The synthesis of a new series of 1β-methylcarbapenems having spiro[2,4];heptane moieties is described. Their in-vitro antibacterial activities against both gram-positive and gram-negative bacteria were tested and the effect of substituents on the pyrrolidine ring was investigated. Most compounds were shown to be more active than the compared meropenem and imipenem against Escherichia coli. One particular compound, IIIb, having hydroxy a moiety showed the most potent antibacterial activity.

The increasing emergence of pathogenic bacterial strains with high resistance to antibiotic therapy has created an urgent need for the development of new antibacterial agents that are directed towards novel targets. We have focused our attention on the Mur ligases (MurC-F), which catalyze the early steps of bacterial peptidoglycan biosynthesis, and which to date represent under-exploited targets for antibacterial drug design. We show that some of our phosphinate inhibitors of UDP-N-acetylmuramoyl-L-alanyl:D-glutamate ligase (MurD) also inhibits UDP-N-acetylmuramoyl-L-alanyl-D-glutamate:L-lysine ligase (MurE). To obtain new information on their structure-activity relationships, three new, structurally related phosphinates were synthesized and evaluated for inhibition of MurD and MurE.

A series of 2-{[2′-(3′′-chloro-2′′-oxo-4′′-substitutedaryl-1′′-azetidinyl)-1′,3′-thiazol-4′-yl]; thio}benzothiazoles (4a–4e) and 2-{[(2′-(2′′-substitutedaryl-4′′-thiazolidinon-3′′-yl)-1′,3′-thiazol-4′-yl];thio}benzothiazoles (5a–5e) have been synthesized from 2-[(2′-substitutedarylidenylimino-1′,3′-thiazol-4′-yl)thio];benzothiazoles (3a–3e). The structure of these compounds has been elucidated by elemental (C, H, N) and spectral (IR, ¹H-NMR, Mass) analysis. Furthermore, compounds 3a–3e, 4a–4e, and 5a–5e were screened for insecticidal activity against Periplaneta americana and antifungal, antibacterial activities in vitro against different strains of fungi and bacteria. Out of the fifteen compounds tested, compound 5b, 2-{[2′-(2′′-p-hydroxy-m-methoxyphenyl)-4′′-thiazolidinon-3′′-yl)-1′,3′-thiazol-4′-yl];thio}benzothiazole, was found to possess most prominent insecticidal activity.

Several 2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-benzimidazole-5-carboxamidine analogues were synthesized for their antibacterial and antifungal activities against S. aureus, Methicillin-resistant S. aureus (MRSA), C. albicans, and C. krusei. MIC values of the targeted compounds 43-58 are comparable to those of Fluconazole and Sultamicillin. The most potent compounds, 51 and 53, showed MIC values as 0.78 and 1.56 μg/mL against S. aureus and C. albicans, respectively.

{2-[2-(N, N-Disubstituted thiocarbamoyl-sulfanyl)acylamino ]thiazol-4-yl}acetic acid ethyl esters (3a—x) were synthesized by the reaction of potassium salts of N, N-disubstituted dithiocarbamoic acids with [2-(2-chloroalkanoyl)amino-thiazol-4-yl]acetic acid ethyl esters. The structures of the synthesized compounds were confirmed by elemental analyses, UV, IR, ¹H-NMR, and EI mass spectral data. The antimicrobial activities of all the compounds were investigated by microbroth dilution technique using Mueller-Hinton broth and Mueller-Hinton agar. In this study, Staphylococcus aureus ATCC 6538, Staphylococcus epidermidis ATCC 12228, Escherichia coli ATCC 8739, Klebsiella pneumoniae ATCC 4352, Pseudomonas aeruginosa AT CC 1539, Salmonella typhi, Shigella flexneri, Proteus mirabilis ATCC 14153 and Candida albicans ATCC10231 were used as test microorganisms. Among the tested compounds 3a, d, e, f, h, k, w activity against S. epidermidis ATCC 12228 (MIC: 156 mg/L, 78 mg/L, 62.5 mg/L, 78 mg/L, 62.5 mg/L, 312 mg/L, 250 mg/L, respectively), compound 3d had some activity against S. aureus ATCC 6538 (MIC: 156 mg/L) and C. albicans ATCC 10231(MIC: 156 mg/L). Compounds 3l, 3x also evaluated for antituberculosis activity against Mycobacterium tuberculosis H37Rv using the BACTEC 460 radiometric system and BACTEC 12B medium. The preliminary results indicated that all of the tested compounds were inactive against the test organism.

New sydnone derivatives bearing a substituted phenyl ring at the 3-position have been synthesized. Two separate series of 3-(carboxyphenyl)sydnone derivatives have been prepared by cyclization of the corresponding N-nitroso-N-(carboxyphenyl)-glycine 3. The obtained 3-(carboxyphenyl)sydnones 4 were subjected to a series of different chemical reactions on the carboxylic acid group. Compound 5, the potassium salt of 4a, was reacted with α-chloroacetanilide derivatives 6 to give the corresponding esters 7. On the other hand, the acid hydrazide 9 was condensed with different aromatic aldehydes to give the corresponding arylidene derivatives 10. The synthesized compounds were tested for their antibacterial activities against both gram-positive and gram-negative organisms. Some of the test compounds exhibited high activity; among them, 10d is considered to be a lead compound possessing high broad-spectrum antibacterial activity.

A general synthetic route to conjoint molecules of cephalosporins and aminoglycosides is described. These molecules were designed as potential substrates for bacterial β-lactamases, enzymes that hydrolyze the β-lactam bond of cephalosporins. Hydrolysis of the β-lactam bond was expected to release the C₁₀-appended aminoglycoside. Since β-lactamases are sequestered in the periplasmic space of gram-negative bacteria, this sequence of events would liberate aminoglycoside inside such bacteria. It is expected that such local delivery of aminoglycosides would circumvent the inherent toxicity of aminoglycosides that occurs during systemic exposure within the mammalian host.

A novel series of 3-[3-(substituted phenyl)-1-isonicotinoyl-1H-pyrazol-5-yl];-2H-chromen-2-one derivatives 4a–k have been synthesized by the reaction of 3-[2,3-dibromo-3-(substituted phenyl) propanoyl];-2H-chromen-2-one 3a–k and isonicotinic acid hydrazide in the presence of triethylamine in absolute ethanol, characterized by spectral data and screened for their in-vitro antibacterial activity against Gram-positive and Gram-negative bacteria. Among the series, compounds 4e, 4i, and 4k displayed an encouraging antibacterial activity profile as compared to the reference drug ampicillin against tested bacterial strains.

A series of eperezolid analogs with glycinyl substitutions were prepared and their antibacterial activities were studied against a panel of susceptible and resistant Gram-positive bacteria. The compounds with N-arylacyl or N-heteroarylacyl glycinyl structural units showed good antibacterial activities. The compounds 11b, 11c, and 11e were twofold more active than linezolid against Staphylococcus epidermidis and Enterococcus faecalis. Several pyridine analogs were also prepared and found to have poor antibacterial activity against most of the tested Gram-positive bacteria, however, one of the compounds 12e showed very high activity against Enterococcus faecalis.

A series of 2-o-arylidineaminophenylindoles and their cyclic derivatives (indolo[1,2-c];quinazolines) were synthesized. The reactions occurred under relatively mild conditions and afforded the desired product in good yields. Molecular structures of the synthesized compounds were confirmed by IR, ¹H-NMR, ¹³C-NMR, MS spectra, and elemental analyses. Furthermore, all the final products were screened for in-vitro antibacterial activity against three Gram-positive and three Gram-negative bacteria and also tested for their inhibitory action against three strains of fungi. Compound IIc showed potent activity against all the bacterial (except S. typhimurium) and fungal strains. Especially, compounds IIi and IIj which have isoquinolyl and pyridyl substituents displayed potent antibacterial as well as antifungal activities compared to those of the respective standard drugs Ampicillin and Ketoconazole.

The enhancement of bacterial resistance of pathogens to currently available antibiotics constitutes a serious public health threat. So, intensive efforts are underway worldwide to develop new antimicrobial agents. To identify compounds with a potent antimicrobial profile, we designed and synthesized low molecular weight 2-mercaptobenzothiazole derivatives 2a–2l and 3a–3l. Both series were screened for in-vitro antibacterial activity against the representative panel of Gram-positive and Gram-negative bacteria strains. The biological screening identified compounds 2e and 2l as the most active ones showing an interesting antibacterial activity with MIC values of 3.12 μg/mL against Staphylococcus aureus and 25 μg/mL against Escherichia coli, respectively. The replacement of the S-H by the S-Bn moiety resulted in considerable loss of the antibacterial action of the 3a–3l series. The antibiotic action of compounds 2e and 2l was also investigated by testing their activity against some clinical isolates with different antimicrobial resistance profile. Moreover, the involvement of the NorA efflux pump in the antibacterial activity of our molecules was evaluated. Finally, in this paper, we also describe the cytotoxic activity of the most interesting compounds by MTS assay against HeLa and MRC-5 cell lines.

A series of novel 7-(3-alkoxyimino-4-methyl-4-methylaminopiperidin-1-yl)fluoroquinolone derivatives were designed, synthesized, and characterized by ¹H-NMR, MS, and HRMS. These fluoroquinolones were evaluated for their in-vitro antibacterial activity against representative Gram-positive and Gram-negative strains. Generally, all of the target compounds have considerable antibacterial activity against the tested forty strains, and exhibit exceptional potency in inhibiting the growth of methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) ATCC33591 (MICs: 0.06 to 2 μg/mL). In particular, compounds 14, 19, 28, and 29 are fourfold more potent than ciprofloxacin against MSSA 08-49. Compounds 23, 26, and 27 are twofold more potent than ciprofloxacin against MRSA ATCC33591 and MSSA ATCC29213. In addition, compound 14 exhibits excellent activity (MIC: 0.06 μg/mL) against Acinetobactes calcoaceticus, which is two- to 16-fold more potent than the reference drugs gemifloxacin, levofloxacin, and ciprofloxacin.

Novel 4″-O-carbamoyl erythromycin-A derivatives were designed, synthesized, and evaluated for their in-vitro antibacterial activities. All of the 4″-O-carbamoyl derivatives showed excellent activity against erythromycin-susceptible Staphylococcus aureus ATCC25923, Streptococcus pyogenes, and Streptococcus pneumoniae ATCC49619. Most of the 4″-O-arylalkylcarbamoyl derivatives displayed potent activity against erythromycin-resistant S. pneumoniae encoded by the mef gene and greatly improved activity against erythromycin-resistant S. pneumoniae encoded by the erm gene or the erm and mef genes. In particular, the 4″-O-arylalkyl derivatives 4c–4e and 4g were found to possess the most potent activity against all the tested erythromycin-susceptible strains, which were comparable to those of erythromycin, clarithromycin, or azithromycin. 4″-O-Arylalkyl derivatives 4e and 4g were the most effective against erythromycin-resistant S. pneumoniae encoded by the mef gene (0.25 and 0.25 µg/mL). 4″-O-Arylalkyl derivatives 4a and 4b exhibited significantly improved activity against erythromycin-resistant S. pneumoniae encoded by the erm gene. In contrast, the 4″-O-alkylcarbamoyl derivatives hardly showed improved activity against all the tested erythromycin-resistant strains.

A new series of 4-hydroxycoumarin derivatives 3a–d was synthesized by the reaction of 3-bromo-4-hydroxy coumarin 1 with various heteroaldehydes 2a–d in good yields. The synthesized compounds were characterized on the basis of their elemental and spectral (IR, ¹H-NMR and mass spectrometry) analysis. All target compounds were evaluated for their in-vitro antimicrobial activity against Streptococcus pyogenes, methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumonia, and Escherichia coli bacterial strains and fungal cultures of Candida albicans, Aspergillus fumigatus, Trichophyton mentagrophytes, and Penicillium marneffei by disk diffusion assay with slight modifications. The minimum inhibitory concentration (MIC) was determined for the test compounds as well as for reference standards. Among the tested compounds, 3a has shown the most potent antibacterial as well as antifungal activities.

A number of 1,2,3-triazolylmethyl piperazino oxazolidinone derivatives with optionally varied substituents at the 4N-piperazine position were synthesized and their antibacterial activity evaluated against a panel of susceptible and resistant Gram-positive and selected Gram-negative bacteria. Substitution with 5-membered heteroaroyl and dinitrobenzoyl moieties potentiated activity against staphylococci and enterococci strains. Furthermore, the compounds having dinitrobenzoyl 7n, 7o, and 5-nitrofuroyl 7t substitutions were four- to eightfold more potent than linezolid against M. catarrhalis. However, substitution of guanidino and other water-solubilizing functionalities at the 4N-piperazine position resulted in compounds that are devoid of antibacterial activity.

A new series of N,N′-(benzene-1,3-diyldi-1,3,4-oxadiazole-5,2-diyl)bis{2-[(5-benzene-1,3-diyl-1,3,4-oxadiazol-2-yl)amino]acetamide}(macrocycle 1), N,N′-(benzene-1,3-diyldi-1,3,4-thiadiazole-5,2-diyl)bis{2-[(5-benzene-1,3-diyl-1,3,4-thiadiazol-2-yl)amino]acetamide} (macrocycle 2) and S,S′-[benzene-1,3-diylbis(4H-1,2,4-triazole-5,3-diyl)]bis{[(5-benzene-1,3-diyl-4H-1,2,4-triazol-3-yl)sulfanyl]ethanethioate}(macrocycle 3) was synthesized from isophthalic dihydrazide (4) through a multistep reaction sequence. All the synthesized compounds were screened for their inhibitory effect against four different bacterial strains: P. aeruginosa ATCC-20852, K. pneumoniae MTCC-618, S. aureus ATCC- 29737, S. typhi MTCC- 3214. The synthesized compounds showed a significant zone of inhibition and the results were comparable with that of the standard drug ciprofloxacin. The synthesized compounds were further studied for their possible in vitro antioxidant effects by DPPH scavenging, total antioxidant capacity, total reductive capacity and H₂O₂ scavenging activity. The results indicated that the in vitro antioxidant activity for all the three molecules was efficient when compared to the standards. The DNA interaction behavior of macrocycles 1–3 with CT-DNA was investigated by the absorption spectra obtained (K_b constant for 1 is 4.53 × 10⁴ M⁻¹, for 2 is 5.75 × 10⁴ M⁻¹ and for 3 is 5.86 × 10⁴ M⁻¹). Based on the results it can be interpreted that the reducing power effect of the newly synthesized compounds demonstrates a direct effect on DNA binding and hence inhibiting the bacterial growth through their action on DNA by inhibiting DNA replication or DNA transcription.

Some new 2-(2-(4(4-substitutedbenzoyl-2-methylphenoxy)acetyl)-N-(2-substitutedphenyl) hydrazinecarbothioamides (4a–4j) and (4-((5-(2-substitutedphenylamino)-1,3,4-oxadiazol-2-yl)methoxy)-3-substitutedphenyl)(phenyl)methanones (5a–5j) have been synthesized from 2-(4-(3-substitutedbenzoyl)-2-methylphenoxy)acetohydrazides (3a, 3b). These newly synthesized compounds (4a–4j and 5a–5j) were characterized by elemental and spectral (IR, ¹H-NMR and MS) analysis. All the synthesized compounds have been screened for their antibacterial activity against both types of Gram negative and Gram positive bacteria. The most potent antibacterial compound of this series was compound 5i which has the low MIC 3.75–0.9375 Âµg/mL value. Both minimal inhibitory concentration (MIC) and inhibition zones were determined in order to monitor the efficacy of the synthesized compounds. Certain compounds inhibit bacterial growth with low MIC (µg/mL) value.

This study examines the synthesis and antibacterial activities of 5,7-dihydroxycoumarin derivatives, whose structures were confirmed using analytical and spectral data. Twenty compounds were tested for their antibacterial activities against five microbial species such as E. coli, S. aureus, K. pneumonia, P. aeruginosa, and S. typhimurium were studied. Compounds 5 and 12 exhibited the most potent activity against Staphylococcus aureus with a MIC value of 2.5 Âµg/mL for each of the compounds.

Two series of chlorinated benzhydryl imidazole and triazole derivatives were synthesized and tested in vitro against representative strains of potent pathogenic bacteria (Staphylococcus aureus CIP 4.83, Escherichia hirae CIP 5855, Pseudomonas aeruginosa CIP 82118, Escherichia coli CIP 53126) and fungi (Aspergillus niger IP 1431.83, Candida albicans IP 48.72, Candida krusei IP 208.52, Trichophython rubrum IP 1657.86). Most of these compounds were devoid of any antimicrobial activity, but several of them inhibited T. rubrum with MIC values in the range of 0.125 to 32 Âµg/mL, similar or superior to those of bifonazole and clotrimazole, used as standard controls. The replacement of the imidazole ring with a triazole moiety in these compounds led to derivatives with less antifungal activity. A preliminary SAR was undertaken on the effect of the number and the position of chlorine atoms on the distribution of negative charge on the surface of some compounds on antifungal activity.

This paper describes preparation and biological evaluation of pyrazinamide analogues. Pyrazinamide with its simple structure gives a good opportunity for further modification regarding an increase of its antimycobacterial activity. We prepared a series of compounds derived from pyrazine-2,5-dicarbonitrile with arylamino substitution in position 3. All compounds were assayed in vitro against major Mycobacterium and various Fungi species. The best activity was found in 3-{[3-(trifluoromethyl)phenyl];amino}pyrazine-2,5-dicarbonitrile 11 with the value of 6.25 μmol^–1 against M. tuberculosis H₃₇Rv and moderate activity against minor Mycobacterium pathogens.

The increasing clinical importance of drug-resistant fungal and bacterial pathogens has lent additional urgency to microbiological research and new antibacterial compound development. For this purpose, new tert-butyl[1-benzyl-2[(4-aryl-2-thiazolyl)hydrazono];ethyl];carbamate derivatives were synthesized and evaluated for antibacterial activity. The reaction of Boc-L-phenylalaninal with thiosemicarbazide gave the thiosemicarbazone which furnished the title compounds by reaction with phenacyl bromides. The newly synthesized compounds were screened for antibacterial activity and toxicity. While microdilution broth susceptibility assay was used for the antibacterial activity evaluation of the compounds against the strains E. coli (NRRL B-3704), M. luteus (NRRL B-4375), B. cereus (NRRL B-3711), P. aeruginosa (NRRL B-23), and S. fecalis (NRRL B-14617), the Artemia salina 96-well assay was used to determine cytotoxicities of the compounds. Observations obtained from the bioassays showed that some of the compounds are highly active against E. coli, M. luteus, and B. cereus when compared with the control agent and showed low toxicity.

A natural antibiotic, 2,4-diacetylophloroglucinol (DAPG), has been prepared by the acetylation of phloroglucinol (PhL) with acetic anhydride in the presence of boron trifluoride etherate complex. The crude DAPG is efficiently purified using chromatographic filtration with boiling eluent.

Novel levofloxacin-containing hybrids carrying a 5-(nitroaryl)-1,3,4-thiadiazol-2-yl group were synthesized and evaluated in vitro against Gram-positive and Gram-negative bacteria. Preliminary data indicated that levofloxacin-nitrofuran and levofloxacin-nitroimidazole hybrids have a potent activity against Gram-positive organisms with enhanced anti-staphylococcal activity compared with the parent quinolone (N-desmethyl levofloxacin).

Dimethyl 2,6-dimethyl-4-oxo-4H-chromen-3-yl-phosphonate (1a) and dimethyl 6-methyl-2-phenyl-4-oxo-4H-chromen-3-yl-phosphonate (1b) were synthesized and reacted with primary aliphatic amines to yield title compounds 4—6. Their antibacterial properties against Gram-positive and Gram-negative bacteria strains were tested by the MIC method. Four of seventeen tested compounds (1d, 3, 4a, and 4b) exhibit detectable activity against S. aureus. Some representative examples of newly synthesized compounds were tested for their alkylating properties in vitro in the Preussmann test. Compounds 1a, 1c, 1d, 3, 5d, and 6a possess highly alkylating activity toward standard derivative 4-(4’-nitrobenzyl)pyridine (NBP).

A series of 23 new 2-[p-substituted-benzyl]-5-[p-substituted-phenyl/benzyl-carbonylamino]benzoxazole derivatives has been synthesized by reacting 5-amino-2-[p-substituted-benzyl]benzoxazoles with the appropriate carboxylic acid chlorides. The structures of the synthesized compounds were confirmed by IR and ¹H-NMR spectral data. Antimicrobial activities of the compounds were investigated using the twofold serial dilution technique against two gram-positive and two gram-negative bacteria and three Candida species in comparison with standard drugs. Microbiological results indicated that the newly synthesized 2-[p-substituted-benzyl]-5-[p-substituted-phenyl/benzyl-carbonylamino]benzoxazole derivatives (3-25) possessed a broad spectrum of activity, showing MIC values of 6.25-200 μg/mL against the gram-positive and gram-negative microorganisms tested. Moreover, they showed significant antifungal activity with MIC values of 3.12-100 μg/mL against the Candida species tested. Especially, with a MIC value of 3.12 μg/mL, 2-benzyl-5-[p-bromobenzyl-carbonylamino]benzoxazole 9 displayed the same activity against C. glabrata as the standard drug myconazol.

>The synthesis of a new series of 1β-methylcarbapenems having a substituted heterocyclic carbamoyl pyrrolidine moiety is described. Their in vitro antibacterial activity against both gram-positive and gram-negative bacteria was tested, and the effect of heterocyclic substituents on the pyrrolidine was investigated. One particular compound (III_d) having a substituted oxadiazole moiety showed the most potent antibacterial activity.

The synthesis of a new series of 1β-methylcarbapenems having a 1,3-diazabicyclo[3.3.0]octan-4-one moiety is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria are tested and the effect of substituent on the bicyclic ring was investigated. A particular compound (11h) having aminoethyl group showed the most potent antibacterial activity.

The synthesis and in vitro synergies of 2β-alkenyl and oxyiminopenam sulfone derivatives are described. Most of the compounds synthesized exhibited good inhibitory activities and synergistic antibacterial activities with piperacillin and ceftriaxone, respectively, against several β-lactamase producing strains. Particularly the 2β-alkenylpenam sulfone derivatives, 1e and 1g, showed good synergistic activity with ceftriaxone against Citrobacter freundi NIH 10018-68 and Proteus vulgaris 20. Also the compounds 2a, 2c, and 2f, 2β-oxyiminopenam sulfone derivatives, exhibited improved synergistic activity with piperacillin against Citrobacter freundi NIH 10018-68.

3-Methyl-1-phenylpyrazole-5-thiol (3a) and its p-nitro-(5) and p-fluorophenyl (8) derivatives were prepared as potential antimicrobial agents in relatively good yields. Compounds 3a and 8 showed good antibacterial activities against MRSA, S. aureus, S. epidermidis, E. faecalis, E. faecium, and S. pyogenes. Moreover, compound 3a also showed a synergistic effect with some aminoglycosides.

The synthesis of new series of 1β-methylcarbapenems having a 2, 2-disubstituted-1, 3-diazabicyclo[3.3.0]octan- and -[4.3.0]nonan-4-one moiety is described.Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of the substituent of the bicyclic ring was investigated. A particular compound (16 f) bearing a hydroxymethyl group showed the most potent antibacterial activity and the compound (17 a) with a 1, 3-diazabicyclo[4.3.0]nonane moiety exhibited excellent stability against renal dehydropeptidase-I (DHP-I) to Meropenem.