Their Antimicrobial Screening

The synthesis of some 3‐(4‐aryl‐benzofuro[3,2‐b]pyridin‐2‐yl)coumarins 3a–r has been carried out by the reaction of 3‐coumarinoyl methyl pyridinium salts 1a–c with 2‐arylidene aurones 2a–f in the presence of ammonium acetate and acetic acid under Kröhnke's reaction conditions. All the synthesized compounds were characterized by analytical and spectral data. They have been screened for their antibacterial activity against Escherichia coli (ATCC 25922) as Gram‐negative bacteria, Bacillus subtillis (ATCC 1633) as Gram‐positive bacteria and antifungal activity against Aspergillus niger (ATCC 9029).     

Synthesis and Antibacterial Activity of 3‐(Substituted arylmethyl)‐4‐acylaminomethyloxazolidin‐2‐ones and Derivatization to Symmetrical Twin‐Drug Type Molecules

In connection with our studies on antibacterial active compounds in the class of new oxazolidinones against Gram‐positive (Staphylococcus aureus) and Gram‐negative (Escherichia coli) strains, some molecular modifications were attempted. In this study, molecular modifications of 4‐aminomethyloxazolidin‐2‐ones ( 3a ) to the corresponding 4‐acylaminomethyloxazolidin‐2‐one derivatives ( 3c–d ) and preparations of the represented twin‐drug type molecules ( 10–14 ) were investigated. Some additional 4‐dialkylaminomethyloxazolidin‐2‐ones ( 2 ) were also synthesized. The synthesized compounds were evaluated for antibacterial activity with Gram‐positive (S. aureus) and Gram‐negative (E. coli) strains.     

Oxidative Rearrangement of Isatins with Arylamines Using H2O2 as Oxidant: A Facile Synthesis of Quinazoline‐2,4‐diones and Evaluation of Their Antibacterial Activity

A green and highly efficient synthetic method for the synthesis of quinazoline‐2,4‐diones with hydrogen peroxide as the terminal oxidant has been developed. The reaction features the mild reaction conditions, broad substrate scope, metal‐free catalysts, and sole byproduct water. A plausible mechanism for this process was proposed. Moreover, an antibacterial activity study was performed to evaluate the antimicrobial activities towards two Gram‐negative bacterial strains (Escherichia coli , and Klebsiella pneumonia ) and two Gram‐positive bacterial strains (Staphylococcus epidermidis , and Staphylococcus aureus ) using the Broth microdilution method.     

Pinensins: The First Antifungal Lantibiotics

Lantibiotics (lanthionine‐containing antibiotics) from Gram‐positive bacteria typically exhibit activity against Gram‐positive bacteria. The activity and structure of pinensin A ( 1 ) and B ( 2 ), lantibiotics isolated from a native Gram‐negative producer Chitinophaga pinensis are described. Surprisingly, the pinensins were found to be highly active against many filamentous fungi and yeasts but show only weak antibacterial activity. To the best of our knowledge, lantibiotic fungicides have not been described before. An in‐depth bioinformatic analysis of the biosynthetic gene cluster established the ribosomal origin of these compounds and identified candidate genes encoding all of the enzymes required for post‐translational modification. Additional encoded functions enabled us to build up a hypothesis for the biosynthesis, export, sensing, and import of this intriguing lantibiotic.     

Design,Synthesis, and In Vitro Antibacterial Activities of Propylene‐tethered Gatifloxacin‐isatin Hybrids

A series of novel mono‐/bis‐isatin‐gatifloxacin hybrids 3a–f and 4a–f tethered through propylene were designed, synthesized, and evaluated for their in vitro antibacterial activities against representative Gram‐positive and Gram‐negative pathogens. The results indicated that all mono‐isatin‐gatifloxacin hybrids exhibited considerable antibacterial activities with minimum inhibitory concentration ranging from 0.06 to 4 μg/mL against the majority of the tested strains. In particular, the mono‐isatin‐gatifloxacin hybrid 3b was found as potent as the parent gatifloxacin against Gram‐positive organisms and could act as a starting point for further optimization.     

Microwave‐Assisted Synthesis and Spectral Characterization of Biological Activity Heterocyclic Thiosemicarbazone and Its Organometallic Derivatives

The thiosemicarbazone coordinates to metal through the thionic sulfur and the azomethine nitrogen. The thiosemicarbazone was obtained by the thiosemicarbazide with 3‐acetyl‐2,5‐dimethylfuran by microwave irradiation. Metal complexes were prepared by the reaction of thiosemicarbazone with metal salts. IR, ¹H, ¹³C NMR, FAB‐mass spectroscopic methods, and elemental analysis elucidated the structure of these compounds. The antibacterial activity of these compounds were first tested in vitro by the disk diffusion assay against two Gram‐positive and two Gram‐negative bacteria, and then minimum inhibitory concentration was determined, chloramphenicol as reference drug. The results showed that copper ( II ) metal complex of the thiosemicarbazone ( 1.1 ) is a better inhibitor as compared with chloramphenicol.     

Synthesis and Biological Evaluation of New Ibuprofen‐1,3,4‐oxadiazole‐1,2,3‐triazole Hybrids

A new hybrid polydentate template comprising distinctive pharmacophoric groups, namely, ibuprofen, 1,3,4‐oxadiazole, and 1,2,3‐triazole linked through a thioether bridge was achieved by one‐pot synthesis by exploring multicomponent Cu‐catalyzed “click chemistry” approach. The target structures were characterized by NMR, IR, and LC‐Mass. The X‐ray analysis of 2‐(1‐(4‐isobutylphenyl)ethyl)‐5‐(((1‐(3‐nitrophenyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl)thio)‐1,3,4‐oxadiazole ( 8a ) confirmed the assigned structure. The in vitro antibacterial and anticancer activity of these compounds revealed that 2‐(1‐(4‐isobutylphenyl)ethyl)‐5‐(((1‐phenyl‐1H‐1,2,3‐triazol‐4‐yl)methyl)thio)‐1,3,4‐oxadiazole ( 8b ) demonstrated more potent antibacterial activity against Gram‐negative strains (Escherichia coli and Pseudomonas aeruginosa) and 2‐(((1‐(2,4‐dimethylphenyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl)thio)‐5‐(1‐(4 isobutylphenyl)ethyl)‐1,3,4‐oxadiazole ( 8e ) exhibited anticancer activity with IC₅₀ of 27.50 and 31.03 μg/mL against HeLa and MCF‐7 cell lines, respectively.     

Improvement of the antimicrobial potency,pharmacokinetic and pharmacodynamic properties of albicidin by incorporation of nitrogen atoms

The worrisome development and spread of multidrug-resistant bacteria demands new antibacterial agents with strong bioactivities particularly against Gram-negative bacteria. Albicidins were recently structurally characterized as highly active antibacterial natural products from the bacterium Xanthomonas albilineans. Albicidin, which effectively targets the bacterial DNA-gyrase, is a lipophilic hexapeptide mostly consisting of para amino benzoic acid units and only one α-amino acid. In this study, we report on the design and synthesis of new albicidins, containing N-atoms on each of the 5 different phenyl rings. We systematically introduced N-atoms into the aromatic backbone to monitor intramolecular H-bonds and for one derivative correlated them with a significant enhancement of the antibacterial activity and activity spectrum, particularly also towards Gram-positive bacteria. In parallel we conducted DFT calculations to find the most stable conformation of each derivative. A drastic angle-change was observed for the lead compound and shows a preferred planarity through H-bonding with the introduced N-atom at the D-fragment of albicidin. Finally, we went to the next level and conducted the first in vivo experiments with an albicidin analogue. Our lead compound was evaluated in two different mouse experiments: In the first we show a promising PK profile and the absence of toxicity and in the second very good efficiency and reduction of the bacterial titre in an E. coli infection model with FQ-resistant clinically relevant strains. These results qualify albicidins as active antibacterial substances with the potential to be developed as a drug for treatment of infections caused by Gram-negative and Gram-positive bacteria.

A systematic pyridine-scan of the albicidin molecule provides a new lead structure with improved antimicrobial properties.     

Microwave‐assisted Synthesis,Characterization, and Density Functional Theory Study of Biologically Active Ferrocenyl Bis‐pyrazoline and Bis‐pyrimidine as Organometallic Macromolecules

Organometallic macromolecules such as ferrocenyl bis‐pyrazoline ( 2 , 3 ) and bis‐pyrimidine ( 4 , 5 ) derivatives were synthesized by reacting ferrocenyl bis‐chalcone 1 with thiosemicarbazide/phenylhydrazine/guanidine hydrochloride/thiourea, respectively, under microwave irradiation. Ferrocenyl bis‐chalcone 1 was synthesized by reacting acetyl ferrocene with terephthalaldehyde. Synthesized compounds were characterized by using IR, ¹H NMR, ¹³C NMR, EI‐MS, and elemental analysis. In vitro antibacterial activity against two Gram‐negative and two Gram‐positive bacteria was determined by the disc diffusion assay. Moreover, minimum inhibition concentrations were also measured with reference to chloramphenicol. Thioamide functionally containing ferrocenyl bis‐pyrazoline derivative 2 shows the best antibacterial activity on Escherichia coli and Salmonella typhimurium, among all tested compounds including the reference drug chloramphenicol. The structure–activity relationship is also developed by using computational calculations with density functional theory (DFT)/B3LYP method.     

Antimicrobial and Antimalarial Activity of Novel Synthetic Mononuclear Ruthenium(II) Compounds

The present work was aimed that the two Ruthenium compounds namely, [Ru(A)₂(B)]Cl₂, where A = 1,10‐phenanthroline; B = 2‐NO₂‐phenyl thiosemicarbazone (Compound R₁)/2‐OH‐phenyl thiosemicarbazone (Compound R₂) have been tested for antibacterial activity at the concentrations of 1 mg/mL against various Gram‐Positive organisms (Lactobacillus, Staphylococcus pyrogenes, Bacillus subtilis, Staphylococcus aureus & Bacillus megatarium) and Gram‐Negative organisms (Pseudomonas aeruginosa, Escherichia coli, Proteus vulgaris, Enterobacter aerogenes, Salmonella paratyphi, Klebsiella pneumonia & Proteus mirabilis). The compounds were also tested for antifungal activity against Aspergillus clavatus, Aspergillus niger, Colletotrichum & Penicillium notatum by using agar diffusion assay and antimalarial activity against Plasmodium falciparum (Strain 3D7) using MTT assay. The results concluded that the compound R₁ exhibited significant antibacterial activity than R₂ against Gram‐Negative bacteria with zones of inhibition ranging from 15‐20 mm. and mild antibacterial activity against Gram‐Positive bacteria in comparison to tetracycline, streptomycin and rifampicin. These complexes were found to have moderate antifungal activity with no activity was however observed against Aspergillus niger. The compound, R₁ exhibited antimalarial activity at 10 μg/mL, whereas R₂ did not show antimalarial activity upto 50 μg/mL. Sensitivity to the compounds was greatest in the gram‐negative bacteria, followed by the gram‐positive bacteria and fungi.     

Synthesis,Characterization, and In Vitro Antibacterial Activities of Macromolecules Derived from Bis‐Chalcone

We investigated the antibacterial activity of some new macromolecules such as bis‐pyrazoline, bis‐pyrazole, bis‐pyrimidines prepared from the reaction of bis‐chalcone with thiosemicarbazide/phenyl hydrazine/guanidine hydrochloride/thiourea. All the macromolecules have been characterized by IR, ¹H NMR, ¹³C NMR, mass and elemental analyses. The antibacterial activity of these compounds was first tested in vitro by the disc diffusion assay against two Gram‐positive and two Gram‐negative bacteria, and then the minimum inhibitory concentration was determined with the reference to standard drug chloramphenicol. The results showed that pyrazoline derivative showed better antibacterial activity on S. typhimurium and E. coli than the reference drug chloramphenicol.     

A Facile and Efficient Synthesis of 2‐(5‐(4‐Substitutedphenyl)‐4, 5‐dihydro‐3‐phenylpyrazol‐1‐yl)‐6‐Substitutedbenzothiazoles and Their Biological Studies

A series of new 1‐substituted 3, 5‐diarylpyrazolines ( 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ) were synthesized in good yield by both conventional and microwave‐assisted synthesis from α, β‐ unsaturated ketones ( 6 , 7 , 8 , 9 ) in n‐butanol and benzothiazole hydrazines ( 2 , 3 , 4 , 5 ). All the new compounds were characterized by IR, NMR, and mass spectral data. The synthesized compounds ( 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ) were evaluated for antibacterial and anthelmintic activities. The compounds showed potent anthelmintic activity against earthworm species (Eudrilus eugeniae) and moderate antibacterial activity against bacterial strains such as Gram positive bacteria, Enterococcus faecalis, Staphylococcus aureus, and Bacillus subtilis, and Gram negative bacteria, Escherichia coli and Proteus mirabilis.     

Di‐N‐Methylation of Anti‐Gram‐Positive Aminoglycoside‐Derived Membrane Disruptors Improves Antimicrobial Potency and Broadens Spectrum to Gram‐Negative Bacteria

The effect of di‐N‐methylation of bacterial membrane disruptors derived from aminoglycosides (AGs) on antimicrobial activity is reported. Di‐N‐methylation of cationic amphiphiles derived from several diversely structured AGs resulted in a significant increase in hydrophobicity compared to the parent compounds that improved their interactions with membrane lipids. The modification led to an enhancement in antibacterial activity and a broader antimicrobial spectrum. While the parent compounds were either modestly active or inactive against Gram‐negative pathogens, the corresponding di‐N‐methylated compounds were potent against the tested Gram‐negative as well as Gram‐positive bacterial strains. The reported modification offers a robust strategy for the development of broad‐spectrum membrane‐disrupting antibiotics for topical use.     

Total Syntheses of Cystobactamids and Structural Confirmation of Cystobactamid 919‐2

The cystobactamids are a family of antibacterial natural products with unprecedented chemical scaffolds that are active against both Gram‐positive and Gram‐negative pathogens. Herein, we describe the first total synthesis of cystobactamid 919‐2 from three fragments. Our convergent synthesis enabled both the confirmation of the correct structure and the determination of the absolute configuration of cystobactamid 919‐2.     

Synthesis and Antimicrobial Studies of Selenadiazolo Benzimidazoles

An efficient and eco‐friendly method has been developed for the synthesis of selenadiazolo benzimidazoles by the condensation of N‐benzylbenzo[c][1,2,5]selenadiazole‐4,5‐diamine with various aromatic aldehydes catalyzed by xanthan sulfuric acid. All the synthesized compounds 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i , 5j were evaluated for in vitro antibacterial activity against Gram‐positive bacterial strains (Bacillus subtilis, Staphylococcus aureus, and Streptococcus pyogenes), and Gram‐negative bacterial strains (Escherichia coli, Klebsiella pneumonia, and Salmonella typhimurium) and antifungal against Aspergillus niger, Candida albicans, and Aspergillus flavus (Fungi). Compound 5i emerged as the most interesting compound in this series exhibiting excellent antimicrobial activity.     

Synthesis and Antibacterial Evaluation of Novel Spiro[indole‐pyrimidine]ones

An efficient route for the synthesis of novel spiro[indole‐pyrimidine]ones in high to excellent yields has been investigated through one‐pot reactions of phenacylidenetriphenylphosphoranes, oxindoles, and thiourea. Their antibacterial activities were studied against Gram‐positive bacteria and Gram‐negative bacteria using disc diffusion method. The results showed that most of the synthesized compounds are effective against Gram‐positive bacteria.