Synthesis and biological evaluation of novel (L)-alpha-amino acid methyl ester, heteroalkyl, and aryl substituted 1,4-naphthoquinone derivatives as antifungal and antibacterial agents

A series of (S)-N-(1,4-naphthoquinon-2-yl)-alpha-amino acid methyl esters 3-9, 2-N,N-dialkylamino-1,4-naphthoquinones 10-11 and 2-hydroxy-3-(2'-mercaptoimidazolyl)-1,4-naphthoquinones and their cyclic analogs 12-15 were synthesized and evaluated for antifungal and antibacterial activities. The structure-activity relationships of these compounds were studied and the results show that the compounds 9b and 13c exhibited in vitro antifungal activity against Candida albicans, Cryptococcus neoformans, and Sporothrix schenckii, whereas compound 6a showed in vitro antibacterial activity against Streptococcus faecalis, K. pneumoniae, Escherichia coli, and Staphylococcus aureus.     

Naphtho[2,3-b][1,4]-thiazine-5,10-diones and 3-substituted-1,4-dioxo-1,4-dihydronaphthalen-2-yl-thioalkanoate derivatives: synthesis and biological evaluation as potential antibacterial and antifungal agents

A series of 3-substituted-1,4-dioxo-1,4-dihydronaphthalen-2-yl-thio-alkanoate derivatives 3-21 and naphtho[2,3-b][1,4]-thiazine-5,10-diones 24 were synthesized and evaluated for their antibacterial and antifungal activities. The structure-activity relationships of these compounds were studied and the results show that the compound 24a exhibited better antibacterial activity than Gentamycin in vitro against Staphylococcus aureus. In addition 24a also imparted marked antifungal activity in vitro against Cryptococcus neoformans, Sporothrix schenckii, and Trichophyton mentagraphytes when compared with Fluconazole. Compounds 15, 18, 19, and 21 also exhibited significant antibacterial activity in vitro against S. aureus.     

Synthesis and evaluation of novel 1,4-naphthoquinone derivatives as antiviral, antifungal and anticancer agents

The synthesis and evaluation of some 2-substituted-1,4-naphthoquinones 2, S-(1,4-naphthoquinon-2-yl)-mercaptoalkanoic acid amides 4, related benzoquinone and naphthoquinone derivatives 6-9 and 2,3-disubstituted 1,4-naphthoquinones 10-11 were carried out. The antifungal, antibacterial, antiviral and anticancer activities were determined by using the standard assay. The results show that compounds 2b and 10a showed in vitro antiviral activity against Influenza-A Virus and Herpes Simplex Virus and possess pronounced antifungal profile whereas 4a showed anticancer activities against Lymphoid Leukaemia P 388.     

Antimicrobial activity of ZnII, CdII, and HgII complexes of 1,2-bis-[2-(5-R)-1H-benzimidazolyl]-1,2-ethanediols and 1,4-bis-[2-(5-R)-1H-benzimidazolyl]-1,2,3,4-butanetetraols

1,2-Bis-[2-(5-H/Me/Cl/NO2)-1H-benzimidazolyl]-1,2-ethanediols (L1-L4), 1,4-bis-[2-(5-H/Me/Cl)-1H-benzimidazolyl]-1,2,3,4-butanetetraols (L5-L7) and their complexes with ZnCl2, CdCl2 and HgCl2 were synthesized and antibacterial activity of the compounds was tested toward Staphylococcus aureus, S. epidermidis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella typhi, Shigella flexneri, Proteus mirabilis and antifungal activity against Candida albicans. HgII complexes have a considerably higher antimicrobial activity against all microorganisms. Some HgII complexes show higher antifungal activity than clotrimazole toward C. albicans. Zn2(L3)Cl4, Zn2(L4)Cl4, and Cd(L3)Cl2 were moderately effective against S. aureus and S. epidermidis; Cd(L4)Cl2 exhibited a weak activity only against S. epidermidis.     

Design, synthesis, and biological evaluation of 1,2,3-trisubstituted-1,4-dihydrobenzo[g]quinoxaline-5,10-diones and related compounds as antifungal and antibacterial agents

A series of (S)-N-(3-chloro-1,4-naphthoquinon-2-yl)-alpha-amino acid ethyl esters 3 and 1,2,3-trisubstituted-1,4-dihydrobenzo[g]quinoxaline-5,10-diones 6-23 were synthesized and evaluated for antifungal and antibacterial activities. The structure-activity relationship of these compounds was studied and the results show that the compounds 3a and 3b exhibited in vitro antifungal activity against Candida albicans, Cryptococcus neoformans, and Sporothrix schenckii whereas compounds 12 and 22 showed in vitro antibacterial activity against Klebsiella pneumoniae and Escherichia coli.     

Antimicrobial activity of 1,2-bis-[2-(5-R)-1H-benzimidazolyl]-1,2-ethanediols, 1,4-bis-[2-(5-R)-1H-benzimidazolyl]-1,2,3,4-butanetetraols and their FeIII, CuII, and AgI complexes

1,2-Bis-[2-(5-H/Me/Cl/NO2)-1H-benzimidazolyl]-1,2-ethanediols (L1-L4), 1,4-Bis-[2-(5-H/Me/Cl)-1H-benzimidazolyl]-1,2,3,4-butanetetraols (L5-L7) and their complexes with FeCl3, CuCl2, and AgNO3 were synthesized; antibacterial activity of the compounds was determined toward Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella typhi, Shigella flexneri, Proteus mirabilis, and antifungal activity against Candida albicans. The AgI complexes have considerable activity toward the microorganisms. Some AgI complexes show higher activity toward S. epidermidis than AgNO3 and cefuroxime. Cu(L3)Cl2 and Fe(L3)Cl3 show an antifungal effect on C. albicans but L3 itself has no activity.     

Synthesis and trypanocidal activity of 1,4-bis-(3,4,5-trimethoxy-phenyl)-1,4-butanediol and 1,4-bis-(3,4-dimethoxyphenyl)-1,4-butanediol

Chagas' disease is endemic in Central and South American countries. Specific chemotherapy with nifurtimox or benznidazole has been recommended for treatment of recent infection but they have limited efficacy. The natural products veraguensin (1) and grandisin (2) have shown potent in vitro activity against trypomastigote parasite (Y strain) with IC(50) 2.3 microM (1) and 3.7 microM (2). We report herein the synthesis and in vitro trypanocidal evaluation of symmetrical and unsymmetrical 1,4-diaryl-1,4-diol derivatives as potential trypanocidal analogs of natural compounds 1 and 2. Among the synthesized products, compounds 1,4-bis-(3,4,5-trimethoxyphenyl)-1,4-butanediol (6a) and 1,4-bis-(3,4-dimethoxyphenyl)-1,4-butanediol (6b) showed better activity against Trypanosoma cruzi trypomastigotes with IC(50) 100 and 105 microM (Y strain), respectively, and 110 microM (Bolivia strain) for both compounds. However, the most active compound of this series was 1,4-bis-(3,4-dimethoxyphenyl)butane-1,4-dione (7b) with IC(50) 10 and 200 microM against Y and Bolivia strains, respectively.     

Synthesis and antifungal evaluation of 6-hydroxy-1H-carbazole-1,4(9H)-diones

6-Hydroxy-1H-carbazole-1,4(9H)-diones were synthesized and tested for in vitro antifungal activity against two pathogenic strains of fungi. Among them tested, many compounds showed good antifungal activity. The results suggest that 6-hydroxy-1H-carbazole-1,4(9H)-diones would be potent antifungal agents.     

A convenient 'one-pot' synthesis and in vitro microbiological evaluation of novel 2,7-diaryl-[1,4] -diazepan-5-ones

A convenient method for the 'one-pot' synthesis of novel target molecule 2,7-diaryl-[1,4]-diazepan-5-ones from the respective 2,6-diaryl-piperidin-4-ones was catalyzed by NaHSO4.Al2O3 heterogeneous catalyst in dry media under microwave irradiation in solvent-free conditions. Moreover, the catalyst could be recovered and re-used up to 4 times after washing with ethyl acetate. They were evaluated for potential antibacterial activity against Staphylococcus aureus, beta-Haemolytic streptococcus, Vibreo cholerae, Salmonella typhii, Escherichia coli, Klebsiella pneumonia, Pseudomonas and antifungal activity against Aspergillus flavus, Aspergillus fumigatus, Mucor, Candida albicans and Rhizopus. Structure-Activity Relationship (SAR) led to the conclusion that, of all the compounds 25-32 tested, compound 30 exerted strong in vitro antibacterial activity against S. aureus, S. typhii, and Pseudomonas and all the compounds 25-32 were less active against E. coli, whereas all the compounds 25-32 displayed potent in vitro antifungal activity against all the fungal strains used, except compound 30, which was more effectual against Mucor.     

Iodine-catalyzed conjugate addition of indoles onto en-1,4-dione: a novel synthesis of 3-(1-(1H-indol-3-yl)-2-oxo-2-phenylethyl)indolin-2-ones as antibacterial and antifungal agents

Indole and its derivatives undergo smooth conjugate addition onto en-1,4-dione derived from isatin and acetophenone, in the presence of a catalytic amount of molecular iodine in acetonitrile under mild conditions to afford a novel class of 3-(1-(1H-indol-3-yl)-2-oxo-2-phenylethyl)indolin-2-one derivatives in good yields with high degree of 1,4-selectivity. Some of these compounds are found to exhibit modest antibacterial and antifungal properties.     

1,4-Bis-(2,3-epoxypropylamino)-9,10-anthracenedione and related compounds as potent antifungal and antimicrobial agents

1,4-Bis-(2,3-epoxypropylamino)-9,10-anthracenedione (1) and related derivatives were assayed for antifungal, antimicrobial, and plant growth regulatory activity. Compound 1 was extremely potent against several strains of fungi, bacteria, and algae (MIC <2 ppm) and controlled two types of downy mildew by 90–100% at a dose of 12 ppm.     

Synthesis,antimicrobial activity,structure-activity relationship and cytotoxic studies of a new series of functionalized (Z)-3-(2-oxo-2-substituted ethylidene)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-ones

A new series of functionalized (Z)-3-(2-oxo-2-substituted ethylidene)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-ones 23–26, incorporating pharmaceutically privileged substructures such as cyclopropyl, naphthyl, biphenyl and cyclohexylphenyl were synthesized in excellent yields. All the synthesized compounds were screened for their in vitro antibacterial activity against gram-(+)ve and gram-(?)ve bacterial species i.e. S. griseus, S. aureus, B. subtillis and E. coli as well as in vitro antifungal activity against fungal species i.e. F. oxysporium, A. niger, P. funiculosum and T. reesei, respectively. In this study, compounds containing cyclopropyl and cyclohexylphenyl substructures were identified as promising antimicrobial agents than standard drugs, ampicillin and chloramphenicol as well as ketoconazole. SAR study illustrates that electron-withdrawing groups increases the antibacterial as well as antifungal activity of 2-oxo-benzo[1,4]oxazines and vice versa. Compounds 23e and 26e, the most active compounds of the series, displayed promising antibacterial activity than Ampicillin and Chloramphenicol. Moreover, compound 26d showed promising antifungal potency as compared to Ketoconazole. Cytotoxic studies of the active compounds i.e. 23c–e, 24e, 25d and 26d–e found to be non-toxic in nature in 3T₃ fibroblast cell lines using MTT assay.     

Enhancement in antimicrobial activity of 2-(phenyl)-3-(2-butyl-4-chloro-1H-imidazolyl)-5-butylate isoxazolidine

The trans rich isomer, 2-(phenyl)-3-(2-butyl-4-chloro-1H-imidazolyl)-5-butylate isoxazolidine A (>96% ee) was synthesized by the condensation of E isomer rich nitrone 4 (>98% ee) with butyl acrylate in an inert solvent. Obtained isoxazolidine was screened for its antifungal activity against Aspergillus niger, Cephalosporium acremonium, Fusarium moniliforme by using Nystatin as positive control. It was also tested for its antibacterial activity against Bacillus subtilis, Escherichia coli, and Staphylococcus aureus by using Streptomycin as positive control. Enhanced antifungal activity was observed in isoxazolidine of >96% ee compared to the isoxazolidine of >69% ee (B), and enhancement was not observed in antibacterial activity.     

Fluconazole analogues containing 2H-1,4-benzothiazin-3(4H)-one or 2H-1,4-benzoxazin-3(4H)-one moieties,a novel class of anti-Candida agents

As a part of our program to develop new antifungal agents, a series of fluconazole analogues was designed and synthesized wherein one of the triazole moieties in fluconazole was replaced with 2H-1,4-benzothiazin-3(4H)-one or 2H-1,4-benzoxazin-3(4H)-one moiety. The new chemical entities thus synthesized were screened against various fungi and it was observed that the compounds 4a and 4i are potent inhibitors of Candida strains. The structure–activity relationship for these compounds is discussed.     

Regioselective synthesis and antimicrobial studies of ester linked 1,4-disubstituted 1,2,3-bistriazoles

A series of 1,4-disubstituted 1,2,3-bistriazoles was synthesized via click chemistry by cycloaddition of various bisalkynes with benzyl/2-phenylethyl azide. Synthesized triazoles were characterized by IR, (1)H NMR, (13)C NMR and mass spectral techniques. All the compounds were evaluated for antibacterial/antifungal activities and found to possess moderate to good antimicrobial activities. Further the docking study for the most active compound against DNA Gyrase was also carried out.     

Antibacterial, antifungal and cytotoxic properties of some sulfonamide-derived chromones

A series of antibacterial and antifungal sulfonamide (sulfanilamide, sulfaguanidine, sulfamethaxozole, 4-aminoethylbenzene-sulfonamide and 4-amino-6-trifluoromethyl-benzene-1,3-disulfonamide) derived chromones, previously reported as inhibitors of carbonic anhydrase, have been screened for in-vitro antibacterial activity against four Gram-negative (Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi and Shigella flexener) and two Gram-positive (Bacillus subtilis and Staphylococcus aureus) bacterial strains, and for in-vitro antifungal activity against Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani, Candida glaberata. All compounds (1)-(5) showed significant antibacterial activity against all four Gram-negative species and both Gram-positive species. However, three of them, (1), (4) and (5), were found to be comparatively much more active compared to (2) and (3). Of these, (5) was found to be the most active one. For antifungal activity, generally compounds (1) and (2) showed significant activity against more than three strains whereas (3)-(5) also showed significant activity against varied fungal strains. In the brine shrimp bioassay for in-vitro cytotoxic properties, only two compounds, (4) and (5) displayed potent cytotoxic activity, LD50 = 2.732 x 10(-4)M) and LD50 = 2.290 x 10(-4)M) respectively, against Artemia salina.     

Synthesis and biological properties of substituted 1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acids

A series of substituted 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinoline carboxylic acids was synthesized and tested for their in vitro and in vivo antibacterial activity. The introduction of a methyl group at the 5-position of quinoline nucleus enhanced characteristically the antibacterial activity against Gram-positive bacteria, including Streptococcus pneumonia, which is a major pathogen in the respiratory tract infection, while retaining Gram-negative activity. Among them, 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid hydrochloride (grepafloxacin) exhibited potent in vitro antibacterial activity against Gram-positive bacteria such as Streptococcus pneumoniae and high in vivo efficacy on the experimental systemic infections caused by the Gram-positive and -negative bacteria tested. It also showed a high distribution to the lung and bronchoalveolar lavage fluid in comparison to reference drugs and is now undergoing clinical evaluation.     

Synthesis and antimicrobial activity of new 3-(1-R-3(5)-methyl-4-nitroso-1H-5(3)-pyrazolyl)-5-methylisoxazoles

A number of new 3-(1-R-3(5)-methyl-4-nitroso-1H-5(3)-pyrazolyl)-5-methylisoxazoles 6a–g (7b–f) were synthesized and tested for antibacterial and antifungal activity. Some of these compounds displayed antifungal activity at non-cytotoxic concentrations. Derivative 6c was 9 times more potent in vitro than miconazole and 20 times more selective against C. neoformans. 6c was also 8- and 125-fold more potent than amphotericin B and fluconazole, respectively. None of the compounds was active against bacteria. Preliminary structure–activity relationship (SAR) studies showed that the NO group at position 4 of the pyrazole ring is essential for the activity. Lipophilicity of the pyrazole moiety, N-alkyl chain length and planarity of the two heterocyclic rings appear to play a decisive role in modulating cytotoxicity and antifungal activity.     

In-vitro antibacterial, antifungal and cytotoxic activity of cobalt (II), copper (II), nickel (II) and zinc (II) complexes with furanylmethyl- and thienylmethyl-dithiolenes: [1, 3-dithiole- 2-one and 1,3-dithiole-2-thione

Some antibacterial and antifungal furanylmethyl-and thienylmethyl dithiolenes and, their Co(II), Cu(II), Ni (II) and Zn (II) complexes have been synthesized, characterized and screened for their in vitro antibacterial activity against four Gram-negative; Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi and Shigella flexeneri, and two Gram-positive; Bacillus subtilis and Staphylococcus aureus bacterial strains, and for in-vitro antifungal activity against Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glaberata. All compounds showed significant antibacterial and antifungal activity. The metal complexes, however, were shown to possess better activity as compared to the simple ligands. The brine shrimp bioassay was also carried out to study their in-vitro cytotoxic properties.     

Synthesis and structure-activity relationships of 3-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines as novel antitumor agents

In order to obtain clinically useful antitumor agent, we have designed and synthesized various 3-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridines, and evaluated their cytotoxic activity. The series of novel 3-substituted derivatives synthesized in this study showed good antitumor activity against murine P388 leukemia. Particularly, the 3-formyl 1,8-naphthyridine displayed an antitumor activity equal to that of the 3-carboxy 1,8-naphthyridine against murine and human tumor cell lines as well as in vivo test for mouse leukemia. These results demonstrate that the carboxy group at the C-3 position of 1,8-naphthyridine ring is not essential for antitumor activity. In addition, the trend of cytotoxic activity for the 3-substituted 1,8-naphthyridines was different from that of antibacterial activity.