Synthesis and potent antimicrobial activity of some novel 2-phenyl or methyl-4H-1-benzopyran-4-ones carrying amidinobenzimidazoles

Series of flavones and methyl-4H-1-benzopyran-4-ones carrying mono or diamidinobenzimidazoles at different positions were synthesized and evaluated for antibacterial and antifungal activities against E. coli, S. aureus, MRSA (methicillin-resistant S. aureus), MRSE (methicillin-resistant S. epidermidis), S. faecalis and C. albicans, C. krusei. The results showed that while all diamidines are inactive, the compounds having monoamidinobenzimidazoles at the C-6 position of the 2-phenyl-4H-1-benzopyran-4-one have potent antibacterial activities, particularly, against Gram-positive bacteria. Compounds 23 and 22 exhibited the best inhibitory activity with MIC values of 1.56 microg/ml against S. aureus, MRSA, MRSE and 3.12 microg/ml against C. albicans, respectively.     

Synthesis of some new 2-substituted-phenyl-1H-benzimidazole-5-carbonitriles and their potent activity against Candida species

New 2-substituted-phenyl-1H-benzimidazole-5-carboxylic acids (35, 38), ethyl-5-carboxylate (36), -5-carboxamides (37, 39),-5-carboxaldehyde (42), -5-chloro (40), -5-trifluoromethyl (41), and -5-carbonitriles (44-53, 55-67), -6-carbonitrile (54) were prepared and evaluated in vitro against Candida species. The cyano substituted compounds 53, 57, 58 and 61 exhibited the greatest activity with MIC values of 3.12 microg/mL, values similar to that of fluconazole.     

Synthesis and antimicrobial activity of some isoindolin-1-ones derivatives

A range of N-substituted isoindolin-1-ones was prepared and their potential as novel antimicrobial agents was investigated. MIC values for active compounds were determined and reported.     

Synthesis and antimicrobial activity of amide derivatives of polyether antibiotic-salinomycin

For the first time a direct and practical approach to the synthesis of eight amide derivatives of polyether antibiotic-salinomycin is described. The structure of allyl amide (3a) has been determined using X-ray diffraction. Salinomycin and its amide derivatives have been screened for their in vitro antimicrobial activity against the typical gram-positive cocci, gram-negative rods and yeast-like organisms, as well as against a series of clinical isolates of methicillin-resistant Staphylococcus aureus and methicillin-sensitive S. aureus. Amides of salinomycin have been found to show a wide range of activities, from inactive at 256 μg/mL to active with MIC of 2 μg/mL, comparable with salinomycin. As a result, phenyl amide (3b) was found to be the most active salinomycin derivative against gram-positive bacteria, MRSA and MSSA.     

Synthesis and characterization of 1-substituted 5-alkylphenazine derivatives carrying functional groups

The following 1-substituted derivatives of 5-methylphenazine and 5-ethylphenazine were synthesized: 1-(3-carboxypropyloxy)-5-methylphenazine (1B), 1-(3-carboxypropyloxy)-5-ethylphenazine (2B), 1-(3-ethoxycarbonylpropyloxy)-5-ethylphenazine (2C) and 1-[N-(2-aminoethyl)carbamoylpropyloxy]-5-ethylphenazine (2D); their spectra, stability and reactivity as electron mediators were investigated, together with those of 5-methylphenazine (1A) and 5-ethylphenazine (2A). The 1-substituted derivatives are all insensitive to light and the derivatives of 5-ethylphenazine are more stable than those of 5-methylphenazine under neutral and alkaline conditions; 2B is the most stable of all the derivatives. The spectral properties of the decomposed compounds showed that photodecomposition of 1A and 2A is associated with hydroxylation at position 1, alkali decomposition of 1A and 1B with elimination of the 5-methyl group and alkali decomposition of 2A, 2B, and 2D with a ring-opening reaction. The second-order rate constant k1 for the reaction of the phenazine derivatives with NADH was measured under steady-state conditions. The k1 values vary depending on the substituents at positions 1 and 5: the values for 1A, 1B, 2A, 2B, 2C and 2D are 1.83 mM-1 s-1, 3.33 mM-1 s-1, 0.75 mM-1 s-1, 1.42 mM-1 s-1, 1.68 mM-1 s-1 and 2.03 mM-1 s-1, respectively. The rate constants, k2 and k3, for the reactions of the reduced form of 2B with oxygen and with 3-(4',5'-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium ion, respectively, were k2 = 1.21 mM-1 s-1 and k3 = 91 mM-1 s-1. These phenazine derivatives have potential applications in the biochemical field.     

Synthesis and anti-hepatitis C virus activity of novel ethyl 1H-indole-3-carboxylates in vitro

A series of ethyl 1H-indole-3-carboxylates 9a_1–6 and 9b_1–2 were prepared and evaluated in Huh-7.5 cells. Most of the compounds exhibited anti-hepatitis C virus (HCV) activities at low concentration. The selectivity indices of inhibition on entry and replication of compounds 9a₂ (>10; >16.7) and 9b₁ (>6.25; >16.7) were higher than those of the other evaluated compounds, including the lead compound Arbidol (ARB, 6; 15). Moreover, the selective index of inhibition on entry of compound 9a₃ (>6.25) was higher than that of ARB (6). Of these three initial hits, compound 9a₂ was the most potent.     

Synthesis of new N-phenylpyrazole derivatives with potent antimicrobial activity

The versatile synthons 4-(2-bromoacetyl)-5-methyl-1-phenyl-3-phenylcarbamoyl-1H-pyrazole (3) and 4-[(E)-3-(dimethylamino)acryloyl]-5-methyl-1-phenyl-3-phenylcarbamoyl-1H-pyrazole (2) were used as precursors for the synthesis of a series of phenylpyrazoles with different aromatic ring systems at position 4. The antimicrobiological evaluation of the newly synthesized compounds was carried out in vitro assays for antifungal and antibacterial activities. Amongst the tested compounds, 4-acetyl-5-methyl-1-phenyl-3-phenylcarbamoyl-1H-pyrazole (1), 4-[(E)-3-(dimethylamino)acryloyl]-5-methyl-1-phenyl-3-phenylcarbamoyl-1H-pyrazole (2), 4-(2-bromoacetyl)-5-methyl-1-phenyl-3-phenylcarbamoyl-1H-pyrazole (3) and 4-(2-aminothiazol-4-yl)-5-methyl-1-phenyl-3-phenylcarbamoyl-1H-pyrazole (17) showed interesting antimicrobial properties. In particular, all tested compounds produced inhibitory effects against pathogenic yeast (Candida albicans) similar or superior to those of reference drug. In addition, compound 3 showed excellent activity against pathogenic mould (Aspergillus). From structure-activity relationship (SAR) point of view, the attachment of bromoacetyl moiety to pyrazole ring can be considered as a breakthrough in developing a new therapeutic antifungal agent related to phenylpyrazole system.     

Synthesis, anti-inflammatory and analgesic activity evaluation of some amidine and hydrazone derivatives

A number of amidine derivatives (3a-i) were synthesized by condensation of cyanopyridine and cyanopyrazine with sulfonylhydrazides in the presence of sodium methoxide. 2-Acetylpyridine and 4-acetylpyridine were condensed with sulfonylhydrazides by microwave irradiation in solid phase to give corresponding hydrazones (5a-d). Indole-3-carboxaldehyde was condensed with sulfonylhydrazides by refluxing in acetic acid to give corresponding condensation product (5e and f). All the compounds, that is, 3a-i and 5a-f were purified by crystallization or by column chromatography. Structures of all the synthesized compounds are supported by correct IR, (1)H NMR, mass spectral and analytical data. Anti-inflammatory activity evaluation was carried out using carrageenin-induced paw oedema assay and compounds 3e,f and 5e exhibited good anti-inflammatory activity, that is 52%, 37% and 38% at 50 mg/kg po, respectively. Analgesic activity evaluation was carried out using acetic acid writhing assay and compounds 3a,c,e and 5f showed good analgesic activity, that is, 50%, 50%, 50% and 60% at 50 mg/kg po, respectively.     

Synthesis and SAR study of novel anticancer and antimicrobial naphthoquinone amide derivatives

A series of novel naphthoquinone amide derivatives of the bioactive quinones, plumbagin, juglone, menadione and lawsone, with various amino acids were synthesized. The compounds were characterized by ¹H NMR, ¹³C NMR, Mass, IR and elemental analysis. All the compounds were evaluated for their anticancer activity against HeLa and SAS cancer cell lines and 3D-QSAR indicated the presence of electron donating group near sulphur enhanced the activity against HeLa cells. Among the derivatives synthesized, compounds 11f, 10a, 10b and 10g were the most active with IC₅₀ values of 16, 12, 14 and 24.5 μM, respectively. The analogues were also screened for antimicrobial activity against two human bacterial pathogens, the Gram-positive Methicillin resistant Staphylococcus aureus (MRSA) and the Gram-negative Pseudomonas aeruginosa and a human yeast pathogen, Fluconazole resistant Candida albicans (FRCA). Among the synthesized compounds, 8g, 10g and 11g exhibited maximum antibacterial activity towards MRSA and antifungal activity against FRCA in well diffusion method.     

Synthesis and in vitro anti-hepatitis B virus activities of some ethyl 5-hydroxy-1H-indole-3-carboxylates

A series of ethyl 5-hydroxy-1H-indole-3-carboxylates 6A-10T were synthesized and evaluated for their anti-hepatitis B virus (HBV) activities in 2.2.15 cells. The IC50 and selective index of inhibition on replication of HBV DNA of compounds 10(L) (1.52 microg/ml, 9.38) and 10(P) (2.00 microg/ml, 8.85) were higher than those of the other evaluated compounds including lamivudine (7.02). Compounds 7E and 10J exhibited significant anti-HBV activities, and the IC50 values on replication of HBV DNA of these compounds were 24.90 and 15.41 microg/ml, respectively, which were far more potent than the positive control lamivudine 228.00 microg/ml.     

Synthesis and anticancer activity of novel amide derivatives of non-acetal deoxoartemisinin

Novel amide derivatives of C-12 non-acetal deoxoartemisinin were synthesized. Some of the derivatives had potent in vitro anticancer activity against major human cancer cell lines. The deoxoartemisinin amide trimer had potent in vivo antiangiogenic activity, according to the mouse matrigel plug assay.     

Synthesis and antimicrobial activity of some new hydrazone-bridged thiazole-pyrrole derivatives

In this work, we synthesized fourteen different compounds which contain hydrazone bridged thiazole and pyrrole rings. For this purpose, pyrrole-2-carboxaldehydes were reacted directly with thiosemicarbazide in ethanol and then obtained thiosemicarbazones were condensed with α-bromoacetophenone derivatives (Hantzsch reaction) to give 1-substituted pyrrole-2-carboxaldehyde [4-(4-substituted phenyl)-1,3-thiazol-2-yl] hydrazones. The structures of the obtained compounds were elucidated by using IR, ¹H-NMR and FAB⁺-MS spectral data and elemental analyses results. All of the compounds were screened for their antibacterial and antifungal activities against twelve different microorganisms by using microbroth dilution method. Ketoconazole and chloramphenicol were used as standard drugs. All of the compounds showed good activity against Staphylococcus aureus and Enterococcus faecalis.     

Synthesis and in vitro anti-hepatitis B virus activities of some ethyl 6-bromo-5-hydroxy-1H-indole-3-carboxylates

A series of ethyl 6-bromo-5-hydroxy-1H-indole-3-carboxylates, 8a-11v, were synthesized and evaluated for their anti-hepatitis B virus (HBV) activities in 2.2.15 cells. The selective indexes of inhibition on replication of HBV DNA of compounds 11s (>8.7) and 11t (10.8), which were introduced halogen on the phenyl ring at position 2, were greater than those of the other evaluated compounds including lamivudine (7.0). Compounds 9e, 9h, 9l, and 11v exhibited significant anti-HBV activities, and the IC(50) values on replication of HBV DNA of these compounds were 3.6, 6.37, 5.2, and 5.4 microg/ml, respectively, which were far more potent than the positive control lamivudine 228 microg/ml.     

Synthesis, antimicrobial activity and cytotoxicity of novel oxadiazole derivatives

In the present study, 5-substituted-1,3,4-oxadiazolin-2-thiones (1a-b) were synthesized via the ring closure reactions of appropriate acid hydrazides with carbon disulphide. N-(Benzothiazol-2-yl)-2-[[5-substituted-1,3,4-oxadiazol-2-yl]sulfanyl]acetamide derivatives (3a-j) were obtained by the nucleophilic substitution reactions of 5-substituted-1,3,4-oxadiazolin-2-thiones (1a-b) with N-(benzothiazol-2-yl)-2-chloroacetamides. The chemical structures of the compounds were elucidated by IR, (1)H NMR, (13)C NMR and FAB(+)-MS spectral data and elemental analyses. The synthesized compounds were screened for their antimicrobial activities against Micrococcus luteus, Bacillus subtilis, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Listeria monocytogenes and Candida albicans. All compounds except compound 3h exhibited the highest antibacterial activity against P. aeruginosa. Among all compounds (3a-j), the compounds bearing 4-methoxyphenoxymethyl moiety on oxadiazole ring (3a-e) exhibited the highest inhibitory activity against C. albicans. Although compound 3j did not possess 4-methoxyphenoxymethyl moiety on oxadiazole ring, this derivative also exhibited the same level of anti-candidal activity. The compounds were also investigated for their cytotoxic effects using MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Compound 3a exhibited the highest cytotoxic activity, whereas compound 3g possessed the lowest cytotoxic activity against NIH/3T3 cells.     

Synthesis,antimicrobial activity and cytotoxicity of some new carbazole derivatives

In this work, some N-(9-Ethyl-9H-carbazole-3-yl)-2-(phenoxy)acetamide derivatives were synthesised and evaluated for their antimicrobial activity and cytotoxicity. The structural elucidation of the compounds was performed by IR, ¹H-NMR, ¹³C-NMR and FAB⁺-MS spectral data and elemental analyses. The title compounds were obtained by reacting 2-chloro-N-(9-ethyl-9H-carbazole-3-yl)acetamide with some substituted phenols. The synthesised compounds were investigated for their antibacterial and antifungal activities against Micrococcus luteus, Bacillus subtilis, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Listeria monocytogenes and Candida albicans. The compounds N-(9-Ethyl-9H-carbazole-3-yl)-2-(4-ethylphenoxy)acetamide (2c) and N-(9-Ethyl-9H-carbazole-3-yl)-2-(quinolin-8-yloxy)acetamide (2n) showed notable antimicrobial activity. The compounds were also studied for their cytotoxic effects using MTT assay, and it was seen that 2n had the lowest cytotoxic activity against NIH/3T3 cells.     

Synthesis and structure activity relationships of glycine amide derivatives as novel Vascular Adhesion Protein-1 inhibitors

Vascular Adhesion Protein-1 (VAP-1) is a promising therapeutic target for the treatment of several inflammatory-related diseases including diabetic microvascular complication. We identified glycine amide derivative 3 as a novel structure with moderate VAP-1 inhibitory activity. Structure-activity relationship studies of glycine amide derivatives revealed that the tertiary amide moiety is important for stability in rat blood and that the position of substituents on the left phenyl ring plays an important role in VAP-1 inhibitory activity. We also found that low TPSA values and weak basicity are both important for high PAMPA values for glycine amide derivatives. These findings led to the identification of a series of orally active compounds with enhanced VAP-1 inhibitory activity. Of these compounds, 4g exhibited the most potent ex vivo efficacy, with plasma VAP-1 inhibitory activity of 60% after oral administration at 1 mg/kg.     

Synthesis and antimicrobial activity of some new thiazolyl thiazolidine-2,4-dione derivatives

In this study, a series of thiazolyl thiazolidine-2,4-dione derivatives (Va-f and VIa-f) were synthesized and evaluated for their antibacterial and antifungal activities against Staphylococcus aureus (ATCC 25923), methicillin resistant S. aureus (MRSA ATCC 43300), methicillin resistant S. aureus (MRSA isolate), and Escherichia coli (ATCC 23556) and C. albicans (ATCC10145). All the compounds were found active against used microorganisms.     

Synthesis and antimicrobial activity of novel 5-aminoimidazole-4-carboxamidrazones

A mild and simple method was developed to prepare a series of fifteen 5-aminoimidazole 4-carboxamidrazones, starting from the easily accessible 5-amino-4-cyanoformimidoyl imidazoles. The antimicrobial activity of these novel amidrazones was screened against Gram positive (Staphylococcus aureus) and Gram negative (Escherichia coli, Pseudomonas aeruginosa) bacteria and Candida sp. (Candida albicans, Candida krusei, Candida parapsilosis). Only a subset of compounds displayed fair-moderate activity against S. aureus and E. coli but all exhibited activity against Candida sp. The three most potent antifungal compounds were further tested against Cryptococcus neoformans, Aspergillus fumigatus and three dermatophytes (Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum gypseum). These three hit compounds strongly inhibited C. krusei and C. neoformans growth, although their activity on filamentous fungi was very weak when compared to the activity on yeasts.     

Synthesis and antiplasmodial activity of some 1-azabenzanthrone derivatives

Some synthetic 1-azabenzanthrones (7H-dibenzo[de,h]quinolin-7-ones) are weakly to moderately cytotoxic, suggesting that they might also show antiparasitic activity. We have now tested a small collection of these compounds in vitro against a chloroquine-resistant Plasmodium falciparum strain, comparing their cytotoxicity against normal human fibroblasts. Our results indicate that 5-methoxy-1-azabenzanthrone and its 2,3-dihydro analogue have low micromolar antiplasmodial activities and showed more than 10-fold selectivity against the parasite, indicating that the dihydro compound, in particular, might serve as a lead compound for further development.