Enzyme Dihydropteroate Synthase Research Articles

Design, Synthesis, DFT, docking Studies, and antimicrobial evaluation of novel benzimidazole containing sulphonamide derivatives

In silico approaches have been employed to design a new series of benzimidazole-containing sulphonamide derivatives and qualified compounds have been synthesized to analyze their potential as antimicrobial agents. Antibacterial screening of all synthesized compounds was done using the broth microdilution method against several human pathogenic bacteria, viz. Gram-positive bacteria [B. cerus (NCIN-2156), B. subtilis (ATCC-6051), S. aureus (NCIM-2079)] and Gram-negative bacteria [P. aeruginosa (NCIM-2036), E. coli (NCIM-2065), and a drug-resistant strain of E. coli (U-621)], and the compounds presented admirable MIC values, ranging between 100–1.56 µg/mL. The combinatorial analysis showed the magnificent inhibitory efficiency of the tested compounds, acquired equipotent to ten-fold more potency compared to original MIC values. An immense synergistic effect was exhibited by the compounds during combination studies with reference drugs chloramphenicol and sulfamethoxazole was presented as fractional inhibitory concentration (∑FIC). Enzyme inhibition studies of all synthesized compounds were done by using peptidyl transferase and dihydropteroate synthase enzymes isolated from E. coli and S. aureus and each of the compound presented the admirable IC50 values, where the lead compound 3 bound to peptidyl transferase (of S. aureus with IC50 363.51 ± 2.54 µM and E. coli IC50 1.04 ± 0.08 µM) & dihydropteroate synthase (of S. aureus IC50 3.51 ± 0.82 µM and E. coli IC50 2.77 ± 0.65 µM), might account for the antimicrobial effect, exhibited excellent inhibition potential. Antifungal screening was also performed employing food poisoning methods against several pathogenic fungal species, viz A. flavus, F. oxysporum, A. niger, and A. brassicae. The obtained result indicated that few compounds can prove to be a potent drug regimen against dreaded MDR strains of microbes. Structural activity relationship (SAR) analysis and docking studies reveal that the presence of electron-withdrawing, polar, and more lipophilic substituents positively favor the antibacterial activity, whereas, electron-withdrawing, more polar, and hydrophilic substituents favor the antifungal activities. A robust coherence has been found in in-silico and in-vitro biological screening results of the compounds.

Sulfonamide tethered 1,4-disubstituted 1,2,3-triazoles: Synthesis and antibacterial evaluation

A series of twenty one sulfonamide tethered 1,4-disubstituted 1,2,3-triazoles was synthesized in good yields through a facile expeditious click synthetic protocol involving Cu(I) mediated cyclization between terminal alkynes containing ester linkage and 4-azidobenzenesulfonamide. All the synthesized triazoles were characterized using FTIR,1H NMR,13C NMR and HRMS techniques. Synthesized compounds were also evaluated for in vitro antibacterial activity against two Gram positive bacteria (Staphylococcus aureus, Bacillus subtilis) and two Gram negative bacteria (Klebsiella pneumoniae, Escherichia coli) by serial dilution method. In the series, compound 6 l, 3-(1-(4-sulfamoylphenyl)-1H-1,2,3-triazol-4-yl)propyl 4-bromobenzoate with Minimum Inhibitory Concentration (MIC) 0.0134 µmol/mL exhibited appreciable antibacterial activity against all bacterial strains comparable with standard drug Ciprofloxacin (MIC 0.0189 µmol/mL). Further, molecular docking study was also performed to gain insight for binding interactions with dihydropteroate synthase enzyme.

The pterin binding site of dihydropteroate synthase (DHPS): In silico screening and in vitro antibacterial activity of existing drugs

Antimicrobial resistance has rendered the sulfonamide class of antibiotics obsolete. An additional binding site on the dihydropteroate synthase (DHPS) enzyme, i.e., the pterin binding site, has been shown to be a valid alternative to the well-known para-aminobenzoic acid binding site. The aim of this study was to identify compounds that may bind to the pterin binding site using a computational approach. Different computer docking/scoring combinations were firstly validated using the root mean square deviation, enrichment factor (EF10%) and the area under the receiver operating characteristic curve (ROC-AUC) as three validation metrics. The most promising docking/scoring combination was used to screen an online database of existing drugs (DrugBank) to identify potential inhibitors of pterin binding. The minimum inhibitory concentration of these drugs was determined against Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonasaeruginosa, Escherichia coli and Klebsiellaaerogenes.The LigandFit/LigScore 1 combination was the most promising (EF10%: 6.3, ROC-AUC: 0.87 ± 0.058) and identified 79 existing drugs as potential inhibitors of pterin binding. Of these drugs, 26 were screened for in vitro antibacterial activity of which amiloride, citric acid, diazolidinyl urea, imidurea, riboflavin, diflunisal, nitrofurantion, sapropterin, zidovudine and N-carbamyl-L-glutamic had antibacterial activity against at least one bacterium. The antibacterial activity of some of these drugs are known, whereas the antibacterial activity for N-carbamyl-L-glutamic acid and sapropterin is novel. The docking results as well as the in vitro activity are indicators that the pterin binding site was the target, however additional DHPS enzyme assays must be carried out to conclusively substantiate these findings.

Sulfamethoxazole: Molecular docking and crystal structure prediction

The conformational stability of sulfonamide derivatives was examined in the active site of the Dihydropteroate synthase enzyme. The best-docked conformer was identified via the molecular docking approach. Possible stable packing of best-docked conformer was predicted and evaluated from the intermolecular interactions. Further, the interactions of stable conformers with the active site residue were characterized by charge density analysis based on Bader’s Quantum Theory of Atoms in Molecules.

Synthesis and antibacterial evaluation of sulfonamide bridged disubstituted 1,2,3-triazoles

In the present study, a series of sulfonamide bridged 1,4-disubstituted 1,2,3-triazoles have been synthesized in good yield via click reaction between sulfonamide linked terminal alkynes and in situ prepared 2/3/4-azidobenzenesulfonamides. The synthesized triazoles were characterized by FTIR, 1H NMR, 13C NMR, and HRMS techniques. Further, all the synthesized compounds were assessed for in vitro antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Klebsiella pneumonia. It has been observed that some of the synthesized triazoles possess appreciable efficacy against the bacterial strains used. Particularly, compound 4-bromo-N-((1-(4-(sulfamoylphenyl)-1H-1,2,3-triazol-4-yl)methyl)benzenesulfonamide 6l (MIC = 0.132 µmol/mL) revealed significant antibacterial activity against B. subtilis, E. coli, and K. pneumonia. Further, the molecular docking study of the above potent compound was also performed in the active site of the enzyme dihydropteroate synthase to have the possible mode of action.

Rational design of biodegradable sulphonamide candidates treating septicaemia by synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme

A new series of co-drugs was designed based on hybridising the dihydropteroate synthase (DHPS) inhibitor sulphonamide scaffold with the COX-2 inhibitor salicylamide pharmacophore through biodegradable linkage to achieve compounds with synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme to enhance antibacterial activity for treatment of septicaemia. Compounds 5 b, 5j, 5n and 5o demonstrated potent in vitro COX-2 inhibitory activity comparable to celecoxib. 5j and 5o exhibited ED50 lower than celecoxib in carrageenan-induced paw edoema test with % PGE2 inhibition higher than celecoxib. Furthermore, 5 b, 5j and 5n showed gastric safety profile like celecoxib. Moreover, in vivo antibacterial screening revealed that, 5j showed activity against S.aureus and E.coli higher than sulfasalazine. While, 5o revealed activity against E.coli higher than sulfasalazine and against S.aureus comparable to sulfasalazine. Compound 5j achieved the target goal as potent inhibitor of COX-2/PGE2 axis and in vivo broad-spectrum antibacterial activity against induced septicaemia in mice.

Antimicrobial evaluation and molecular docking studies of Swertiamarin and Quercetin targeting dihydropteroate synthase enzyme

Antimicrobial evaluation and molecular docking studies of Swertiamarin and Quercetin targeting dihydropteroate synthase enzyme

Structure based design, synthesis, and biological evaluation of imidazole derivatives targeting dihydropteroate synthase enzyme

In this study, we have designed and synthesized 2-((5-acetyl-1-(phenyl)-4-methyl-1H-imidazol-2-yl)thio)-N-(4-((benzyl)oxy)phenyl) acetamide derivatives. Antimicrobial activities of all the imidazole derivatives have been examined against Gram-positive and Gram-negative bacteria and results showed that the conjugates have appreciable antibacterial activity. Besides, several analogous were evaluated for their in vitro antiresistant bacterial strains such as Extended-spectrum beta-lactamases (ESBL), Vancomycin-resistant Enterococcus (VRE), and Methicillin-resistant Staphylococcus aureus (MRSA). The SAR revealed that the 12l compound resulted in potency against all bacterial strains as well as ESBL, VRE, and MRSA strains. Lipinski’s rule of five, and ADME studies were preformed for all the synthesized compounds with Staphylococcus aureus dihydropteroate synthase (saDHPS) protein (PDB ID: 6CLV) and were found standard drug-likeness properties of conjugates. Moreover, the binding mode of the ligands with the protein study has been examined by molecular docking and results are quite promising. Besides, all the analogous were tested for their in vitro antituberculosis, antimalarial, and antioxidant activity.

Novel biaryl imines and amines as potential competitive inhibitors of dihydropteroate synthase

Antibiotic-resistant bacteria account for over 2.8 million infections and 35,000 deaths annually in the United States. The evolution of new resistant strains necessitates the continued development of new antimicrobial compounds. A target for further pharmaceutical development is the enzyme dihydropteroate synthase (DHPS), which plays a key role in prokaryotic biosynthesis of folic acid. A class of drugs called sulfonamides, including drugs sulfamethoxazole and sulfatrim, bind and act as competitive substrates to p-aminobenzoic acid (pABA), a substrate of DHPS, but are limited by their numerous side effects on the human body and bacterial resistance mutations that block larger molecules from entering the binding pocket. Here, we report the design, combinatorial synthesis, and antibacterial properties of a library of novel biaryl small molecules to target the binding pocket of DHPS. We hypothesize that the synthesized compounds in this study will have strong antibiotic efficacy because of their structural similarities to dihydropteroate, an intermediate in the biosynthesis of folate by the enzyme DHPS. Compounds were first screened in silico via docking to the binding pocket in DHPS. The antibiotic efficacy of these compounds was then tested on three species of bacteria related to human pathogens through a Kirby Bauer assay. Two hit compounds were discovered as having larger radii of inhibition compared to other compounds from the data of the assay. The larger radii of inhibition indicates that the bacteria tested against were susceptible to the use of the hit compounds. The results of the assay establish a definitive structure-activity relationship for the compounds studied and provide a basis for the future development of antibiotics targeting DHPS.

Design, Synthesis, Antibacterial Evaluation and Molecular Docking Study of New 3‐Aminoquinoxaline‐2‐alkynyl Carboxylate Esters

AbstractAntibacterial chemotherapy is the clinical application of the antibiotic drug to treat infectious disease. A new series of 3‐aminoquinoxaline‐2‐alkynyl carboxylate esters have been synthesized through the multi‐component copper‐free Sonogashira coupling reaction. Aromatic and aliphatic carboxylic acids were successfully reacted with 3‐bromoprop‐1‐yne and different amine substituted 3‐chloroquinoxalines in the presence of a Pd‐catalyst to produce the new 3‐(3‐(aminoquinoxalin‐2‐yl)prop‐2‐yn‐1‐yl carboxylates. All the newly synthesized compounds were screened in vitro for their antibacterial activities against the two bacterial strains Micrococcus luteus and Pseudomonas aeruginosa. According to the results obtained, compounds 4 a, 4 d, and 4 e showed the lowest MIC value that was comparable to that for tetracycline with strong inhibition (MIC=62.5 mg/mL) against M. luteus and also compound 4 b exhibited the lowest MIC (62.5 mg/mL) against P. aeruginos. Moreover, the results of the antibacterial activity of the synthesized compounds were investigated using molecular docking calculations. In silico studies showed that the screened molecules could occupy both pterin and p‐aminobenzoic acid binding pockets of the dihydropteroate synthase enzyme. Thus, the active compounds could act using the inhibition of bacterial dihydropteroate synthase.

Design, Synthesis, and Antimicrobial Evaluation of a New Series of N-Sulfonamide 2-Pyridones as Dual Inhibitors of DHPS and DHFR Enzymes.

Sulfonamides and trimethoprim (TMP) drugs are normally used to inhibit the action of dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) enzymes, respectively. In this work, a new series of N-sulfonamide 2-pyridone derivatives that combine the inhibitory activities of DHPS and DHFR into one molecule were synthesized and evaluated for its in vitro antimicrobial activity and the ability to inhibit the action of both enzymes simultaneously. The synthesis was carried out via the reaction of novel benzothiazol sulfonylhydrazide with ketene dithioacetal derivatives, and the structures of the resultant compounds were confirmed using spectral and elemental techniques. Among the synthesized compounds, five compounds 3b, 5a, 5b, 11a, and 11b were found to possess significant antimicrobial activities against tested bacterial and fungi strains. The compounds were also examined for their cytotoxicity on HFB4 human dermal fibroblast cell line using MTT assay. The in vitro enzyme assay study of these compounds against DHPS and DHFR enzymes showed that compound 11a was the most potent inhibitor against both enzymes with IC50 values of 2.76 and 0.20 μg/mL, respectively. Docking studies showed that this compound has occupied both the p-aminobenzoic acid and pterin binding pockets of DHPS as well as the pterin binding pocket of DHFR. The results of these investigations confirmed that compound 11a is the most potent dual DHPS/DHFR inhibitor.

A facile synthesis, drug-likeness, and in silico molecular docking of certain new azidosulfonamide–chalcones and their in vitro antimicrobial activity

New azidosulfonamide–chalcone derivatives were designed and synthesized. Their structures were elucidated by 1H and 13C NMR spectral analyses, in addition to elemental analyses. The synthesized derivatives were tested for their antimicrobial activity against a wide variety of Gram-positive, Gram-negative, and fungal strains. Three azidosulfonamide–chalcones showed relatively broad activity against tested strains. Two compounds exhibited eminent antibacterial activity toward S. aureus, M. luteus, and S. marcens (better than ampicillin trihydrate). The synthesized compounds exhibited moderate activity against K. pneumonia and a lower ability to inhibit E. coli growth. Among six tested fungal species, the most potent derivatives demonstrated strong activity toward only two of the fungal strains (T. rubrum and G. candidum). Assessment of drug-likeness, bioavailability, and promiscuity indicated that the compounds are viable drug candidates. In silico molecular docking analysis revealed that the synthesized azidosulfonamide–chalcones successfully occupied pterin-binding site of the dihydropteroate synthase (DHPS), implying that the prepared compounds could exert their activity by the inhibition of the microbial DHPS enzyme. These results provided essential information for the prospective design of more effective antimicrobial compounds.

Origin of the Mobile Di-Hydro-Pteroate Synthase Gene Determining Sulfonamide Resistance in Clinical Isolates.

Sulfonamides are synthetic chemotherapeutic agents that work as competitive inhibitors of the di-hydro-pteroate synthase (DHPS) enzyme, encoded by the folP gene. Resistance to sulfonamides is widespread in the clinical setting and predominantly mediated by plasmid- and integron-borne sul1-3 genes encoding mutant DHPS enzymes that do not bind sulfonamides. In spite of their clinical importance, the genetic origin of sul1-3 genes remains unknown. Here we analyze sul genes and their genetic neighborhoods to uncover sul signature elements that enable the elucidation of their genetic origin. We identify a protein sequence Sul motif associated with sul-encoded proteins, as well as consistent association of a phosphoglucosamine mutase gene (glmM) with the sul2 gene. We identify chromosomal folP genes bearing these genetic markers in two bacterial families: the Rhodobiaceae and the Leptospiraceae. Bayesian phylogenetic inference of FolP/Sul and GlmM protein sequences clearly establishes that sul1-2 and sul3 genes originated as a mobilization of folP genes present in, respectively, the Rhodobiaceae and the Leptospiraceae, and indicate that the Rhodobiaceae folP gene was transferred from the Leptospiraceae. Analysis of %GC content in folP/sul gene sequences supports the phylogenetic inference results and indicates that the emergence of the Sul motif in chromosomally encoded FolP proteins is ancient and considerably predates the clinical introduction of sulfonamides. In vitro assays reveal that both the Rhodobiaceae and the Leptospiraceae, but not other related chromosomally encoded FolP proteins confer resistance in a sulfonamide-sensitive Escherichia coli background, indicating that the Sul motif is associated with sulfonamide resistance. Given the absence of any known natural sulfonamides targeting DHPS, these results provide a novel perspective on the emergence of resistance to synthetic chemotherapeutic agents, whereby preexisting resistant variants in the vast bacterial pangenome may be rapidly selected for and disseminated upon the clinical introduction of novel chemotherapeuticals.

Tecoma stans: Alkaloid Profile and Antimicrobial Activity.

Aim:Tecoma stans (L.) Kunth is a promising species in the trumpet creeper family Bignoniaceae. This study aimed at showing the antibacterial and antifungal potentials of T. stans methanolic leaf extract (TSME) correlated to its phytoconstituents.Materials and Methods:The antimicrobial potential of TSME was evaluated using agar diffusion method. The main alkaloids were separated on silica gel column and identified using nuclear magnetic resonance spectral analysis. Molecular docking was performed for the isolated compounds against MurD ligase, penicillin-binding protein, and dihydropteroate synthase enzyme to rationalize the observed antibacterial effect.Results and Discussion:TSME showed significant antibacterial effect against all tested microorganisms with comparable minimum inhibitory concentration (MIC) to the ampicillin and gentamicin with MIC values ranging between 0.98 and 1.95 µg/mL, in addition to a promising antifungal effect when compared to amphotericin with MIC values 3.9 and 15.63 µg/mL for Aspergillus flavus and Candida albicans, respectively. Several alkaloids were separated, purified, and identified as tecostanine, 4-OH tecomanine, 5-hydroxyskytanthine, and tecomanine, which were previously isolated from T. stans. The docking study showed that the alkaloids bind in a similar fashion to the co-crystallized ligands of the crystal structures of MurD ligase. The binding poses and scores in the case of penicillin-binding protein and dihydropteroate synthase did not match the co-crystallized ligands in their crystal structures. The in silico results suggest an antibacterial mechanism that involves the inhibition of MurD ligase.Conclusion:T. stans alkaloids could represent the basic skeleton for a powerful antimicrobial agent.

Antibacterial and antifungal potential of marine Streptomyces sp. VITAK1 derived novel compound Pyrrolidinyl-Hexadeca-Heptaenone by in Silico docking analysis

The rapid emergence of antibiotic resistance by pathogenic bacteria underlines the need for new antibacterial agents from natural sources. With those objective marine actinomycetes derived novel compound was screened for antibacterial and antifungal activity by in-silico molecular docking studies. Twelve actinomycetes were isolated from marine soil samples collected from Andaman and Nicobar Islands of India. All the isolates were screened for antibacterial activity against selected ATCC bacterial pathogens and the isolate VITAK1 showed significant antibacterial activity. It was characterized by molecular taxonomic and phylogeny and identified as Streptomyces species and designated as Streptomyces sp. VITAK1. The 16S rRNA partial gene sequence (1296 nucleotides) of VITAK1 was submitted to the GenBank under the accession ID: KF478916. Bioactivity-guided extraction, purification and characterization of the compound through GC-MS, FT-IR and NMR (H1and C13) lead to the identification of compound, [(3E, 5E, 7E, 9E, 11E, 13E, 15E)-16-(pyrrolidin-1-yl) hexadeca-3, 5, 7, 9, 11, 13, 15-heptaen-2-one] with a molecular weight of 295.41 Da and molecular formula C20H25NO. The extracted compound was found to be anovelbased on PUBCHEM and SciFinderdatabase. The compound exhibited the least free binding energy of -8.8 Kcal/mol with the fungal drug target enzyme N-myristoyl transferase and also showed the free binding energy of -8.14 Kcal/mol with folate synthesising enzyme dihydropteroate synthase. The results of the in Silico studies suggest that the novel compound PHDH exhibit antibacterialactivity by inhibiting folate synthesis in the target bacteria and antifungal activity by inhibiting the ergosterol synthesis.

Design, synthesis, antibacterial evaluation and molecular docking studies of some new quinoxaline derivatives targeting dihyropteroate synthase enzyme

Development of new antimicrobial agents is a good solution to overcome drug-resistance problems. From this perspective, new quinoxaline derivatives bearing various bioactive heterocyclic moieties (thiadiazoles, oxadiazoles, pyrazoles and thiazoles) were designed and synthesized. The newly synthesized compounds were evaluated for their in vitro antibacterial activity against nine bacterial human pathogenic strains using the disc diffusion assay. In general, most of the synthesized compounds exhibited good antibacterial activities. The thiazolyl 11c displayed significant antibacterial activities against P. aeruginosa (MIC, 12.5 µg/mL vs levofloxacin 12.5 µg/mL). Molecular docking studies indicated that the synthesized compounds could occupy both p-amino benzoic acid (PABA) and pterin binding pockets of the dihydropteroate synthase (DHPS), suggesting that the target compounds could act by the inhibition of bacterial DHPS enzyme. The results provide important information for the future design of more potent antibacterial agents.

Facile synthesis, characterization, and antimicrobial studies of some disubstituted 1,2,3-triazoles with sulfonamide functionality

ABSTRACTAn expedient synthesis of some 1,4-disubstituted 1,2,3-triazoles (3a–3x) having sulfonamide functionality from various terminal alkynes and aromatic azides through Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition has been reported. The structures of newly synthesized compounds were confirmed by IR, 1H NMR, 13C NMR, high-resolution mass spectra and screened for in vitro antimicrobial activity against Staphylococcus aureus (Gram-positive bacteria), Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes (Gram-negative bacteria), Candida albicans, and Aspergillus niger (fungi). Some of the synthesized compounds were found to exhibit good potency against above-tested microbial strains. Moreover, to study the binding interactions, docking simulation of broadly active compound 3x was also performed against E. coli dihydropteroate synthase enzyme.

Synthesis and antimicrobial activity of substituted 1,4-bis-spiro[benzocycloheptene-6(5h),3′(3h-pyrazol)-5-one]-benzene under microwave irradiation and molecular docking study

Background and objective Spiropyrazole derivatives are one of the most bioactive spiro compounds that play a vital role in drug discovery, such as antibacterial, anti-inflammatory, antifungal, antiviral, analgesic, and antidepressant activities. Moreover, microwave as an energy source enhances the reaction rates and improves the regioselectivity. The aim of this study was to synthesize the spiropyrazole derivative compounds. Molecular docking was performed. Materials and methods 1,3-Dipolar cycloaddition of 6,6′-(1,4-phenylene-bis(methanylylidene))-bis(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one) to a variety of nitrilimines (generated in situ by triethylamine dehydrohalogenation of the corresponding hydrazonoyl halides) under microwave irradiation proceeded regioselectively affording spiro[benzo[7]-annulene-6,3′-pyrazol]-4′-yl)phenyl)-spiro[benzo[7]annulene-6,3′-pyrazol]-5(7H)-ones. The structure of the newly synthesized compounds was confirmed on the basis of spectral data and elemental analyses. The antimicrobial activity of the bis(spiropyrazoles) derivatives was tested for antimicrobial activity. Molecular docking was performed and analyzed with the molecular modeling environment program. Results and conclusion Compound 7f has high potency against all fungi (except Candida albicans) and bacterium species (except Pseudomonas aeruginosa) compared with the reference drug fungicide amphotericin B and the standard bactericides ampicillin and gentamicin. Docking of the most active antibacterial compounds 7f and 7g against the dihydropteroate synthase enzyme gave comparable scores for hydrogen bond interaction (−22.9123, −17.5995 kcal/mol(and binding mode to the reference antibiotic sulfamethoxazole (−13.00 kcal/mol).

DOCKING STUDIES IN TARGET PROTEINS INVOLVED IN ANTIBACTERIAL ACTION MECHANISMS: ALKALOIDS ISOLATED FROM SCUTELLARIA GENUS

ABSTRACTObjective: In the present work, docking study was performed for 22 selected alkaloids isolated from the genus Scutellaria to evaluate their affinityto bacterial proteins that are known targets for many antibiotics with a different mechanism of action: Inhibitors of cell wall synthesis, inhibitors ofnucleic acids synthesis and antimetabolites.Methods: Molecular docking study was carried out using AutoDock 4.2 version and the visualization result using Chimera 1.10 and DiscoveryStudio 4.5.Result: Among the 22 alkaloids studied, with the DNA gyrase protein 1KZN and a dihydropteroate synthase enzyme 3TYE, the compoundscutebarbatine E showed a docking score of −8.5 and −8.7 Kcal/mol, respectively, involving with hydrophilic and hydrophobic interactions. Withrespect to MurD ligase involved in cell wall synthesis 1UAG and 2X5O, the compound 6,7,nicotinyl scutebarbatine G fared well with a dockingscore of −10.1 and −10.2 Kcal/mol, respectively. Scutebarbatine G performed well with respect to 3UDI with binding scores of −9.3 K cal/mol.Conclusion: Overall, it seems that for the selected alkaloids from the genus Scutellaria, the main mechanism of the action is the inhibition of cell wallsynthesis.Keywords: Scutebarbatine, Alkaloids, Molecular docking, Antimicrobial studies.

Design, synthesis, antimicrobial evaluation and molecular docking studies of some new 2,3-dihydrothiazoles and 4-thiazolidinones containing sulfisoxazole

Microbial resistance to the available drugs poses a serious threat in modern medicine. We report the design, synthesis and in vitro antimicrobial evaluation of new functionalized 2,3-dihydrothiazoles and 4-thiazolidinones tagged with sulfisoxazole moiety. Compound 8d was most active against Bacillis subtilis (MIC, 0.007 µg/mL). Moreover, compounds 7c–d and 8c displayed significant activities against B. subtilis and Streptococcus pneumoniae (MIC, 0.03–0.06 µg/mL and 0.06–0.12 µg/mL versus ampicillin 0.24 µg/mL and 0.12 µg/mL; respectively). Compounds 7a and 7c–d were highly potent against Escherichia coli (MIC, 0.49–0.98 µg/mL versus gentamycin 1.95 µg/mL). On the other hand, compounds 7e and 9c were fourfolds more active than amphotericin B against Syncephalastrum racemosum. Molecular docking studies showed that the synthesized compounds could act as inhibitors for the dihydropteroate synthase enzyme (DHPS). This study is a platform for the future design of more potent antimicrobial agents.