Distinct subunit architecture and assembly pattern of DNA gyrase from mycobacteria.

DNA gyrase, the sole negative supercoiling type II topoisomerase, is composed of two subunits, GyrA and GyrB, encoded by the gyrA and gyrB genes, respectively, that form a quaternary complex of A2 B2 . In this study, we have investigated the assembly of mycobacterial DNA gyrase from its individual subunits, a step prerequisite for its activity. Using analytical size-exclusion chromatography, we show that GyrA from Mycobacterium tuberculosis and Mycobacterium smegmatis forms tetramers (A4 ) in solution unlike in Escherichia coli and other bacteria where GyrA exists as a dimer. GyrB, however, persists as a monomer, resembling the pattern found in E. coli. GyrB in both mycobacterial species interacts with GyrA and triggers the dissociation of the GyrA tetramer to facilitate the formation of catalytically active A2 B2 . Despite oligomerisation, the GyrA tetramer retained its DNA binding ability, and DNA binding had no effect on GyrA's oligomeric state in both species. Moreover, the presence of DNA facilitated the assembly of holoenzyme in the case of M. smegmatis by stabilising the GyrA2 B2 tetramer but with little effect in M. tuberculosis. Thus, in addition to the distinct organisation and regulation of the gyr locus in mycobacteria, the enzyme assembly also follows a different pattern.

Novel Thiazole Derivatives Containing Imidazole and Furan Scaffold: Design, Synthesis, Molecular Docking, Antibacterial, and Antioxidant Evaluation.

Carbothioamides 3a,b were generated in high yield by reacting furan imidazolyl ketone 1 with N-arylthiosemicarbazide in EtOH with a catalytic amount of conc. HCl. The reaction of carbothioamides 3a,b with hydrazonyl chlorides 4a-c in EtOH with triethylamine at reflux produced 1,3-thiazole derivatives 6a-f. In a different approach, the 1,3-thiazole derivatives 6b and 6e were produced by reacting 3a and 3b with chloroacetone to afford 8a and 8b, respectively, followed by diazotization with 4-methylbenzenediazonium chloride. The thiourea derivatives 3a and 3b then reacted with ethyl chloroacetate in ethanol with AcONa at reflux to give the thiazolidinone derivatives 10a and 10b. The produced compounds were tested for antioxidant and antibacterial properties. Using phosphomolybdate, promising thiazoles 3a and 6a showed the best antioxidant activities at 1962.48 and 2007.67 µgAAE/g dry samples, respectively. Thiazoles 3a and 8a had the highest antibacterial activity against S. aureus and E. coli with 28, 25 and 27, 28 mm, respectively. Thiazoles 3a and 6d had the best activity against C. albicans with 26 mm and 37 mm, respectively. Thiazole 6c had the highest activity against A. niger, surpassing cyclohexamide. Most compounds demonstrated lower MIC values than neomycin against E. coli, S. aureus and C. albicans. A molecular docking study examined how antimicrobial compounds interact with DNA gyrase B crystal structures. The study found that all of the compounds had good binding energy to the enzymes and reacted similarly to the native inhibitor with the target DNA gyrase B enzymes' key amino acids.

Identification of potential inhibitors against E.coli via novel approaches based on deep learning and quantum mechanics-based atomistic investigations.

Currently, drug resistance to commercially available antibiotics is imparting negative consequences to global health, and the development of novel antibiotics in a timely manner is a prime need of the hour. In the current study, an e-pharmacophore model was built using the 3D structure of DNA gyrase in complex with a standard inhibitor. The generated model was subjected to a pharmacophore based virtual screening against 45,257,086 molecules having 223,460,579 conformers available in MCULE database. Pharmacophore based screening retrieved eight molecules as top hit based on pharmacophoric features in comparison to standard inhibitors. Afterward, all eight compounds were subjected molecular docking based on deep learning algorithm. The molecular docking revealed that compound MCULE-6042843173 and MCULE-2362244223 had significant binding orientation inside active pocket of targeted protein with binding affinity of -9.52 and -9.24 kcal/mol respectively. In addition, density functional theory studies (DFT) were performed to evaluate quantum mechanics of top ranked compounds which were investigated through quantum mechanics (QM) computations which strongly assisted the findings of other in-silico investigations. Consequently, the MCULE-6042843173 and MCULE-2362244223 were subjected to MD simulation studies for evaluation of stability, hydrogen bond analysis, van der Waals interactions, and the contact profile of compounds with targeted amino acid residues. Findings of current study suggested MCULE-6042843173 and MCULE-2362244223 as potential and novel inhibitor of DNA Gyrase enzyme.

Virtual Screening and ADMET Prediction to Uncover the Potency of Flavonoids from Genus Erythrina as Antibacterial Agent through Inhibition of Bacterial ATPase DNA Gyrase B.

The emergence of antimicrobial resistance due to the widespread and inappropriate use of antibiotics has now become the global health challenge. Flavonoids have long been reported to be a potent antimicrobial agent against a wide range of pathogenic microorganisms in vitro. Therefore, new antibiotics development based on flavonoid structures could be a potential strategy to fight against antibiotic-resistant infections. This research aims to screen the potency of flavonoids of the genus Erythrina as an inhibitor of bacterial ATPase DNA gyrase B. From the 378 flavonoids being screened, 49 flavonoids show potential as an inhibitor of ATPase DNA gyrase B due to their lower binding affinity compared to the inhibitor and ATP. Further screening for their toxicity, we identified 6 flavonoids from these 49 flavonoids, which are predicted to have low toxicity. Among these flavonoids, erystagallin B (334) is predicted to have the best pharmacokinetic properties, and therefore, could be further developed as new antibacterial agent.

Novel 6-hydroxyquinolinone derivatives: Design, synthesis, antimicrobial evaluation, in silico study and toxicity profiling.

Infectious diseases of bacteria and fungi have become a major risk to public health because of antibiotic and antifungal resistance. However, the availability of effective antibacterial and antifungal agents is becoming increasingly limited with growing resistance to existing drugs. In response to that, novel agents are critically needed to overcome such resistance. A new series of 6-hydroxyquinolinone 3, 4, 5a, 5b, 6a and 6b bearing different side chains were synthesized and evaluated as antimicrobials against numbers of bacteria and fungi, using inhibition zone technique. As one of these derivatives, compound 3 was identified as a potent antibacterial and antifungal agent against all tested microorganisms with good minimum inhibitory concentration values comparable to reference drugs. Molecular docking studies were performed on antibacterial and antifungal targets; microbial DNA gyrase B of Staphylococcus aureus (PDB ID: 4URO); N-myristoyltransferase of Candida albicans (PDB ID: 1IYK), respectively, to predict the most probable type of interaction at the active site of the target protein in addition to binding affinities and orientations of docked ligands. Additionally, in silico prediction in terms of detailed physicochemical ADME and toxicity profile relating drug-likeness as well as medicinal chemistry friendliness was performed to all synthesized compounds. The results indicated that a novel 4,6-dihydroxyquinolin-2(1H)-one (3) is likely to be a newly synthesized drug candidate, indicating low toxicity in addition to good in silico absorption. In order to pave the way for more logical production of such compounds, structure-activity and toxicity relationships are also discussed.

Synthesis of Computationally Designed 2,5(6)-Benzimidazole Derivatives via Pd-Catalyzed Reactions for Potential E. coli DNA Gyrase B Inhibition.

A pharmacophore model for inhibitors of Escherichia coli's DNA Gyrase B was developed, using computer-aided drug design. Subsequently, docking studies showed that 2,5(6)-substituted benzimidazole derivatives are promising molecules, as they possess key hydrogen bond donor/acceptor groups for an efficient interaction with this bacterial target. Furthermore, 5(6)-bromo-2-(2-nitrophenyl)-1H-benzimidazole, selected as a core molecule, was prepared on a multi-gram scale through condensation of 4-bromo-1,2-diaminobenzene with 2-nitrobenzaldehyde using a sustainable approach. The challenging functionalization of the 5(6)-position was carried out via palladium-catalyzed Suzuki-Miyaura and Buchwald-Hartwig amination cross-coupling reactions between N-protected-5-bromo-2-nitrophenyl-benzimidazole and aryl boronic acids or sulfonylanilines, with yields up to 81%. The final designed molecules (2-(aminophen-2-yl)-5(6)-substituted-1H-benzimidazoles), which encompass the appropriate functional groups in the 5(6)-position according to the pharmacophore model, were obtained in yields up to 91% after acid-mediated N-boc deprotection followed by Pd-catalyzed hydrogenation. These groups are predicted to favor interactions with DNA gyrase B residues Asn46, Asp73, and Asp173, aiming to promote an inhibitory effect.

Phytochemical Profiling, In Vitro and In Silico Anti-Microbial and Anti-Cancer Activity Evaluations and Staph GyraseB and h-TOP-IIß Receptor-Docking Studies of Major Constituents of Zygophyllum coccineum L. Aqueous-Ethanolic Extract and Its Subsequent Fractions: An Approach to Validate Traditional Phytomedicinal Knowledge.

Zygophyllum coccineum, an edible halophytic plant, is part of the traditional medicine chest in the Mediterranean region for symptomatic relief of diabetes, hypertension, wound healing, burns, infections, and rheumatoid arthritis pain. The current study aimed to characterize Z. coccineum phytoconstituents, and the evaluations of the anti-microbial-biofilm, and anti-cancers bioactivities of the plant's mother liquor, i.e., aqueous-ethanolic extract, and its subsequent fractions. The in silico receptors interaction feasibility of Z. coccineum major constituents with Staph GyraseB, and human topoisomerase-IIß (h-TOP-IIß) were conducted to confirm the plant's anti-microbial and anti-cancer biological activities. Thirty-eight secondary metabolites of flavonoids, stilbene, phenolic acids, alkaloids, and coumarin classes identified by LC-ESI-TOF-MS spectrometric analysis, and tiliroside (kaempferol-3-O-(6''''-p-coumaroyl)-glucoside, 19.8%), zygophyloside-F (12.78%), zygophyloside-G (9.67%), and isorhamnetin-3-O-glucoside (4.75%) were identified as the major constituents. A superior biofilm obliteration activity established the minimum biofilm eradication concentration (MBEC) for the chloroform fraction at 3.9-15.63 µg/mL, as compared to the positive controls (15.63-31.25 µg/mL) against all the microbial strains that produced the biofilm under study, except the Aspergillus fumigatus. The aqueous-ethanolic extract showed cytotoxic effects with IC50 values at 3.47, 3.19, and 2.27 µg/mL against MCF-7, HCT-116, and HepG2 cell-lines, respectively, together with the inhibition of h-TOP-IIß with IC50 value at 45.05 ng/mL in comparison to its standard referral inhibitor (staurosporine, IC50, 135.33 ng/mL). This conclusively established the anti-cancer activity of the aqueous-ethanolic extract that also validated by in silico receptor-binding predicted energy levels and receptor-site docking feasibility of the major constituents of the plant's extract. The study helped to authenticate some of the traditional phytomedicinal properties of the anti-infectious nature of the plant.

Identification of 4-diphenylamino 3-iodo coumarin as a potent inhibitor of DNA gyrase B of S. aureus.

A necessity of therapeutics against antibiotic-resistant bacteria has led to a search for novel antibacterial compounds. The strategy to isolate compounds from non-microbial sources is the key to prevent antibiotic resistance. Here, we report isolation and characterization of an antibacterial coumarin derivative, 4-diphenylamino 3-iodo coumarin (4-DPA3IC) from a traditional drug formulation. The compound elicited high activity against MDR strains of S. aureus. Targets were identified through computational methods encompassing modules of Schrodinger 10.4. The 4-DPA3IC targeted S. aureus DNA gyrase enzyme B subunit. Amino acid residues and interactions involved here are totally different from those of novobiocin and clorobiocin. The validation was done by in vitro DNA gyrase supercoiling inhibition assay. This study proved 4-DPA3IC could potentially act against novobiocin and cholorbiocin resistant strains of S. aureus. Thus, the 4-DPA3IC is a unique inhibitor of bacterial DNA gyrase due to its plant origin as compared to other reported inhibitors.

Design, synthesis and biological evaluation of novel Pseudomonas aeruginosa DNA gyrase B inhibitors.

In the present study, we attempted to develop a novel class of compounds active against Pseudomonas aeruginosa (Pa) by exploring the pharmaceutically well exploited enzyme targets. Since, lack of Pa gyrase B crystal structures, Thermus thermophilus gyrase B in complex with novobiocin (1KIJ) was used as template to generate model structure by performing homology modeling. Further the best model was validated and used for high-throughput virtual screening, docking and dynamics simulations using the in-house database for identification of Pa DNA gyrase B inhibitors. This study led to an identification of three lead molecules with IC50 values in range of 6.25-15.6 µM against Pa gyrase supercoiling assay. Lead-1 optimization and expansion resulted in 15 compounds. Among the synthesized compounds six compounds were shown good enzyme inhibition than Lead-1 (IC50 6.25 µM). Compound 13 emerged as the most potential compound exhibiting inhibition of Pa gyrase supercoiling with an IC50 of 2.2 µM; and in-vitro Pa activity with MIC of 8 µg/mL in presence of efflux pump inhibitor; hence could be further developed as novel inhibitor for Pa gyrase B.

Synthesis, molecular docking and antimicrobial activity of new fused pyrimidine and pyridine derivatives.

Synthesis of some new heterocyclic ring systems incorporated pyrimidine and pyridine moieties starting from 1-(furan-2-yl)-3-(thiophen-2-yl) chalcone was achieved. The structure of the new compounds was interpreted by spectral studies and ESI-MS analysis. Antimicrobial investigations of the designated compounds were performed towards some harmful pathogenic microbes. Antimicrobial tests proved that compound 11 unveiled a greater antimicrobial activity than other designed compounds. Docking of compound 11 into active site of DNA gyrase B chain displayed binding-energy of -13.05 kJ mol-1 and distance at 3.18 Ao. Furthermore, docking investigation was approved for the goal compounds into DNA gyrase B chain and exhibiting binding energy extended from -13.05 to -20.48 kJ mol-1.

Antimicrobial screening and pharmacokinetic profiling of novel phenyl-[1,2,4]triazolo[4,3-a]quinoxaline analogues targeting DHFR and E. coli DNA gyrase B.

A novel series of [1,2,4]triazolo[4,3-a]quinoxaline derivatives of different heteroaromatization members were synthesized. The newly synthesized molecules were explored for their potential antimicrobial activities against a panel of pathogenic organisms. Among these derivatives, the chalcone compound 6e with a methoxy substituent exhibited broad potent antimicrobial activity against most of the bacterial and fungal strains. Furthermore, the analysis of the SAR disclosed that the linker and terminal aromatic fragments perform critical roles in exerting antibacterial activity. The molecular docking calculations were executed on two of the most bacterial targets, ATP-binding sites of DNA gyrase B, and the folate-binding site of DHFR enzymes. The results presented good binding data to the pockets of both enzymes showing different linkers contributions through the hydrogen-bonding and aromatic stacking interactions that stabilize the compounds in their pockets taking 6e compound as representative of most active analogs. In addition, good pharmacokinetic profiling data for the 6e compound was obtained and compared to reference drugs. Accordingly, our findings suggest that [1,2,4]triazolo[4,3-a]quinoxaline scaffold is an interesting precursor for the design of potent antimicrobial agents with multitarget inhibition.

Pegylated triarylmethanes: Synthesis, antimicrobial activity, anti-proliferative behavior and in silico studies.

We describe herein the synthesis, characterization and biological studies of novel PEGylated triarylmethanes. Non-symmetrical and symmetrical triarylmethanes series have been synthesized by Friedel-Crafts hydroxyalkylation or directly from bisacodyl respectively followed by a functionalization with PEG fragments in order to increase bioavailability and biological effectiveness. The antimicrobial activity was investigated against Gram-positive and Gram-negative foodborne pathogens and against Candida albicans, an opportunistic pathogenic yeast. The anti-biocidal activity was also studied using Staphylococcus aureus as a reference bacterium. Almost all PEGylated molecules displayed an antifungal activity comparable with fusidic acid with MIC values ranging from 6.25 to 50 µg/mL. Compounds also revealed a promising antibiofilm activity with biofilm eradication percentages values above 80% for the best molecules (compounds 4d and 7). Compounds 7 and 8b showed a modest antiproliferative activity against human colorectal cancer cell lines HT-29. Finally, in silico molecular docking studies revealed DHFR and DNA gyrase B as potential anti-bacterial targets and in silico predictions of ADME suggested adequate drug-likeness profiles for the synthetized triarylmethanes.

Novel phthalimide based analogues: design, synthesis, biological evaluation, and molecular docking studies.

Pyrazolylphthalimide derivative 4 was synthesized and reacted with different reagents to afford the target compounds imidazopyrazoles 5-7, pyrazolopyrimidines 9, 12, 14 and pyrazolotriazines 16, 17 containing phthalimide moiety. The prepared compounds were established by different spectral data and elemental analyses. Additionally, all synthesized derivatives were screened for their antibacterial activity against four types of Gram + ve and Gram-ve strains, and for antifungal activity against two fungi micro-organisms by well diffusion method. Moreover, the antiproliferative activity was tested for all compounds against human liver (HepG-2) cell line in comparison with the reference vinblastine. Moreover, drug-likeness and toxicity risk parameters of the newly synthesized compounds were calculated using in silico studies. The data from structure-actvity relationship (SAR) analysis suggested that phthalimide derivative bearing 3-aminopyrazolone moiety, 4 illustrated the best antimicrobial and antitumor activities and might be considered as a lead for further optimization. To investigate the mechanism of the antimicrobial and anticancer activities, enzymatic assay and molecular docking studies were carried out on E. coli topoisomerase II DNA gyrase B and VEGFR-2 enzymes.

Introducing Broadened Antibacterial Activity to Rhodanine Derivatives Targeting Enoyl-Acyl Carrier Protein Reductase.

Broadened antibacterial activity was introduced to rhodanine derivatives targeting Mycobacterial tuberculosis enoyl-acyl carrier protein reductase (Mtb InhA) by recruiting feature of xacins to bring DNA Gyrase B inhibitory capability. This is significant for preventing further bacterial injections in the tuberculosis treatment. The most potent compound Cy14 suggested comparable bioactivity (IC50 = 3.18 µM for Mtb InhA; IC50 = 10 nM for DNA Gyrase B) with positive controls. Structure-activity relationship discussion and molecular docking model revealed the significance of rhodanine moiety and derived methoxyl on meta-position, pointing out orientations for future modification.

The intergenic transcribed spacer region 1 as a molecular marker for identification and discrimination of Enterobacteriaceae associated with acute oak decline.

AIMS: We assessed the veracity of intergenic spacer region 1 (ITS1) ribotyping for the rapid, inexpensive and accurate identification of Brenneria goodwinii and Gibbsiella quercinecans that are associated with acute oak decline (AOD) in the UK. METHODS AND RESULTS: Agarose gel electrophoresis and polyacrylamide gel electrophoresis (PAGE) were applied for the typing of ITS1 PCR amplicons from strains of B. goodwinii, G. quercinecans and related species (n = 34). The number and length of ITS1 amplicons varied significantly between strains. ITS1 profiles generated via PAGE were used to differentiate species using a neighbour-joining phylogram. The ITS1 phylogram was compared against DNA gyrase B (gyrB) gene sequences from the same strains, demonstrating that ITS1 ribotyping is as effective as gyrB at resolving G. quercinecans and B. goodwinii to the species level. CONCLUSIONS: The ITS1 gene has been successfully employed as a novel marker to resolve newly described AOD-associated Enterobacteriaceae, B. goodwinii and G. quercinecans, to species level. SIGNIFICANCE AND IMPACT OF THE STUDY: ITS1 ribotyping of B. goodwinii and G. quercinecans provides equivalent sensitivity to the current standard method for strain identification (sequence analysis of the gyrB gene), but with reduced processing time and cost. Furthermore, the ITS1 gene is widely applicable as a rapid and inexpensive typing system for Enterobacteriaceae.

Successful application of serum shift prediction models to the design of dual targeting inhibitors of bacterial gyrase B and topoisomerase IV with improved in vivo efficacy.

A series of dual targeting inhibitors of bacterial gyrase B and topoisomerase IV were identified and optimized to mid-to-low nanomolar potency against a variety of bacteria. However, in spite of seemingly adequate exposure achieved upon IV administration, the in vivo efficacy of the early lead compounds was limited by high levels of binding to serum proteins. To overcome this limitation, targeted serum shift prediction models were generated for each subclass of interest and were applied to the design of prospective analogs. As a result, numerous compounds with comparable antibacterial potency and reduced protein binding were generated. These efforts culminated in the synthesis of compound 10, a potent inhibitor with low serum shift that demonstrated greatly improved in vivo efficacy in two distinct rat infection models.

Synthesis, Characterization, and Biological Evaluation of Meldrum's Acid Derivatives: Dual Activity and Molecular Docking Study.

In the presented study, eight novel Meldrum's acid derivatives containing various vanillic groups were synthesized. Vanillidene Meldrum's acid compounds were tested against different cancer cell lines and microbes. Out of nine, three showed very good biological activity against E. coli, and HeLa and A549 cell lines. It is shown that the O-alkyl substituted derivatives possessed better antimicrobial and anticancer activities in comparison with the O-acyl ones. The decyl substituted molecule (3i) has the highest activity against E. coli (MIC = 12.4 µM) and cancer cell lines (HeLa, A549, and LS174 = 15.7, 21.8, and 30.5 µM, respectively). The selectivity index of 3i is 4.8 (HeLa). The molecular docking study indicates that compound 3i showed good binding affinity to DNA, E. coli Gyrase B, and topoisomerase II beta. The covalent docking showed that 3i was a Michael acceptor for the nucleophiles Lys and Ser. The best Eb was noted for the topoisomerase II beta-LYS482-3i cluster.

Identification of potential Escherichia coli DNA gyrase B inhibitors targeting antibacterial therapy: an integrated docking and molecular dynamics simulation study.

The alarming rise in the rate of antibiotic resistance is a matter of significant concern. DNA gyrase B (GyrB), a critical bacterial enzyme involved in DNA replication, transcription, and recombination, has emerged as a promising target for antibacterial agents. Inhibition of GyrB disrupts bacterial DNA replication, leading to cell death, making it an attractive candidate for antibiotic development. Although several classes of antibiotics targeting GyrB are currently in clinical use, the emergence of antibiotic resistance necessitates the exploration of novel inhibitors. In this study, we aimed to identify potential Escherichia coli GyrB inhibitors from a database of phytoconstituents sourced from Indian medicinal plants. Utilizing virtual screening, we performed a rigorous search to identify compounds with the most promising inhibitory properties against GyrB. Two compounds, namely Zizogenin and Cucurbitacin S, were identified based on their favorable drug likeliness and pharmacokinetic profiles. Employing advanced computational techniques, we analyzed the binding interactions of Zizogenin and Cucurbitacin S with the ATP-binding site of GyrB through molecular docking simulations. Both compounds exhibited robust binding interactions, evidenced by their high docking energy scores. To assess the stability of these interactions, we conducted extensive 100 ns molecular dynamics (MD) simulations, which confirmed the stability of Zizogenin and Cucurbitacin S when bound to GyrB. In conclusion, our study highlights Zizogenin and Cucurbitacin S as promising candidates for potential antibacterial agents targeting GyrB. Experimental validation of these compounds is warranted to further explore their efficacy and potential as novel antibiotics to combat antibiotic-resistant bacteria.Communicated by Ramaswamy H. Sarma.

Antibacterial mechanism of action and in silico molecular docking studies of Cupressus funebris essential oil against drug resistant bacterial strains.

The primary objective of this research work was to study the antibacterial effects of Cupressus funebris essential oil (EO) against various drug resistant bacterial pathogens along with studying the molecular docking interactions of the major components of the EO with the key bacterial proteins/enzymes. Gas chromatography-mass spectrometry was used to analyse the chemical composition of the Cupressus funebris EO. The initial antibacterial screening was performed by using disc diffusion and microdilution methods. Scanning electron microscopy was also performed in order to study effects of the EO on bacterial cell morphology. Further, molecular docking studies were performed using Autodock Vina and results were visualised by BIOVIA Discovery Studio. The chemical composition of the EO showed the presence of 15 components with citronellal, terpinene-4-ol, α-phellandrene and 1,8-cineole as the major components of the EO. Results indicated that the EO of Cupressus funebris exhibited dose-dependent as well as time dependent antibacterial effects. The scanning electron microscopy indicated that the Cupressus funebris EO led to membrane rupture and permeabilization of the bacterial cells. Molecular docking studies indicated that the major compounds of the EO (citronellal and terpinene-4ol) showed strong interactions with the active site of the bacterial DNA gyrase enzyme explaining the antibacterial mode of action of the EO. Ciprofloxacin was also used for docking which showed stronger interactions with the target protein than citronellal or terpinene-4-ol. In conclusion, the major findings of the current study were that the EO of Cupressus funebris causes bacterial membrane rupture and permeabilization, shows time-dependent and dose-dependent antibacterial action, along with interacting with crucial bacterial enzyme viz., DNA gyrase as indicated by molecular docking studies.

Structure-based drug discovery and antimicrobial activity of ciprofloxacin-grafted Ugi adducts.

A new series of ciprofloxacin-derived Ugi adducts were rationally designed and synthesized. The synthesized molecules were explored for their potential antimicrobial activities against four pathogenic microorganisms. Among these derivatives, compound 7h with a 4-nitrophenyl substituent at R2 exhibited significant activity against two tested Gram-positive bacteria with a minimum inhibitory concentration value of 0.097 µg/mL while 7i bearing 4-chlorophenyl pendant demonstrated the best antimicrobial activities against Gram-negative bacteria. Furthermore, the analysis of the structure-activity relationships disclosed that types of substitutions differently affect the bacteria so the most potent derivative against Gram-negative infections was the least active one in Gram-positive microorganisms. Also, the molecular docking and molecular dynamic simulations were executed on 7i as the most potent Gram-negative anti-bacterial agent against ATP-binding sites of DNA gyrase B. Accordingly, our findings suggest that ciprofloxacin-based Ugi adducts are an interesting precursor for the design of potent antimicrobial agents.Communicated by Ramaswamy H. Sarma.