Azoalkyl ether imidazo[2,1-b]benzothiazoles as potentially antimicrobial agents with novel structural skeleton

A series of new azoalkyl ether imidazo[2,1-b]benzothiazoles were developed via a convenient synthetic procedure. The antimicrobial assays showed that a good number of the prepared derivatives exhibited significant inhibitory properties against most of the tested strains. Especially 2-methyl-5-nitroimidazole derivative 5a presented superior inhibit activity against MRSA and B. typhi with MIC?=?4?μg/mL and MIC?=?1?μg/mL, respectively. The highly active compound 5a showed low toxicity against mammalian cells without obvious triggering of the development of bacterial resistance, and it also possessed rapid bactericidal efficacy. Molecular docking study exposed that the active molecule 5a could interact with the active site of S. aureus gyrase through hydrogen bond. Quantum chemical studies were also performed to explain the high antibacterial activity. Further investigation revealed that compound 5a could significantly associate with gyrase–DNA complex by mean of hydrogen bonds and could efficiently intercalate into MRSA DNA to form 5a–DNA supramolecular complex, which impart potent bioactivity.     

Synthesis and antibacterial activity of benzyl-[3-(benzylamino-methyl)-cyclohexylmethyl]-amine derivatives

A series of benzyl-[3-(benzylamino-methyl)-cyclohexylmethyl]-amine derivatives with different substitution pattern on the aromatic ring have been prepared and evaluated for their antibacterial activity against Gram-positive and Gram-negative bacterial strains. Most of the compounds exhibit potent activity against Pseudomonas aeruginosa and Staphylococcus epidermidis while compounds 6l and 6m showed antibacterial activity against all the four bacterial strains with MIC values ranging from 0.002 to 0.016 μg/mL and no hemolytic activity up to 512 μg/mL in mammalian erythrocytes was observed.     

Design,synthesis and biological activity evaluation of novel 2,6-difluorobenzamide derivatives through FtsZ inhibition

Novel series of 3-substituted 2,6-difluorobenzamide derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their in vitro antibacterial activity against various phenotype of Gram-positive and Gram-negative bacteria, and their cell division inhibitory activity against three representative strains. As a result, 3-chloroalkoxy derivative 7, 3-bromoalkoxy derivative 12 and 3-alkyloxy derivative 17 were found to exhibit the best antibacterial activity against Bacillus subtilis with MICs of 0.25–1 μg/mL, and good activity (MIC < 10 μg/mL) against both susceptible and resistant Staphylococcus aureus. Additionally, all the three compounds displayed potent cell division inhibitory activity with MIC values of below 1 μg/mL against Bacillus subtilis and Staphylococcus aureus.     

Convenient framework of poly functionalized (E)-2-benzylideno-(Z)-carbazolylideno cyanoacetamides via rearrangements as an efficient antibiofilm inhibitors with SAR study

A simple and one-pot approach for the synthesis of highly functionalized novel (E)-2-benzylideno-(Z)-carbazolylideno cyanoacetamide derivatives from different 2-(2′,3′,4′,9′-tetrahydro-carbazol-1′-ylidene)-propanedinitriles and aryl/heteroaryl carbaldehydes via vinylogous aldol reaction. The structures of the molecules were designated by FT-IR, ¹H NMR, ¹³C NMR studies, elemental and X-ray crystallographic analysis. The synthesized pure products have been screened for in vitro antibiofilm inhibitory activity towards antibiotic-resistant pathogenic organisms. All the synthesized compounds showed biofilm inhibition. Promisingly, the moieties 3a, 3d and 3h showed higher antibiofilm activity at biofilm inhibitory concentration (BIC) (200?μg/mL) against bacterial pathogens. Among the three moieties, 3a showed high prospective against E. coli biofilm with minimal and maximal BIC percentage of 32% (10?μg/mL) and 89% (100?μg/mL) and chosen lowest BIC for further evaluation. Also, the 3a generate ROS two fold at 1?h treatment in E. coli biofilm. The 3a exhibited no toxic effect on cell viability upto 75?μg/mL in HEK293 cell lines. The results of the present study reveal that among (E)-2-benzylideno-(Z)-carbazolylideno cyanoacetamides, (E)-2-benzylideno-6-methyl-2,3,4,9-tetrahydro-1H-carbazol-(Z)-α-carbamino-α-cyano-1-ylidene (3a) could be exploited as an excellent antibiofilm agent against carbapenem-resistant E. coli bacteria strains.     

Antimicrobial,anticoagulant, and cytotoxic evaluation of multidrug resistance of new 1,4-dihydropyridine derivatives

A new series of 1,4-dihydropyridine derivatives (2a–h, 3a–e, and 4a–e) were systematically designed and synthesized via ultrasound irradiation methods with easy work-up and good yields. Compounds structures were confirmed by IR, ¹H NMR, ¹³C NMR, and mass spectra. The synthesized compounds were screened for both antimicrobial and anticoagulant activities. Compound 2e (MIC: 0.25?μg/mL) was highly active against Escherichia coli and compound 2c (MIC: 0.5?μg/mL) was also highly active against Pseudomonas aeruginosa compared with ciprofloxacin. (MIC: 1?μg/mL) The antifungal activity of 2c (MIC: 0.5?μg/mL) against Candida albicans was high relative to that of clotrimazole (MIC: 1?μg/mL). Anticoagulant activity was determined by activated partial thromboplastin time (APTT) and prothrombin time (PT) coagulation assays. Compound 4-(4-hydroxyphenyl)-2,6-dimethyl-N³,N⁵-bis(5-phenyl-1,3,4-thiadiazol-2-yl)-1,4-dihydropyridine-3,5-dicarboxamide 3d (>1000?s in APTT assays) was highly active in anticoagulant screening compared with the reference of heparin.Cytotoxicity was evaluated using HepG2 (liver), HeLa (cervical), and MCF-7 (breast) cancer cell lines, with high toxicities observed for 2c (GI₅₀?=?0.02?μm) against HeLa cell line and 2e (GI₅₀?=?0.03?μm) equipotant against MCF-7 cell line. Therefore, the compounds 2e, 2c and 3d can serve as lead molecules for the development of new classes of antimicrobial and anticoagulant agent.     

Antibacterial serrulatane diterpenes from the Australian native plant Eremophila microtheca

Chemical investigations of the aerial parts of the Australian plant Eremophila microtheca resulted in the isolation of three serrulatane diterpenoids, 3-acetoxy-7,8-dihydroxyserrulat-14-en-19-oic acid (1), 3,7,8-trihydroxyserrulat-14-en-19-oic acid (2) and 3,19-diacetoxy-8-hydroxyserrulat-14-ene (3) as well as the previously reported compounds verbascoside (4) and jaceosidin (5). Acetylation and methylation of the major serrulatane diterpenoid 2 afforded 3,8-diacetoxy-7-hydroxyserrulat-14-en-19-oic acid (6) and 3,7,8-trihydroxyserrulat-14-en-19-oic acid methyl ester (7), respectively. The antibacterial activity of 1–7 was assessed against a panel of Gram-positive and Gram-negative bacterial isolates. All of the serrulatane compounds exhibited moderate activity against Streptococcus pyogenes (ATCC 12344) with minimum inhibitory concentrations (MICs) ranging from 64–128 μg/mL. Serrulatane 1 demonstrated activity against all Gram-positive bacterial strains (MICs 64–128 μg/mL) except for Enterococcus faecalis and Enterococcus faecium. This is the first report of natural products from E. microtheca.     

Synthesis and antibacterial activity of novel 3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin derivatives

A novel series of 3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin derivatives, were designed, synthesized and evaluated for their in vitro antibacterial activity. These derivatives were found to have strong activity against susceptible and resistant bacteria strains. Among them, compounds 7a and 7q showed the most potent activity (0.125?µg/mL) against erythromycin-resistant S. pneumoniae expressing the mefA gene. Moreover, compounds 7f, 7i, 7p and 7z displayed remarkably improved activity (4?µg/mL) against penicillin-resistant S. aureus ATCC31007, and compounds 7a, 7b, 7f, 7p and 7z showed improved activity (8?µg/mL) against erythromycin-resistant S. pyogenes. In particular, compound 7z exhibited potent and balanced activity against the tested drug-susceptible and -resistant bacterial strains.     

Synthesis,biological evaluations and computational studies of N-(3-(-2-(7-Chloroquinolin-2-yl)vinyl) benzylidene)anilines as fungal biofilm inhibitors

In the present investigation, new chloroquinoline derivatives bearing vinyl benzylidene aniline substituents at 2nd position were synthesized and screed for biofilm inhibitory, antifungal and antibacterial activity. The result of biofilm inhibition of C. albicans suggested that compounds 5j (IC₅₀ value?=?51.2?μM) and 5a (IC₅₀ value?=?66.2?μM) possess promising antibiofilm inhibition when compared with the standard antifungal drug fluconazole (IC₅₀?=?40.0?μM). Two compounds 5a (MIC?=?94.2?μg/mL) and 5f (MIC?=?98.8?μg/mL) also exhibited good antifungal activity comparable to standard drug fluconazole (MIC?=?50.0?μg/mL). The antibacterial screening against four strains of bacteria viz. E. coli, P. aeruginosa, B. subtilis, and S. aureus suggested their potential antibacterial activity and especially all the compounds except 5g were found more active than the standard drug ciprofloxacin against B. subtilis. To further gain insights into the possible mechanism of these compounds in biofilm inhibition through the agglutinin like protein (Als), molecular docking and molecular dynamics simulation studies were carried out. Molecular modeling studies suggested the clear role in inhibition of this protein and the resulting biofilm inhibitory activity.     

Synthesis and antimicrobial activity of polyhalobenzonitrile quinazolin-4(3H)-one derivatives

A novel series of polyhalobenzonitrile quinazolin-4(3H)-one derivatives were synthesized and characterized by NMR, IR, MS, and HRMS spectra. All of the newly prepared compounds were screened for antimicrobial activities against four strains of bacteria (Gram-positive bacterial: Staphylococcus aureus and Bacillus cereus; Gram-negative bacterial: Escherichia coli and Pseudomonas aeruginosa) and one strain of fungi (Candida albicans). Among the synthesized compounds, 5-(dimethylamino)-8-(2,4,5-trichloro-isophthalonitrile) quinazolin-4(3H)-one (7k) exhibited significant activity towards Gram-positive bacterial, Gram-negative bacterial, and the fungi strains. The MIC (0.8–3.3 μg/mL) and MBC (2.6–7.8 μg/mL) for this compound were close to those of nofloxacin, chlorothalonil, and fluconazole, making it the most potent antimicrobial agents in the series.     

Pyrazolo[3,4-d]pyrimidine derivatives containing a Schiff base moiety as potential antiviral agents

A series of pyrazolo[3,4-d]pyrimidine derivatives containing a Schiff base moiety were synthesized, characterised, and evaluated for their activity against tobacco mosaic virus (TMV). Biological assays indicated that several of the derivatives exhibited significant activity against TMV. In particularly, compounds 5y and 5aa displayed excellent inactivating activity against TMV, with half maximal effective concentration (EC₅₀) values of 70.3 and 53.65?μg/mL, respectively, which were much better than that of ribavirin (150.45?μg/mL), and 5aa was superior to ningnanmycin (EC₅₀?=?55.35?μg/mL). Interactions of compounds 5y and 5aa with TMV coat protein (TMV-CP) were investigated using microscale thermophoresis and molecular docking. Compounds 5y and 5aa displayed strong binding capability to TMV-CP with dissociation constant (K_d) values of 22.6 and 9.8?μM, respectively. These findings indicate that pyrazolo[3,4-d]pyrimidine derivatives containing a Schiff base may be potential antiviral agents.     

Design,synthesis and antimicrobial activities evaluation of Schiff base derived from secnidazole derivatives as potential FabH inhibitors

FabH, β-ketoacyl-acyl carrier protein (ACP) synthase III, is critically important to the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and Gram-negative bacteria. A series of novel secnidazole derivatives (1–20) were synthesized and fully characterized by spectroscopic methods and elemental analysis. Among these compounds, 6, 8, 11, 13, 14, 16–20 were reported for the first time. These compounds were tested for antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. The compounds inhibitory assay and docking simulation indicated that compound 20 (E)-2-(2-methyl-5-nitro-1H-imidazol-1-yl)-N′-(3,4,5-trimethylbenzylidene)acetohydrazide with MIC of 3.13–6.25 μg/mL against the tested bacterial strains was a potent inhibitor of Escherichia coli FabH.     

New β-lactam – Tetramic acid hybrids show promising antibacterial activities

β-Lactams are the most important class of antibiotics, for which the emergence of resistance threatens their utility. As such, we explored the extent to which the tetramic acid motif, frequently found in naturally occurring antibiotics, can be used to generate novel β-lactam antibiotics with improved antibacterial activity. We synthesized new ampicillin – tetramic acid, cephalosporin – tetramic acid, and cephamycin – tetramic acid analogs and evaluated their activities against problematic Gram-positive and Gram-negative pathogens. Amongst the analogs, a 7-aminocephalosporanic acid analog, 3397, and a 7-amino-3-vinyl cephalosporanic acid, 3436, showed potent activities against S. aureus NRS 70 (MRSA) with MICs of 6.25?μg/mL and 3.13?μg/mL respectively. These new analogs were ≥16-fold more potent than cefaclor and cephalexin. Additionally, a Δ² cephamycin – tetramic acid analog 3474 which contained a basic guanidinium substituent at the 5-position of the tetramic acid core displayed potent activity against several clinical strains of K. pneumoniae and E. coli.     

Antibacterial activity of indolyl-quinolinium derivatives and study their mode of action

Filamenting temperature-sensitive mutant Z (FtsZ) is recognized as a promising target for new antibiotics development because of its high conservatism and pivotal role in the bacteria cell division. The aromatic heterocyclic scaffold of indole is known showing merit medical functions in antiviral and antimicrobial. In the present study, a series of 1-methylquinolinium derivatives, which were integrated with an indole fragment at its 2-position and a variety of amino groups (cyclic or linear, mono- or di-amine) at the 4-position were synthesized and their antibacterial activities were evaluated. The results of antibacterial study show that the representative compounds can effectively inhibit the growth of testing strains including MRSA and VRE, with MIC values of 1–4?μg/mL by bactericidal mode. The mode of action assays revealed that c2 can effectively disrupt the rate of GTP hydrolysis and dynamic polymerization of FtsZ, and thus inhibits bacterial cell division and then causes bacterial cell death. In addition, the result of resistance generation experiment reveals that c2 is not likely to induce resistance in S. aureus.     

Characterization of a xylose containing oligosaccharide,an inhibitor of multidrug resistance in Staphylococcus aureus,from Ipomoea pes-caprae

Pescaprein XVIII (1), a type of bacterial efflux pump inhibitor, was obtained from the CHCl₃-soluble resin glycosides of beach morning glory (Ipomoea pes-caprae). The glycosidation sequence for pescaproside C, the glycosidic acid core of the lipophilic macrolactone 1 containing d-xylose and l-rhamnose, was characterized by means of several NMR techniques and FAB mass spectrometry. Recycling HPLC also yielded eight non-cytotoxic bacterial resistance modifiers, the two pescapreins XIX (2) and XX (3) as well as the known murucoidin VI (4), pecapreins II (6) and III (7), and stoloniferins III (5), IX (8) and X (9), all of which contain simonic acid B as their oligosaccharide core. Compounds 1–9 were tested for in vitro antibacterial and resistance-modifying activity against strains of Staphylococcus aureus possessing multidrug resistance efflux mechanisms. All of the pescapreins potentiated the action of norfloxacin against the NorA over-expressing strain by 4-fold (8 μg/mL from 32 μg/mL) at a concentration of 25 μg/mL.     

Antiviral properties and interaction of novel chalcone derivatives containing a purine and benzenesulfonamide moiety

A new concise and facile method was explored to synthesize a series of novel chalcone derivatives containing a purine and benzenesulfonamide moiety and their antiviral properties were evaluated against TMV and CMV. Biological assays indicated that several of the derivatives exhibited significant anti-TMV and anti-CMV activities in vivo. In particular, compound d2 displayed excellent inactivating activity against TMV, with the EC₅₀ value of 51.65?μg/mL, which was better than that of ribavirin (150.45?μg/mL). Molecular docking showed that there are four hydrogen bonds between compound d2 and TMV coat protein (TMV-CP). Compound d2 demonstrated strong binding capacity to TMV-CP with K_a?=?1.58?×?10⁵?L/mol and K_d?=?12.16?μM. These findings indicated that chalcone derivatives are worthy of further research and development as templates for new antiviral agents.     

Filamenting temperature-sensitive mutant Z inhibitors from Glycyrrhiza glabra and their inhibitory mode of action

FtsZ is an essential protein for bacterial cell division, and an attractive and underexploited novel antibacterial target protein. Screening of Indonesian plants revealed the inhibitory activity of the methanol extract of Glycyrrhiza glabra on the Bacillus subtilis FtsZ (BsFtsZ) GTPase, and further bioassay-guided fractionation of the active methanol extract led to the isolation of seven known polyketides (1–7). Among them, gancaonin I (1), glycyrin (3), and isolicoflavanol (5) exhibited anti-BsFtsZ GTPase activities, at levels comparable to that of the synthetic FtsZ inhibitor, Zantrin Z3. Enzymatic assays using a BsFtsZ Val307R mutant protein and in silico simulations suggested that 1, 3, and 5 bind to the cleft on BsFtsZ, as in the case of the previously reported uncompetitive FtsZ inhibitor, PC190723, and thereby display their significant anti-BsFtsZ inhibitory activities. Furthermore, 1 also showed significant inhibitory activity against B. subtilis, with a MIC value of 5 μM. The present study provides new insights into the naturally occurring B. subtilis growth inhibitors.     

The synthesis and antistaphylococcal activity of N-sulfonaminoethyloxime derivatives of dehydroabietic acid

A series of N-sulfonaminoethyloxime derivatives of dehydroabietic acid were synthesized and investigated for their antibacterial activity against Staphylococcus aureus Newman strain and multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108 and NRS-271). Most of the target compounds having chloro, bromo, trifluoromethyl phenyl moiety exhibited potent in vitro antistaphylococcal activity. The meta-CF₃ phenyl derivative T23 showed the highest activity with MIC of 0.39–0.78?μg/mL against S. aureus Newman, while several analogues showed similar potent antibacterial activity with MIC values between 0.78 and 1.56?μg/mL against five multidrug-resistant S. aureus. The stability of T35 in plasma of SD rat and the cellular cytotoxicity were also evaluated.     

Synthesis of novel dihydrotriazine derivatives bearing 1,3-diaryl pyrazole moieties as potential antibacterial agents

Three novel series of dihydrotriazine derivatives bearing 1,3-diaryl pyrazole moieties were designed, synthesized and evaluated in terms of their antibacterial and antifungal activities. Most of the synthesized compounds showed potent inhibition of several Gram-positive bacterial strains (including multidrug-resistant clinical isolates) and Gram-negative bacterial strains with minimum inhibitory concentration values in the range of 1–64?µg/mL. Compounds 4b and 4c presented the most potent inhibitory activity against Gram-positive bacteria (S. aureus 4220, MRSA 3167, QRSA 3519) and Gram-negative bacteria (E. coli 1924), with minimum inhibitory concentration values of 1 or 2?µg/mL. Compared with previous studies, these compounds exhibited a broad spectrum of inhibitory activity. The cytotoxic activity of the compounds 4a, 4b, 4c and 11n were assessed in L02 cells. In vitro enzyme study implied that compound 4c exerted its antibacterial activity through DHFR inhibition.     

Synthesis and antiviral evaluation of novel 1,3,4-oxadiazole/thiadiazole-chalcone conjugates

A series of novel 1,3,4-oxadiazole/thiadiazole–chalcone conjugates were synthesized and their in vitro and in vivo antiviral activities were evaluated via microscale thermophoresis method and half-leaf method, respectively. The in vitro results indicated that compounds 7g, 7l, 8h, and 8l displayed good antiviral activity against TMV, with the binding constant values of 5.93, 6.15, 6.02, and 5.04 μM, respectively, which were comparable to that of Ninnanmycin (6.78 μM) and even better than that of Ribavirin (99.25 μM). The in vivo results demonstrated that compounds 7g, 7l, 8h, and 8l exhibited remarkable anti-TMV activity with the EC₅₀ values of 33.66, 33.97, 33.87 and 30.57 µg/mL, respectively, which were comparable to that of Ningnanmycin (36.85 µg/mL) and superior to that of Ribavirin (88.52 µg/mL). Interestingly, the trend of antiviral activity in vivo was consistent with the in vitro results.     

Synthesis of novel benzimidazole functionalized chiral thioureas and evaluation of their antibacterial and anticancer activities

A small library of benzimidazole functionalized chiral thioureas was prepared starting from natural amino acids (S)-alanine, (S)-phenylalanine, (S)-valine and (S)-leucine and also their (R)-isomers and studied their antimicrobial activity against a various Gram-positive and Gram-negative bacterial strains. In this study, compounds 5g and 5j were found to exhibit good antibacterial activity against both Gram-positive and Gram-negative bacterial strains such as Staphylococcus aureus, Bacillus subtilis, Micrococcus luteus, Klebsiella planticola, Escherichia coli and Pseudomonas aeruginosa. In the cytotoxicity study, thioureas derived from non-natural amino acids 5a–l showed good activity against human cancer cell lines A549, MCF7, DU145, HeLa, and no cytotoxicity was observed with their antipodes 6a–l.