Synthesis and discovery of N-(1-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl)-[1,1′-biphenyl]-2-carboxamide derivatives as antimicrobial agents

Novel dihydro-1H-imidazole-2-yl)-[1,1′-biphenyl]-2-carboxamides ( 4a-l ) was achieved using a three-step synthesis process and evaluated as antimicrobial agents. These compounds were characterized through FTIR, NMR, LCMS and evaluated for DNA gyrase inhibition potentials and antimicrobial properties against Gram-negative bacteria Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 424), Klebsiella pneumoniae MTCC 530 and Gram-positive bacteria Staphylococcus aureus (MTCC 3160), Corynebacterium diphtheriae (MTCC 116) and Streptococcus pyogenes (MTCC 442). Excellent DNA gyrase inhibition exhibited by compound 4f (IC₅₀ 0.2 μM and relative percentage activity 96.24%). A broad spectrum of antimicrobial activity showed by compounds 4d , 4f and 4 k with a Minimal Inhibitory Constant (MIC) of 1.05, 1.35 and 1.25 μg mL⁻¹, respectively.     

Synthesis and biological activities of nitro-hydroxy-phenylquinolines; validation of antibiotics effect over DNA gyrase inhibition and antimicrobial activity

A family of 11 nitrophenol 2-nitro-5-(4-substituted phenylquinolin-2-yl)phenol derivatives (4, 4a-j) was effectively synthesized as antimicrobial medications. A mixture of the substituted 3-hydroxy-4-nitrobenzaldehyde substituted aromatic amine and substituted phenylacetylenes were used to synthesis the title compounds 4, 4a-j. Antimicrobialactivity potential of 4, 4a-j was evaluated against Streptococcus pyogenes (MTCC 442), Staphylococcus aureus (MTCC 96), Pseudomonas aeruginosa (MTCC 424), and Escherichia coli (MTCC 443). DNA gyrase inhibition studies carried out to understand the mechanism ofaction of the antimicrobial effect of target compounds. HRBC membrane stabilization (in vitro) property was also assessed as a representative human cellular cytotoxic effect of 4, 4a-j since HRBC alike lysosomal cells and the lysozyme activity leads to inflammation and its adverse effects in cellular systems. Results reveal that compounds 4c and 4h have remarkable antibacterial activity and screened for further preclinical studies.     

Novel pyrazole-biphenyl-carboxamides for SARS-CoV2 entry-level restriction and microbial infections

Microbial diseases including viral infection are big issues globally. Effective medicinal discovery for them is the need for the day. In this study, we report pyrazole-biphenyl-carboxamides ( 4a-l ) validated for their SARS-CoV2 entry-level restriction effect over studying the protein–protein interaction of SARS-CoV2 with human ACE protein. Their extended antimicrobial properties were also evaluated. Online and offline software tools predicted MD simulation and ADMET druggability in silico. The antimicrobial efficacy of all compounds was also evaluated against Gram+^ve Streptococcus pneumoniae (MTCC 1936), Staphylococcus aureus (MTCC 737) and Gram-^ve Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 424) (bacteria). In the results, compounds 4g and 4i were evenly active against both bacteria at a low concentration range (MIC: 1.00 to 9.5 μg/mL) and displayed lesser toxicity to tested mammalian cells (EC₁₀₀ = 75 μg/mL). Furthermore, it was able to kill metabolically inactive bacterial cells and eradicate established biofilms of Methicillin-resistant Staphylococcus aureus (MRSA). Both the compounds inhibited DNA gyrase well with an IC₅₀ 0.25 μM (96% relative activity) and 0.52 μM (97% relative activity) respectively. Compounds ( 4a-l ) showed restrictive efficiency of SARS-CoV2 spike protein (SC2SP) and human angiotensin-converting enzyme 2 (hACE2) entry-level association in COVID-19 in silico. To assess this ability, firstly, we identified the crucial amino acid residues involved in the interface of SARS-CoV-2 and hACE2 virtually. We recognized the ability of 4a-l binding to the binding interface to SARS-CoV2; thus, the interaction of SC2SP-hACE2 was effectively inhibited.     

Synthesis,Antimicrobial, and Antioxidant Screening of Aryl Acetic Acid Incorporated 1,2,4‐Triazolo‐1,3,4‐Thiadiazole Derivatives

Some novel [1,2,4]triazolo[3,4‐b][1,3,4]thiadiazole derivatives were synthesized from aryl acetic acids. All the synthesized derivatives were selected for the screening of antibacterial potential against Gram‐positive bacteria [Staphylococcus aureus (MTCC 3160) and Micrococcus luteus (MTCC 1538)] and Gram‐negative bacteria [Escherichia coli (MTCC 1652) and Pseudomonas aeruginosa (MTCC 424)] and antifungal potential against Aspergillus niger (MTCC 8652) and Candida albicans (MTCC 227), and free radical scavenging activity through 2,2‐diphenyl‐2‐picrylhydrazyl hydrate method. The compounds TH‐4 , TH‐13 , and TH‐19 were found to be more potent antimicrobial agents compared to standard drugs. The compounds TH‐3 , TH‐9 , and TH‐18 also showed significant antimicrobial activity. The compound TH‐13 showed antioxidant activity with IC₅₀ value better than the standard compound. The structures of all the synthesized compounds were confirmed by Fourier transform infrared, ¹H‐NMR, liquid chromatography–mass spectrometry, and CHN analyzer.     

Microwave‐Assisted Rapid and Efficient Synthesis of New Series of Chromene‐Based 1,2,4‐Oxadiazole Derivatives and Evaluation of Antibacterial Activity with Molecular Docking Investigation

A new series of novel chromene‐based oxadiazole derivatives were synthesized from a variety of chromene‐based amidoximes with readily available carboxylic acids under conventional oil bath heating as well as under microwave irradiation. The use of commercially available EDCI and HOBt as coupling reagents in DMF combined with microwave heating resulted in high yields and purities of the product 1,2,4‐oxadiazoles in an expeditious manner. This methodology is successfully applied to synthesize 18 numbers of new 2H‐chromene‐substituted 1,2,4‐oxadiazole derivatives in good to high yields. The structure of the product was ascertained by X‐ray crystallographic analysis. All the synthesized compounds were evaluated for their in vitro antibacterial activity against two different pathogenic bacterial strains, that is, Escherichia coli (MTCC614) and Klebsiella pneumoniae (MTCC4031). The obtained results from in vitro antimicrobial assays indicated that 6g and 6h exhibited good antibacterial activity nearer to the standard drug, gentamicin. The molecular docking studies showed that compounds 6g and 6h show hydrogen bonding interaction with the bacterial target DNA gyrase of E. coli.     

Facile Synthesis,Antimicrobial Activity and Molecular Docking of Novel 2,4,5‐Trisubstituted‐1H‐Imidazole–Triazole Hybrid Compounds

In the present work, a series of 18 imidazole–triazole hybrids ( 4a–r ) has been synthesized in good yield from substituted naphthaldehydes and 1,2‐diketones in the presence of ammonium acetate. The synthesized imidazole–triazole hybrid compounds were characterized by spectral techniques and screened in vitro for their antimicrobial activity. Compound 4h was found to be most active against Staphylococcus epidermidis, and compound 4e exhibited promising activity against Escherichia coli. In the fungal species under test, compound 4q was most potent against Aspergillus niger, even better than the fluconazole. Further, compound 4e was docked in the binding site of DNA gyrase topoisomerase II of E. coli.     

Synthesis,Characterization, and Biological Evaluation of Some Tri‐Substituted Imidazole/thiazole Derivatives

A novel compound series of tri‐substituted imidazole/thiazole derivatives ( 3a , 3b , 3c , 3d , 3e , 3f , 3g , 3h , 3i ) were prepared by Radziszewski reaction. Benzil ( 1 ), ammonium acetate or ammonium thiocynate, and 1‐phenyl‐3‐(p‐substituted phenyl)‐1H‐pyrazole‐4‐carbaldehyde ( 2a , 2b , 2c , 2d , 2e , 2f , 2g ) were reacted to give the desired product. Synthesized compounds were characterized by elemental analysis (CHNS) and spectral analysis (FTIR, ¹H and ¹³C FT NMR, and LC–MS). All the compounds were screened for their antibacterial, antifungal, and antimycobacterial activities. Antimicrobial activity was evaluated against some bacterial strains such as Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 1688), Staphylococcus aureus (MTCC 96), Streptococcus pyogenes (MTCC 442), and the H₃₇Rv strain of Mycobacterium tuberculosis, and the fungal activity was observed against strains, for example, Candida albicans (MTCC 227), Aspergillus niger (MTCC 282), and Aspergillus clavatus (MTCC 1323). All the synthesized compounds were found to possess moderate to excellent activity against the above selected strains.     

Indeno[1,2-b]pyridin-5-one derivatives containing azo groups and their hydrazonal precursors: Synthesis,antimicrobial profile,DNA gyrase binding affinity,and molecular docking

The prevalence of germs that are resistant to many antibiotics is rising rapidly the world over. There is a large group of researchers actively looking for better medicines. Here, we designed two series of hydrazonal and indeno[1,2-b]pyridin-5-one bearing hydrazone and azo-groups to test their antimicrobial activity. Molecular structures of all derivatives were assured based on their spectral data and elemental analyses. Results of the antimicrobial activity of the tested hydrazone and azo compounds showed promising potential for several derivatives. The minimum inhibitory concentrations (MICs) of hydrazones 4a - h and 6a - g displayed good antibacterial reactivities with a range of 3.91–250 μg/mL and moderate antifungal activity with a range of 15.6–500 μg/mL. The most promising hydrazone 4f and azo- 6a compounds demonstrated MIC values against Streptococcus faecalis and Escherichia coli equal to 3.91 and 7.81 μg/mL, respectively. Moreover, azo compound 6a showed MIC value equal to 3.91 μg/mL against Enterobacter cloacae species. Additionally, derivative 4f exhibited a significant inhibitory profile against the E. coli gyrase A enzyme (IC₅₀ = 5.53 μg/mL). On the other hand, compound 6a (IC₅₀ 14.05 μg/mL) exhibited the lowest DNA gyrase inhibitory activity as compared to compounds 4f and reference standard drug novobiocin, IC₅₀ 5.53 and 1.88 μg/mL, respectively. Pharmacokinetic and pharmacodynamic profiles and molecular docking studies for the two most promising molecules 4f and 6a were computed and revealed that both compounds have good ADME profiles and high binding affinity to DNA gyrase binding site.     

Synthesis and investigation of binding interactions of 1,4-benzoxazine derivatives on topoisomerase IV in Acinetobacter baumannii$

Abstract

Acinetobacter baumannii has emerged as an important pathogen for nosocomial infections having high morbidity and mortality. This pathogen is notorious for antimicrobial resistance to many common antimicrobial agents including fluoroquinolones, which have both intrinsic and acquired resistance mechanisms. Fluoroquinolones targeting the bacterial topoisomerase II (DNA gyrase and Topo IV) show potent broad-spectrum antibacterial activity by the stabilization of the covalent enzyme–DNA complex. However, their efficacy is now being threatened by an increasing prevalence of resistance. Fluoroquinolones cause stepwise mutations in DNA gyrase and Topo IV, having alterations of their binding sites. Furthermore, the water–Mg⁺² bridge, which provides enzyme–fluoroquinolone interactions, has a significant role in resistance. In this study, 13 compounds were synthesized as 1,4-benzoxazine derivatives which act as bacterial topoisomerase II inhibitors and their antibacterial activities were determined against multi-drug resistant Acinetobacter strains which have ciprofloxacin (CIP) resistant and GyrA mutation. Afterwards we performed docking studies with Topo IV (pdb:2XKK) of these compounds to comprehend their binding properties in Discovery Studio 3.5. The results of this study show significant conclusions to elucidate the resistance mechanism and lead to the design of new antibacterial agents as bacterial topoisomerase II inhibitors.     

Di-isatin heteronuclear compounds and their antibacterial activity

Twenty propylene and butylene tethered di-isatin heteronuclear compounds 5a-t were synthesized, and their antibacterial activities were evaluated. Most of the synthesized di-isatin heteronuclear derivatives were active against both Gram-positive and Gram-negative strains, and some of them exhibited considerable activities against drug-resistant organisms. In particular, di-isatin 5a (MIC: 32-512 μg/mL) was more active than the reference vancomycin against Gram-negative pathogens, demonstrating the antibacterial potential of di-isatin heteronuclear compounds. The inhibitory activity of di-isatin 5a was higher than mono-isatin against Escherichia coli DNA gyrase, suggesting the dimers could improve the inhibitory activity against DNA gyrase when compared with the isatin. The structure-activity relationship was discussed to provide an insight for rational designs of more efficient antibacterial candidates.     

Synthesis,Characterization, and Antimicrobial Studies of New Rigid Linker‐Based Bispyrazolines

The bispyrazolines 4a , 4b , 4c , 4d , 4e were synthesized from the cyclization reaction of bischalcones 3a , 3b , 3c , 3d , 3e with phenyl hydrazine by refluxing under alcoholic medium in the presence of glacial acetic acid. The bischalcones were obtained from the Claisen–Schmidt reaction of acetophenone with dibenzaldehydes 1a , 1b , 1c , 1d , 1e and later were obtained in good yield from the O‐alkylation of 4‐hydroxybenzaldehyde with suitable alkylating agents. The structures of the prepared compounds were determined from the rigorous analysis of their spectral data (UV–vis, IR, ¹H‐NMR, ¹³C‐NMR, and ESI‐MS). The elemental analysis also confirmed the purity of these compounds. All the bischalcones 3a , 3b , 3c , 3d , 3e and bispyrazolines 4a , 4b , 4c , 4d , 4e were screened for their antimicrobial activity using the serial dilution method. Seven bacterial and five fungal species were used as the antimicrobial test strains, namely Klebsiella pneumoniae (MTCC 3384), Pseudomonas aeruginosa (MTCC 424), Escherichia coli (MTCC 443), Staphylococcus aureus (MTCC 443), Bacillus subtilis (MTCC 441), Pseudomonas fluorescens (MTCC 103), and Staphylococcus pyrogens (MTCC 442), and Aspergillus janus (MTCC 2751), Penicillium glabrum (MTCC 4951), Fusarium oxysporum (MTCC 2480), Aspergillus sclerotiorum (MTCC 1008), and Aspergillus niger (MTCC 281), respectively. The minimum inhibitory concentrations (MIC in µg/mL) were determined by using different dilutions.     

Discovery of Quinazoline-2,4(1H,3H)-Dione Derivatives as Potential Antibacterial Agent: Design,Synthesis, and Their Antibacterial Activity

In this paper, we report on the design and synthesis of a novel series of quinazoline-2,4(1H,3H)-dione derivatives as fluoroquinolone-like inhibitors of bacterial gyrase and DNA topoisomerase IV to identify and develop antimicrobial agents to prevent bacterial resistance problems. Their structures were confirmed using spectroscopic analyses (IR, NMR, and EI-MS). The novel quinazoline-2,4(1H,3H)-dione derivatives were evaluated for their antimicrobial activities against Gram-positive and Gram-negative bacterial strains using the Agar well diffusion method to study the antimicrobial activities and compared them with the standard drugs. Most compounds displayed moderate activity. Among the tested compounds, the most promising compounds 13 and 15 provided broad bioactive spectrum against Gram-positive and Gram-negative strains compared to the standard drugs.     

2‐(3,4‐Dichlorophenylimino)‐5‐((3‐(p‐substitutedphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl)methylene)thiazolidin‐4‐one as an Antibacterial,Antifungal and Antimycobacterial Agent

2‐(3,4‐Dichlorophenylimino)‐5‐((3‐(p‐substitutedphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl)methylene) thiazolidin‐4‐one has been selected as a target bio‐active molecules. Newly synthesized compounds were screened with Eschericha coli (MTCC 443), Pseudomonas aeruginosa (MTCC 1688), Staphylococcus aureus (MTCC 96), Streptococcus pyogenes (MTCC 442) for antibacterial, Candida albicans (MTCC 227), Aspergillus niger (MTCC 282), Aspergillus clavatus (MTCC 1323) for antifungal activity and H ₃₇ Rv for antimycobacterial activity. Compounds 3a , 3c , 3d , 3e , and 3h are potentially active against Staphylococcus aureus , while 3h is active against C. albicans . Compounds 3d and 3f are active against H ₃₇Rv for mycobacterium tuberculosis. Other possesses moderate to good activity. The structures of synthesized compounds were firmly established by well‐defined elemental analyses (C, H, N, S/O) and spectral analysis technique likes, IR, ¹H NMR and GC–MS.     

Characterization of Citrus nobilis Peel Methanolic Extract for Antioxidant,Antimicrobial, and Anti-Inflammatory Activity

Currently, the potential utilization of fruits and vegetable waste as a source of micronutrients and antioxidants has increased. The present study, therefore, aimed to determine the antimicrobial and anti-inflammatory activities of Citrus nobilis peel extract. A modified solvent evaporation technique was employed for peel extract preparation. For effective utilization of the natural product, quantitative analysis of phenolic compounds was carried out using liquid chromatography and mass spectroscopy technique. Phenolic and flavonoids were present in high amounts, while β-carotene and lycopene were present in vestigial amounts. The antimicrobial efficiency of peel extract was evaluated against four bacterial strains including Staphylococcus aureus (MTCC 3160), Klebsiella pneumoniae (MTCC 3384), Pseudomonas aeruginosa (MTCC 2295), and Salmonella typhimurium (MTCC 1254), and one fungal strain Candida albicans (MTCC 183), and zone of inhibition was comparable to the positive control streptomycin and amphotericin B, respectively. The extract of Citrus nobilis peels showed effective anti-inflammatory activity during human red blood cell membrane stabilization (HRBC) and albumin denaturation assay. The extracts also exhibited 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity ranging from 53.46 to 81.13%. Therefore, the obtained results suggest that Citrus nobilis peel could be used as an excellent source of polyphenols and transformed into value-added products.     

Synthesis and Antimicrobial Activity of Linked Heterocyclics Containing Pyrazole and Oxadiazoles

A new series of 3‐(arylaminomethyl)‐5‐(5‐methyl‐1‐phenyl‐1H‐4‐pyrazolyl)‐2,3‐dihydro‐1,3,4‐oxadiazole‐2‐thiones 6a , 6b , 6c , 6d , 6e , 6f , 6g , 6h , 6i , 6j has been synthesized by the reaction of 5‐(5‐methyl‐1‐phenyl‐1H‐4‐pyrazolyl)‐1,3,4‐oxadiazol‐2‐ylhydrosulfide 5 with formaldehyde and corresponding anilines. The chemical structures of newly synthesized compounds were elucidated by IR, ¹H, ¹³C‐NMR, MS, and elemental analyses. The compounds 6a , 6b , 6c , 6d , 6e , 6f , 6g , 6h , 6i , 6j were evaluated for their antibacterial activity against three representative Gram positive bacteria viz. Bacillus subtilis (MTCC 441), Bacillus sphaericus (MTCC 11) and Staphylococcus aureus (MTCC 96), and three Gram negative bacteria viz. Pseudomonas aeruginosa (MTCC 741), Klobsinella aerogenes (MTCC 39) and Chromobacterium violaceum. Among the screened 6b , 6d , 6i , and 6j in which oxadiazole moiety bearing 4‐fluoroanilinomethyl, 4‐chloroanilinomethyl, 2‐trifluoromethylanilinomethyl, and 2,5‐difluoroanilinomethyl groups, respectively, showed high activity against all the microorganisms used. In addition these compounds were also screened for their antifungal activity against four fungal organisms viz. Candida albicans (ATCC 10231), Aspergillus fumigatus (HIC 6094), Trichophyton rubrum (IFO 9185), and Trichophyton mentagrophytes (IFO 40996). Most of these new compounds showed appreciable activity against test fungi, and emerged as potential molecules for further development.     

A Facile Synthesis of New 4,6‐Dichloropyridine Derivatives,Their Biological Evaluation for Antimicrobial and Antioxidant Activity,and Docking Studies

A facile synthesis of new 4,6‐dichloropyridine derivatives 5 ( a–f ), 6 ( a–c ), and 7 ( a–c ) were synthesized using both conventional heating and solvent‐free microwave irradiation techniques. The results revealed that the latter method is superior to the conventional heating method. The easy work‐up of the products, rapid reaction, and mild conditions are noticeable features of this protocol. Structural elucidation of the synthesized compounds was made on the basis of various spectroscopic methods. The synthesized compounds were evaluated for their in vitro antimicrobial activity (minimum inhibitory concentration; MIC) against various microbial strains using the agar well‐diffusion method. Among the compounds, 5c showed best antimicrobial activity against most of the employed strains, especially against Staphylococcus aureus, Escherichia coli, Rhizopus arrhizus, and Candida albicans. Compounds 5a , 6a , 6c , 7a , and 7c showed significant antioxidant activity when compared to the other compounds. In addition to this, theoretical docking studies were performed for the highly potent compounds 5a , 6a , 6c , 7a , and 7c against three different drug targets belonging to the oxidoreductase family, and the results were found to be highly satisfactory.     

Molecular Docking Study of Newly Synthesized Thiopyrimidines as Antimicrobial Agents Targeting DNA Gyrase Enzyme

A new series of thiopyrimidine‐5‐carbonitrile derivatives were synthesized and the chemical identity of them was established on the basis of spectral methods. The antimicrobial properties of all derivatives were investigated against Gram‐positive and Gram‐negative bacteria as well as fungal strains. The results of the antimicrobial screening showed that compounds 4 , 11 , and 12 have a higher and broad spectrum efficacy against all the tested organisms in comparison with the reference drugs. Interestingly, the most active compounds 4 and 12 showed good binding assay results with Escherichia coli DNA gyrase comparable to that of the reference, methotrexate. Furthermore, a molecular docking study of these compounds was carried out to investigate their binding pattern with the target, DNA gyrase.     

Synthesis,antimicrobial activity,and molecular docking study of formylnaphthalenyloxymethyl‐triazolyl‐N‐phenylacetamides

In the present study, substituted formylnaphthalenyloxymethyl‐triazolyl‐N‐phenylacetamide derivatives ( 6a – k ) have been designed and synthesized employing click chemistry approach and evaluated for their in vitro antifungal and antibacterial activities. All the newly synthesized compounds were thoroughly characterized by ¹H NMR, ¹³C NMR, and HRMS spectral techniques. Among the screened compounds, 6d , 6e , 6j , and 6k have shown good antifungal and antibacterial activities. Compound 6k has shown very effective antimicrobial activity. We further performed exploratory docking studies on microbial DNA gyrase to rationalize the in vitro biological data and to demonstrate the mechanism of antimicrobial activity. This is the first report to demonstrate the formylnaphthalenyloxymethyl, triazole, and N‐phenylacetamide hybrids as potential antimicrobial agents.     

Efficient and convenient synthesis,characterization, and antimicrobial evaluation of some new tetracyclic 1,4-benzothiazines

In the present study, 20 new tetracyclic 1,4-benzothiazines (4a–4 t) were conveniently synthesized in good yields and characterized by different spectral and physical techniques. The in vitro antimicrobial evaluation of the synthesized benzothiazine derivatives was performed by serial dilution against two Gram-positive bacteria [Bacillus subtilis (MTCC 441) and Staphylococcus epidermidis (MTCC 6880)], two Gram-negative bacteria [Escherichia coli (MTCC 1652) and Pseudomonas aeruginosa (MTCC 424)], and two fungal strains [Candida albicans (MTCC 227) and Aspergillus niger (MTCC 8189)]. The derivatives 4 l and 4 t were found to be more potent than standard drug, i.e., fluconazole, against A. niger and C. albicans, respectively.