Synthesis and antibacterial activity of novel 6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-4-oxoquinoline-3-carboxylic acids bearing cyclopropane-fused 2-amino-8-azabicyclo[4.3.0]nonan-8-yl substituents at the C-7 position

A series of novel 6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-4-oxoquinoline-3-carboxylic acids bearing cyclopropane-fused 2-amino-8-azabicyclo[4.3.0]nonan-8-yl substituents at the C-7 position were synthesized to obtain potent drugs for the treatment of Gram-positive infections. Some compounds exhibited excellent antibacterial activity, and potent inhibitory activity against bacterial DNA topoisomerase IV. In addition, some of the potent compounds showed reduced inhibitory activity against human DNA topoisomerase II compared with the corresponding noncyclopropane-fused compounds.     

Synthesis and antibacterial activity of a novel series of DNA gyrase inhibitors: 5-[(E)-2-arylvinyl]pyrazoles

The 2-arylvinyl moiety in 1-(3-chlorophenyl)-3-(4-piperidyl)-5-[(E)-2-(5-chloro-1H-indol-3-yl)vinyl]pyrazole 2, which has previously shown improved DNA gyrase inhibition and target-related antibacterial activity, was transformed to other groups and the in vitro antibacterial activity of the synthesized compounds was evaluated. Many of the 5-[(E)-2-arylvinyl]pyrazoles synthesized in this study exhibited potent antibacterial activity against quinolone-resistant clinical isolates of gram-positive bacteria with minimal inhibitory concentration values equivalent to those against susceptible strains.     

Synthesis, antibacterial activities and molecular docking studies of Schiff bases derived from N-(2/4-benzaldehyde-amino) phenyl-N'-phenyl-thiourea

A series of novel Schiff base derivatives have been designed and synthesized, and their biological activities were also evaluated as potential inhibitors of FabH. These compounds were assayed for antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. Compounds with potent antibacterial activities were tested for their E. coli FabH inhibitory activity. Compound 3v showed the most potent antibacterial activity with MIC of 1.56-6.25 μg/mL against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with IC(50) of 4.3 μM. Docking simulation was performed to position compound 3v into the E. coli FabH active site to determine the probable binding conformation.     

Synthesis, molecular modeling and biological evaluation of β-ketoacyl-acyl carrier protein synthase III (FabH) as novel antibacterial agents

A series of novel cinnamic acid secnidazole ester derivatives have been designed and synthesized, and their biological activities were also evaluated as potential inhibitors of FabH. These compounds were assayed for antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. Compounds with potent antibacterial activities were tested for their E. coli FabH inhibitory activity. Compound 3n showed the most potent antibacterial activity with MIC of 1.56-6.25 μg/mL against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with IC?? of 2.5 μM. Docking simulation was performed to position compound 3n into the E. coli FabH active site to determine the probable binding conformation.     

Synthesis of novel tricyclic oxazolidinones by a tandem SN2 and SNAr reaction: SAR studies on conformationally constrained analogues of Linezolid

A series of conformationally constrained analogues of Linezolid were synthesised by employing a tandem SN(2) and SNAr reaction as the key step and tested for antibacterial activity. While the hexahydroazolo-quinoxaline compounds were inactive, the tetrahydroazolo-benzothiazine compounds exhibited interesting antibacterial activity. The introduction of fluorine in the aromatic ring further made the compounds more potent in acetamide compounds resulting in an interesting analogue 32. However, the introduction of fluorine (analogue 34) on the already potent non-fluorine thiocarbamate 21 did not have any influence on the activity.     

5-Adamantan thiadiazole-based thiazolidinones as antimicrobial agents. Design,synthesis, molecular docking and evaluation

In continuation of our efforts to develop new compounds with antimicrobial properties we describe design, synthesis, molecular docking study and evaluation of antimicrobial activity of seventeen novel 2-{[5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl]-imino}-5-arylidene-1,3-thiazolidin-4-ones. All compounds showed antibacterial activity against eight Gram positive and Gram negative bacterial species. Twelve out of seventeen compounds were more potent than streptomycin and all compounds exhibited higher potency than ampicillin. Compounds were also tested against three resistant bacterial strains: MRSA, P. aeruginosa and E. coli. The best antibacterial potential against ATCC and resistant strains was observed for compound 8 (2-{[5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl]-imino}-5-(4-nitrobenzylidene)-1,3thiazolidin-4-one). The most sensitive bacterium appeared to be S. typhimirium, followed by B. cereus while L. monocitogenes and M. flavus were the most resistant. Compounds were also tested for their antifungal activity against eight fungal species. All compounds exhibited antifungal activity better than the reference drugs bifonazole and ketokonazole (3-115 times). It was found that compound 8 appeared again to be the most potent. Molecular docking studies on E. coli MurB, MurA as well as C. albicans CYP 51 and dihydrofolate reductase were used for the prediction of mechanism of antibacterial and antifungal activities confirming the experimental results.     

Synthesis and antibacterial activity of novel and potent DNA gyrase inhibitors with azole ring

The 4-piperidyl moiety and the pyrazole ring in 1-(3-chlorophenyl)-5-(4-phenoxyphenyl)-3-(4-piperidyl)pyrazole 2, which has previously shown improved DNA gyrase inhibition and target-related antibacterial activity, were transformed to other groups and the in vitro antibacterial activity of the synthesized compounds was evaluated. The selected pyrazole, oxazole and imidazole derivatives showed moderate inhibition against DNA gyrase and topoisomerase IV with similar IC(50) values (IC(50)=9.4-25 microg/mL). In addition, many of the pyrazole, oxazole and imidazole derivatives synthesized in this study exhibited potent antibacterial activity against quinolone-resistant clinical isolates and coumarin-resistant laboratory isolates of Gram-positive bacteria with minimal inhibitory concentration values equivalent to those against susceptible strains.     

Synthesis and structure–activity relationship of dicationic diaryl ethers as novel potent anti-MRSA and anti-VRE agents

A series of dicationic diaryl ethers have been synthesized and evaluated for in vitro antibacterial activities, including drug resistant bacterial strains. Most of these compounds have shown potent antibacterial activities. Several compounds, such as piperidinyl and thiomorpholinyl compounds 9e and 9l, improved the antimicrobial selectivity and kept potent anti-MRSA and anti-VRE activity. The most potent bis-indole diphenyl ether 19 exhibited anti-MRSA MIC value of ?0.06 μg/mL and enhanced antimicrobial selectivity.     

Structure-activity relationships of novel potent MurF inhibitors

A novel class of MurF inhibitors was discovered and structure-activity relationship studies have led to several potent compounds with IC(50)=22 approximately 70 nM. Unfortunately, none of these potent MurF inhibitors exhibited significant antibacterial activity even in the presence of bacterial cell permeabilizers.     

Biomimetic synthesis, antimicrobial, antileishmanial and antimalarial activities of euglobals and their analogues

In the present communication, naturally occurring phloroglucinol-monoterpene adducts, euglobals G1-G4 (3b/a and 4a/b) and 16 new analogues (13a/b-18a/b and 19-22) were synthesized by biomimetic approach. These synthetic compounds differ from natural euglobals in the nature of monoterpene and acyl functionality. All of these compounds were evaluated for their antibacterial, antifungal, antileishmanial and antimalarial activities. Analogue 17b possessed good antibacterial activity against methicillin-resistant Staphylococcus aureus, while analogues 19-22 possessed potent antifungal activity against Candida glabrata with IC50s ranging from 1.5 to 2.5 microg/mL. Euglobals along with all synthesized analogues exhibited antileishmanial activity. Amongst these, euglobal G2 (3a), G3 (4a) and analogues 13a and 14a showed potent antileishmanial activity with IC50s ranging from 2.8 to 3.9 microg/mL. Analogue 16a possessed antimalarial activity against chloroquine sensitive D6 clone of Plasmodium falciparum. None of the compounds showed toxicity against mammalian kidney fibroblasts (vero cells) upto the concentration of 4.76 microg/ml.     

Solid-phase synthesis and antibacterial activity of hydroxycinnamic acid amides and analogues against methicillin-resistant Staphylococcus aureus and vancomycin-resistant S. aureus

A library of hydroxycinnamic acid amides (HCAAs) and analogues were synthesized using solid-phase synthesis technique. These compounds were screened for antibacterial against methicillin-resistant Staphylococcus aureus (MRSA) (11 strains) and vancomycin-resistant S. aureus (VRSA) (4 strains). Dihydrocaffeoyl analogues showed activity against VRSA which were better than the reference drugs, vancomycin and oxacillin. These compounds also exhibited antibacterial activity against MRSA, which were more potent than oxacillin.     

Synthesis and antibacterial activity of new carbapenems containing isoxazole moiety

The synthesis and biological activity of a series of new 1beta-methylcarbapenems 1a-g containing 5'-isoxazolopyrrolidin-3'-ylthio derivatives as C-2 side chain are described. Most compounds exhibited potent and well-balanced antibacterial activity as well as high stability to DHP-I comparable to that of meropenem. 1e and 1c showed the best combination of antibacterial activity and stability to DHP-I, respectively.     

Synthesis and antibacterial activity of novel fluoroquinolones containing substituted piperidines

The design and synthesis of new fluoroquinolone antibacterial agents having substituted piperidine rings at the C-7 position are described. Most of the new compounds demonstrated high in vitro antibacterial activity. Several of them exhibited significant activities against gram-positive organisms, which were more potent than those of gemifloxacin, Linezolid, and vancomycin.     

Synthesis and antibacterial activity of oxazolidinone containing sulphonyl group

A series of oxazolidinone derivatives carrying sulphonyl group was synthesized and their antibacterial activity was evaluated in vitro. Many of such compounds demonstrated potent antibacterial activity. The activity of a novel compound (YC-20) was 2-4-fold more potent than that of linezolid.     

Synthesis and antibacterial activity of some new benzo[5,6]chromeno[2,3-<Emphasis Type="Italic">d</Emphasis>]pyrimidines

The synthesis and antibacterial activity of some new benzo[5,6]chromeno[2,3-d]pyrimidine derivatives are described. The title compounds were obtained by the reaction of 1H-benzo[f]chromenes with aliphatic and aromatic amines. The structures of all newly synthesized compounds were confirmed by IR, ¹HNMR, ¹³C NMR, and NOESY experiments. The compounds exhibited potent antibacterial activity against gram-positive and gram-negative bacterial species. 10-Methyl-12-(4-hydroxyphenyl)-10,12-dihydro-11H-benzo[5,6]chromeno[2,3-d] pyrimidin-11-imine displayed greater antibacterial activity against gramnegative bacterial species than did ciprofloxacinandamoxicillin.     

Synthesis and antioxidant, cytotoxicity and antimicrobial activities of novel curcumin mimics

Claisen-Schmidt condensation of 3-(1,2,3,6-tetrahydro-1-methylpyridin-4-yl)-2,4,5- trimethoxybenzaldehyde 3 and various aromatic, heterocyclic and alicyclic amides of 3- aminoacetophenone 6(a-s) afforded novel curcumin mimics. All the synthesized compounds were characterized by IR, (1)H NMR, Mass spectroscopy and evaluated for antioxidant, cytotoxicity and antimicrobial activity. Out of the 20 compounds screened, compounds 7i, 7l, 7q, and 7n have shown excellent radical scavenging activity, compounds 7o, 7t, 7f, and 7r have shown significant xanthine oxidase inhibition, and compounds 7a, 7k and 7l were found to be potent inhibitors of selected cancer cell lines. Compounds 7h, 7t, 7l, 7i, and 7e have shown good antibacterial activity, whereas compounds 7j, 7f, 7o, 7h, and 7t exhibited significant antifungal activity.     

Synthesis and SAR study of novel 7-(pyridinium-3-yl)-carbonyl imidazo[5,1-b]thiazol-2-yl carbapenems

A new series of 1beta-methyl carbapenems, possessing a 7-substituted imidazo[5,1-b]thiazol-2-yl group directly attached to the C-2 position of the carbapenem nucleus, was synthesized and evaluated for antibacterial activity. These compounds showed potent activities against Gram-positive bacteria, in particular methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP). They also exhibited potent activity against beta-lactamase-negative ampicillin-resistant Haemophilus influenzae (BLNAR).     

Design,synthesis and biological evaluations of novel 7-[3-(1-aminocycloalkyl)pyrrolidin-1-yl]-6-desfluoro-8-methoxyquinolones with potent antibacterial activity against multi-drug resistant Gram-positive bacteria

A series of novel 6-desfluoro [des-F(6)] and 6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methoxyquinolones bearing 3-(1-aminocycloalkyl)pyrrolidin-1-yl substituents at the C-7 position (1–6) was synthesized to obtain potent drugs for nosocomial infections caused by Gram-positive pathogens. The des-F(6) compounds 4–6 exhibited at least four times more potent activity against representative Gram-positive bacteria than ciprofloxacin or moxifloxacin. Among the derivatives, 7-[(3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl] derivative 4, which showed favorable profiles in preliminary toxicological and non-clinical pharmacokinetic studies, exhibited potent antibacterial activity against clinically isolated Gram-positive pathogens that had become resistant to one or more antibiotics.     

Synthesis and biological activity of novel 1beta-methylcarbapenems with oxyiminopyrrolidinylamide moiety

The synthesis and antibacterial activity of novel 1β-methylcarbapenems 1a–f bearing oxyiminopyrrolidinylamide moiety at C-5 position of pyrrolidine are described. Most compounds exhibited comparable antibacterial activity to meropenem against a wide range of Gram-positive and Gram-negative organisms including Pseudomonas aeruginosa isolates. Of these carbapenems, 1a showed potent and broad spectrum of antibacterial activity and similar stability to DHP-I to meropenem. Against clinical isolates of 40 Gram-negative bacterial species including MDR and ESBL-producing strains, the selected carbapenem 1a possessed excellent in vitro activity except for MDR P. aeruginosa, and was comparable in potency to meropenem.     

Design and synthesis of biaryloxazolidinone derivatives containing amide or acrylamide moiety as novel antibacterial agents against Gram-positive bacteria

A series of novel biaryloxazolidinone derivatives containing amide and acrylamide structure were designed, synthesized and evaluated for their antibacterial activity. Most compounds generally exhibited potent antibacterial activity with MIC values of 1 μg/mL against S. aureus, MRSA, MSSA, LREF and VRE pathogens, using linezolid and radezolid as positive controls. Compound 17 exhibited good antibacterial activity with MIC values of 0.5 μg/mL against S. aureus, MRSA, MSSA and VRE and 0.25 μg/mL against LREF. The results indicated that compound 17 might serve as a potential hit-compound for further investigation.