The emergence of bacterial resistance requires the development of new antibiotics with an alternative mode of action. Based on class I, developed in our previous study, a new series of RNA polymerase (RNAP) inhibitors targeting the switch region was designed. Feasible synthetic procedures for the aryl-ureido-heterocyclic-carboxylic acids were developed including three regioisomeric thiophene classes (II–IV), as well as three isosteric furan (V, VI) and thiazole (VII) classes. Biological evaluation using a RNAP transcription inhibition assay revealed that class II compounds possess the same activity as the parent class I, whereas classes III, V–VII were active, however with lower potency. Structure–activity relationship (SAR) studies, supported by molecular modeling, elucidated the structural requirements necessary for interaction with the binding site. Beside the RNAP inhibitory effects, the new compounds displayed good antibacterial activities against Gram positive bacteria and the Gram negative E. coli TolC strain. Moreover, they showed no cross resistance with the clinically used RNAP inhibitor rifampicin (Rif) and a lower rate of resistance compared to Rif.

Aim: Antibiotic resistance has become a major health problem. The σ70:core interface of bacterial RNA polymerase is a promising drug target. Recently, the coiled-coil and lid-rudder-system of the β’ subunit has been identified as an inhibition hot spot. Materials & methods & Results: By using surface plasmon resonance-based assays, inhibitors of the protein–protein interaction were identified and competition with σ70 was shown. Effective inhibition was verified in an in vitro transcription and a σ70:core assembly assay. For one hit series, we found a correlation between activity and affinity. Mutant interaction studies suggest the inhibitors’ binding site. Conclusion: Surface plasmon resonance is a valuable technology in drug design, that has been used in this study to identify and evaluate σ70:core RNA polymerase inhibitors.

The presence of free carboxylic acid group in majority of non-steroidal anti-inflammatory drug (NSAIDs) is responsible from GI irritation. Coupling of the appropriate NSAIDs (diclofenac, naproxen, dexibuprofen and meclofenamic acid) 1–4, respectively with the appropriate amino acid ester 5 using dicyclohexylcarbodiimide afforded prodrugs 6–13. The structures of the prodrugs were verified based on spectral data. Chemical hydrolysis studies performed in three different non enzymatic buffer solutions at pH 1.2, 5.5 and 7.4, as well as in 80% human plasma and 10% rat liver homogenate using HPLC indicate no conversion of prodrugs to their respective NSAID in the studied buffers, while they underwent a reasonable plasma and rat liver homogenate hydrolysis. Furthermore, ulcerogenicity of prodrugs 9 and 12 were studied and results revealed no gastro-ulcerogenic effects.NULL

Square wave adsorptive stripping voltammetric (SQWASV) method has been utilized to confirm and elucidate the possible complexation reaction between pantoprazole sodium and cobalt as a transition metal in Britton- Robinson buffer (pH=7.0). The current signal due to the oxidation process was a function of the amount of pantoprazole sodium, pH of the medium, cobalt concentration and accumulation time at the electrode surface. The oxidation peak current has varied linearly with the concentration over the range of 0.1–9.0 nM. The limit of detection was found to be 0.04 nM. The validity of the method was successfully applied for the determination of pantoprazole sodium in pharmaceutical formulations with a pharmacokinetic study in rabbit plasma. The simplicity, rapidity, sensitivity and selectivity of this method make it a very attractive alternative to the other existing methods in the quality control laboratories.

Square wave adsorptive stripping voltammetric (SQWASV) method has been utilized to confirm and elucidate the possible complexation reaction between pantoprazole sodium and cobalt as a transition metal in Britton- Robinson buffer (pH=7.0). The current signal due to the oxidation process was a function of the amount of pantoprazole sodium, pH of the medium, cobalt concentration and accumulation time at the electrode surface. The oxidation peak current has varied linearly with the concentration over the range of 0.1–9.0 nM. The limit of detection was found to be 0.04 nM. The validity of the method was successfully applied for the determination of pantoprazole sodium in pharmaceutical formulations with a pharmacokinetic study in rabbit plasma. The simplicity, rapidity, sensitivity and selectivity of this method make it a very attractive alternative to the other existing methods in the quality control laboratories.

Square wave adsorptive stripping voltammetric (SQWASV) method has been utilized to confirm and elucidate the possible complexation reaction between pantoprazole sodium and cobalt as a transition metal in Britton- Robinson buffer (pH=7.0). The current signal due to the oxidation process was a function of the amount of pantoprazole sodium, pH of the medium, cobalt concentration and accumulation time at the electrode surface. The oxidation peak current has varied linearly with the concentration over the range of 0.1–9.0 nM. The limit of detection was found to be 0.04 nM. The validity of the method was successfully applied for the determination of pantoprazole sodium in pharmaceutical formulations with a pharmacokinetic study in rabbit plasma. The simplicity, rapidity, sensitivity and selectivity of this method make it a very attractive alternative to the other existing methods in the quality control laboratories.

New derivatives of 2-thiobenzimidazole incorporating triazole moiety were synthesized, characterized and tested in vitro for antiviral activity against hepatitis C virus (HCV) and hepatitis B virus (HBV). Their cytotoxicity was determined by the reduction in the number of viable cell. All of the synthesized compounds are inactive against HBV and some showed activity against HCV. In particular, two compounds showed significant activity, 2-{4-[(1-benzoylbenzimidazol-2-ylthio)methyl]-1H-1,2,3-triazol-1-yl}-N-(p-nitro-phenyl)-acetamide (13) and 2-(4-{[1-(p-chlorobenzoyl)-benzimidazol-2-ylthio)methyl]-1H-1,2,3-triazol-1-yl}-N-(p-nitrophenyl)-acetamide (17). The results give an insight into the importance of the substituent at position 2 of benzimidazole for the inhibition of HCV.

New derivatives of 2-thiobenzimidazole incorporating triazole moiety were synthesized, characterized and tested in vitro for antiviral activity against hepatitis C virus (HCV) and hepatitis B virus (HBV). Their cytotoxicity was determined by the reduction in the number of viable cell. All of the synthesized compounds are inactive against HBV and some showed activity against HCV. In particular, two compounds showed significant activity, 2-{4-[(1-benzoylbenzimidazol-2-ylthio)methyl]-1H-1,2,3-triazol-1-yl}-N-(p-nitro-phenyl)-acetamide (13) and 2-(4-{[1-(p-chlorobenzoyl)-benzimidazol-2-ylthio)methyl]-1H-1,2,3-triazol-1-yl}-N-(p-nitrophenyl)-acetamide (17). The results give an insight into the importance of the substituent at position 2 of benzimidazole for the inhibition of HCV.

6-Chloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (1) was utilized as key intermediate for the synthesis of new 6-amino derivatives (2-17) by heating with a number of aliphatic amines. Heating 1 with aromatic amines under similar conditions failed to give the corresponding amino derivatives. The new compounds were fully characterized and some of them were preliminary screened for anticancer, COX inhibition and antimicrobial activities. The compounds are not cytotoxic and some of them are potent and selective COX-2 inhibitors. In particular compound 6-benzylamino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (4) with IC50 = 0.11 μM and SI = 33 for COX-2. 6-Hexylamino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (6) exhibited antifungual and antibacterial activities (Gram -ve) comparable to the reference drugs. The results show clearly that the natur of N-substituent significanlty affect the biological activity.

6-Chloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (1) was utilized as key intermediate for the synthesis of new 6-amino derivatives (2-17) by heating with a number of aliphatic amines. Heating 1 with aromatic amines under similar conditions failed to give the corresponding amino derivatives. The new compounds were fully characterized and some of them were preliminary screened for anticancer, COX inhibition and antimicrobial activities. The compounds are not cytotoxic and some of them are potent and selective COX-2 inhibitors. In particular compound 6-benzylamino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (4) with IC50 = 0.11 μM and SI = 33 for COX-2. 6-Hexylamino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (6) exhibited antifungual and antibacterial activities (Gram -ve) comparable to the reference drugs. The results show clearly that the natur of N-substituent significanlty affect the biological activity.