Synthesis, antibacterial and antifungal activities of bifonazole derivatives

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 μg/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.     

Synthesis of new triazolyl-N,N-Dialkyldithiocarbamates as antifungal agents

N,N-Dialkylditihiocarbamate derivatives have been well known as broad-range fungicides. In this study, the triazole derivatives of ten new N,N-disubstituted dithiocarbamates (3a-j) were synthesized and their structures were identified by spectral and elemental analysis. Results of the antifungal activity studies showed that some of the compounds tested were active against M. canis, M. gypseum, and T. rubrum at the concentration of 12.5 microg/mL when clotrimazol was used as a standard.     

Synthesis of 4-hydroxycoumarin heteroarylhybrids as potential antimicrobial agents

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, (1)H-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.     

Synthesis and biological evaluation of some 2,4,5-trisubstituted thiazole derivatives as potential antimicrobial and anticancer agents

We report on the synthesis and biological evaluation of two series of 2,4,5-polysubstituted thiazoles comprising the acid hydrazide functionality and some derived pharmacophores known to contribute to various chemotherapeutic activities. All newly synthesized compounds were subjected to in-vitro antibacterial and antifungal screening. Of the compounds tested, 13 derivatives displayed inhibitory effect on the growth of three Gram-positive strains while they lack activity against Gram-negative bacteria. Moreover, four compounds were able to exert antifungal activity against C. albicans. Potential antibacterial and antifungal activities were linked to the thiosemicarbazide function 6a-f and those substituted with both the thioureido and thiosemicarbazide moieties 12a-f. Compounds 6f and 12f (R = 4-F-C(6)H(4)) could be considered as the most active members in this investigation with a broad spectrum of antibacterial activity against three types of Gram-positive bacteria, together with an appreciable antifungal activity against C. albicans. Compounds 6d, 6f, and 12f were twice as active as ampicillin against B. subtilis. The best antifungal activity was shown by compound 6d 50% less active than clotrimazole. 17 compounds were selected and tested for their preliminary in-vitro anticancer activity according to the current one-dose protocol of the NCI. Three cell lines, non-small cell lung cancer Hop-92, ovarian cancer IGROV1, and melanoma SK-MEL-2, exhibited some sensitivity against most of the tested compounds. Compound 12f proved to be the most active anticancer member with a broad spectrum of activity against most of the tested subpanel tumor cell lines. Consequently, 12f was carried over to be tested in the five-dose assay.     

Synthesis of novel isoxazolidine derivatives and their antifungal and antibacterial properties

The synthesis of some biologically interesting isoxazolidine derivatives has been accomplished by the cycloaddition reaction of C-(4-biphenyl)-N-(3-methylphenyl) nitrone and C-(4-biphenyl)-N-(3-chlorophenyl) nitrone to monosubstituted alkenes. The compounds were screened for their antibacterial and antifungal activities. Among the tested compounds 3a (ii), 3a (vii), 3a (viii), 3b (iv), 3b (vii), and 3b (viii) showed significant antifungal activity comparable with that of the standard drug Nystatin against Botrydiplodia theobromae.     

Synthesis,antibacterial and antifungal activities of electron-rich olefins derived benzimidazole compounds

New benzimidazole derivatives were synthesised by electron-rich olefines (7, 8 and 9) with appropriate reagents. The compounds synthesised were identified by 1H NMR, 13C NMR, FT-IR spectroscopic techniques and elemental analysis. All compounds studied in this work were screened for their in vitro antimicrobial activities against the standard strains: Enterococcus faecalis (ATCC 29212), Staphylococcus aureus (ATCC 29213), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853) and the yeasts Candida albicans and Candida tropicalis. Eleven of the compounds inhibited the growth of gram-positive bacteria (E. faecalis and S. aureus) at MIC values between 50 and 400 microg/ml. None of the compounds exhibit antimicrobial activity against Gram-negative bacteria (E. coli and P. Aeruginosa) at the concentrations studied (6.25-800 microg/ml). Nine of the tested compounds showed an antifungal activity with a range of the MICs between 50 and 400 microg/ml.     

Synthesis,HIV-1 RT inhibitory,antibacterial, antifungal and binding mode studies of some novel N-substituted 5-benzylidine-2,4-thiazolidinediones

Background

Structural modifications of thiazolidinediones at 3^rd and 5^th position have exhibited significant biological activities. In view of the facts, and based on in silico studies carried out on thiazolidine-2,4-diones as HIV-1- RT inhibitors, a novel series of 2,4-thiazolidinedione analogs have been designed and synthesized.

Methods

Title compounds were prepared by the reported method. Conformations of the structures were assigned on the basis of results of different spectral data. The assay of HIV-1 RT was done as reported by Silprasit et al. Antimicrobial activity was determined by two fold serial dilution method. Docking study was performed for the highest active compounds by using Glide 5.0.

Results

The newly synthesized compounds were evaluated for their HIV-1 RT inhibitory activity. Among the synthesized compounds, compound 24 showed significant HIV-1 RT inhibitory activity with 73% of inhibition with an IC₅₀ value of 1.31 μM. Compound 10 showed highest activity against all the bacterial strains.A molecular modeling study was carried out in order to investigate the possible interactions of the highest active compounds 24, 10 and 4 with the non nucleoside inhibitory binding pocket(NNIBP) of RT, active site of GlcN-6-P synthase and cytochrome P450 14-α-sterol demethylase from Candida albicans (Candida P450DM) as the target receptors respectively using the Extra Precision (XP) mode of Glide software.

Conclusion

A series of novel substituted 2-(5-benzylidene-2,4-dioxothiazolidin-3-yl)-N-(phenyl)propanamides (4–31) have been synthesized and evaluated for their HIV-1 RT inhibitory activity, antibacterial and antifungal activities. Some of the compounds have shown significant activity. Molecular docking studies showed very good interaction.     

Synthesis of 2-mercaptobenzimidazole derivatives as potential anti-microbial and cytotoxic agents

A series of novel 2-(1H-benzimidazol-2-ylsulfanyl)-N-(4-oxo-2-phenyl-thiazolidin-3yl)-acetamide 5a-j have been synthesized from various aldehydes and 2-(5-phenyl-[1,3,4]-oxadiazol-2-ylmethylsulfanyl)-1H-benzimidazole 6a-j from various benzoic acids. These compounds were screened for their in-vitro anti-bacterial activity against Staphylococcus aureus and Enterococcus faecalis as Gram positive, Klebsiella pneumoniae and Escherichia coli as Gram negative bacterial strains and for in-vitro anti-fungal activity against Asperigillus fumigatus and Candida albicans. The in vitro cytotoxic properties were studied using brine shrimp bioassay. Results revealed that, compounds 5b, 5d, 5g, 5i, 6b, 6e, 6f, and 6i showed excellent activity against a panel of microorganisms. The cytotoxic activities of 5b, 5g, 5i, 6b, 6f, 6h, and 6i were found to be good. All the newly synthesized compounds were characterized by elemental analysis, IR, (1)H-NMR, (13)C-NMR and MS.     

Synthesis and biological evaluation of some novel fused pyrazolopyrimidines as potential anticancer and antimicrobial agents

Synthesis and evaluation of anticancer and antimicrobial activity of some novel pyrazolopyrimidines and fused pyrazolopyrimidines are reported. Twelve analogs were selected to be evaluated for their in vitro anticancer potential against a panel of three human tumor cell lines: hepatocellular carcinoma HepG2, cervical carcinoma HelaS3 and colon carcinoma CaCo. The obtained data revealed that eight compounds namely; 6b, 6d, 7c, 8c, 10b, 12b, 13a and 13b were able to exhibit variable degrees of anticancer activities against the three used cell lines, of which compound 6d proved to be the most active. On the other hand, all the newly synthesized compounds were subjected to in vitro antibacterial and antifungal screening. Almost all the tested compounds were found to possess variable degrees of antimicrobial activities. Collectively, compounds 7c, 8c, 12b, 13a and 13b could be considered as possible agents with dual anticancer and antimicrobial activities.     

Synthesis of some pyrazolines and pyrimidines derived from polymethoxy chalcones as anticancer and antimicrobial agents

The synthesis of a series of certain polymethoxy chalcones and some derived pyrazole, pyrimidine, and thiazolopyrimidine ring structures is reported. Eleven compounds 4 , 6 , 9 , 11 , 14–17 , 22 , 24 , and 25 were selected by the National Cancer Institute (NCI) to be screened for their in‐vitro anticancer activity, whereas all the synthesized compounds were evaluated for their in‐vitro antimicrobial activity. Compounds 4 , 6 , and 11 were found to possess a significant broad spectrum antitumor potential against most of the tested subpanel tumor cell lines. The pyrazolines 4 and 6 displayed remarkable growth inhibitory activities (GI₅₀ MG‐MID values of 2.10 and 1.38 µM, respectively), together with moderate cytostatic effects (TGI MG‐MID values of 47.9 and 42.7 µM, respectively). Meanwhile, the pyrimidin‐2‐one 11 showed a noticeable overall tumor growth inhibitory activity, together with high cytostatic and cytotoxic efficacies (GI₅₀, TGI and LC₅₀ MG‐MID values of 3.39, 17.4, and 61.7 µM, respectively). On the other hand, compounds 3 , 4 , 13 , 15 , 19 , 20 , and 23 were found to be the most active antimicrobial members in this investigation with a broad spectrum of activity. Compound 23 was four times superior to ampicillin against Pseudomonas aeruginosa. The best antifungal activity was demonstrated by compounds 4 , 5 , and 11 which possessed almost half the activity of clotrimazole against Candida albicans. Collectively, the obtained biological results suggest that compound 4 could be considered as a possible dual antimicrobial‐anticancer agent.     

Synthesis and biological evaluation of some pyrazolinylpyridines and pyrazolylpyridines

Various new 2-(1'-acetyl-5'-substituted-aryl-2'-pyrazolin-3'-yl)aminopyridines (3a-3e) and 2-(1'-phenyl 5'-substituted aryl-2'-pyrazol-3'-yl)aminopyridines (4a-4e) have been derived from 2-(substituted benzylidenylacetyl)aminopyridines (2a-2e). The structure of these compounds have been elucidated by elemental and spectral (IR, 1H-NMR, mass) analysis. Furthermore, above said compounds were evaluated for their insecticidal, antifungal, and antibacterial activities. Compound 4b 2-[1'-phenyl-5'-(o-chlorophenyl)-2'-pyrazol-3'-yl]aminopyridine, when compared for insecticidal and antifungal activities with parathion and fluconazole, respectively, was found to be the most potent one in this series. It also possessed remarkable antibacterial properties.     

Synthesis and biological testing of novel analogues of sydnone as potential antibacterial agents

Several series of 3-phenylsydnone derivatives conjugated to well-known moieties with antibacterial activity were synthesized via several routes. These derivatives include 3-cyano-2-oxopyridine, 2-amino-3-cyanopyridine, 2-arylidene-1-ethylidenehydrazine and 2-aroyl-1-ethylidenehydrazine moieties. Thus, the key intermediate 3-(4-acetylphenyl)sydnone (3) was allowed to react with the appropriate aldehyde, ethyl cyanoacetate or malononitrile in presence of excess ammonium acetate in two steps (method 1) or through a one-pot reaction technique (methods 2 and 3) to give the corresponding sydnone derivatives 5 and 6, respectively. Moreover, condensation of compound 3 with hydrazine hydrate followed by the reaction with the appropriate aldehyde, mono- and dicarboxylic acid hydrazide yielded the corresponding sydnone derivatives 8, 9 and 10, respectively. Most of the synthesized compounds were screened for their in vitro antibacterial activity against various pathogenic organisms of both Gram-positive and Gram-negative bacteria. The minimum inhibitory concentrations (MICs) were determined using agar dilution method.     

Synthesis of new 2-thiouracil-5-sulphonamide derivatives with antibacterial and antifungal activity

2-Thiouracil-5-sulphonic acid N-(4-acetylphenyl) Amide (1) was reacted with a series of aromatic aldehydes giving chalcones 2 (Claisen-Schemidt reaction), some of these chalcones were reacted with urea and thiourea giving pyrimidine-2-one and pyrimidine-2 thione derivatives respectively of the type 3a,b and 4a,b. In addition many chalcones were reacted with hydroxylamine hydrochloride giving isoxazoline derivatives 5a,b. They could also reacted with phenylhydrazine to give pyrazoline derivatives 6a,b, chalcones also were reacted withethylcyano acetate and/or malononitryl in pyridine giving pyran derivatives 7a,c and 8a,c. In another pathway chalcones were epoxidised by H2O2 giving epoxides 9a,c which in turn were reacted with phenylhydrazine giving 4-hydroxypyrazoline derivatives 10a,c. In another reaction chalcones were reacted with ethylcyanoacetate in presence of amm.acetate giving pyridone derivatives 11a,d which could be prepared also in exellent yield from compound 1 by its reaction with certain aromatic aldehydes and ethylcyanoacetate in presence of ammonium acetate. Finally, compound 1 was reacted with semicarbazide giving semicarbazone intermediate 12 which in turn was reacted with thionyl chloride giving thiadiazole derivative 13. The biological effects of some of the new synthesized compounds were also investigated.     

Synthesis and Evaluation of Novel Indolylthiadiazinoazetidinones and Indolylthiadiazinothiazolidinones as Antimicrobial Agents

Some new 5‐methoxy/ethoxy‐2,3‐[2′‐(3′′‐chloro‐2′′‐oxo‐4′′‐substituted‐aryl‐1′′‐azetidinyl)‐1′,3′,4′‐thiadiazino]indoles 13–20 and 5‐methoxy/ethoxy‐2,3‐[2′‐(2′′‐substituted‐aryl‐4′′‐oxo‐1′′,3′′‐thiazolidin‐3′′‐yl)‐1′,3′,4′‐thiadiazino]indoles 21–28 have been synthesized from 5‐methoxy/ethoxy‐2,3‐[2′‐(substituted‐benzylidinylimino)‐1′,3′,4′‐thiadiazino]indoles 5–12 . These newly synthesized compounds were characterized by elemental and spectral analysis. Further, compounds 5–28 of the present series have been screened for their antibacterial and antifungal activities. Both minimal inhibitory concentration (MIC) and inhibition zones were determined in order to monitor the efficacy of the synthesized compounds. Compounds 14 and 16 were found to be the most potent members of the present series, they showed maximal antibacterial and antifungal properties much better than the standard drugs.     

抗菌药物药效学非临床研究技术指南

抗菌药物药效学非临床研究属于抗菌药物临床前研究的重要内容,是指研究药物在体外或体内抑制病原菌生长和复制(抑菌)或使病原菌死亡(杀菌)的作用,主要包括抗菌药物对细菌的最低抑菌浓度、最低杀菌浓度、杀菌曲线、抗生素后效应和半数有效剂量等测定。本技术指南对抗菌药物药效学非临床研究的常用术语、研究内容及方法进行论述,旨在为创新抗菌药物,包括化学药物、生物药物和中药的临床前药效学研究提供参考。     

Synthesis of bis,tris and tetra(dihydrocaffeoyl)polyamine conjugates as antibacterial agents against VRSA

Bis, tris and tetra(dihydrocaffeoyl)polyamine conjugates were synthesized using solid phase synthesis technique. These compounds were screened for antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) (11 strains) and vancomycin-resistant S. aureus (VRSA) (4 strains). Bis, tris and tetra(dihydrocaffeoyl)polyamine analogues showed antibacterial activity against VRSA which were better than the reference drugs, vancomycin. Tetra(dihydrocaffeoyl)polyamine conjugate exhibited the highest activity. These compounds showed no cytotoxicity against vero cells.     

Synthesis and antibacterial activity of new cephalosporins with lactonyloxyimino moiety

A series of 7-{2-(2-aminothiazol-4-yl)-2-Z-(γ-lacton-3-yl) oxyiminoacetamidol} cephalosporins with various substituents at the 3-position in cephem nucleus were synthesized and evaluated microbiologically. The tested compounds showed potent activities but were somewhat less active than cefotaxime or cefixime against a wide variety of Gram-positive and Gram-negative bacteria.