Synthesis, spectral analysis and pharmacological study of N'- substituted-2-(5-((2,4-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-ylthio)acetohydrazides

A series of molecules bearing multiple functional groups were synthesized to study their antibiotic effect against Gram-positive and Gram-negative bacteria and lipoxygenase activity as well. 2,4-Dimethylcarbolic acid (1) was refluxed with ethyl 2-bromoacetate to synthesize ethyl 2-(2,4-dimethylphenoxy)acetate (2). Compound 2 was converted to the corresponding hydrazide 3, again on refluxing with hydrazine. The compound 5-((2,4-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-thiol (4) was synthesized by the reaction of 3 and CS2 in the presence of KOH. Compound 4 was further converted to the corresponding ester 5 and then 2-(5-((2,4-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-ylthio)acetohydrazide (6). The final molecules N'-substituted-2-(5-((2,4-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-ylthio)acetohydrazide, 8a-m, bearing ether, 1,3,4-oxadiazole, thioether, hydrazone and azomethine functional groups were synthesized by stirring the aryl carboxaldehydes 7a-m with 6 in methanol at room temperature. The depicted structures of all synthesized molecules were corroborated by IR, 1H-NMR and EIMS spectral data analysis. 8m and 8i showed substantial antibacterial activity and lipoxygenase inhibitory activity, respectively

Synthesis of 3-[4-(2-furoyl)-1-piperazinyl]-N- (substituted)propanamides as promising antibacterial agents with mild cytotoxicity

Purpose: To evaluate the antibacterial activity and cytotoxicity of a series of molecules with amalgamation of furoyl, piperazine and amide moieties.Methods: New derivatives, namely 3-[4-(2-furoyl)-1-piperazinyl]-N-(substituted) propanamides, were synthesized and evaluated for their antibacterial activity and toxicity to mammalian cells. The synthesis was initiated by treating different aryl/aralkyl amines (1a-u) with 3-bromopropionyl chloride (2) to obtain the solid electrophiles 3a-u, which were collected by filtration. Thereafter, the different N-aryl/aralkyl-3- bromopropionamides (3a-u) and 2-furoyl-1-piperazine (4) at equimolar ratios were allowed to react in acetonitrile and in the presence of a base, K2CO3, to form the target compounds, 5a-u. Structural elucidation was carried out using EI-MS (electron impact mass spectrometry), IR (infrared) and 1H-NMR (proton nuclear magnetic resonance). The antibacterial activity of the synthesized compounds was evaluated against various bacterial strains. Furthermore, hemolysis was determined to assess cytotoxicity using bovine red blood cells.Results: Molecules 5g, 5a, 5p, 5g and 5i were found to be potent agents against S. aureus, S. typhi, P. aeruginosa, E. coli and B. subtilis with respective minimum inhibitory concentration (MIC) values of 8.34 ± 0.55, 8.37 ± 0.12, 8.65 ± 0.57, 8.97 ± 0.12 and 9.24 ± 0.50 μM, compared to 7.80 ± 0.19, 7.45 ± 0.58, 7.14 ± 0.58, 7.16 ± 0.58 and 7.29 ± 0.90 μM for the reference standard, ciprofloxacin. The most active compounds, 5a, 5g, 5i and 5p, showed a hemolysis of 15.48, 8.03, 5.52 and 4.35 %, respectively.Conclusion: The synthesized compounds exhibit good antibacterial activity. The hemolysis data indicate that these compounds have a low toxicity level. However, in vivo studies are required to ascertain their potentials as new drug candidates.Keywords: 4-(2-Furoyl)-1-piperazine, 1H-NMR, EI-MS, Antimicrobial activity, Hemolytic activit

Synthesis of new 2-{2,3-dihydro-1,4-benzodioxin-6- yl[(4-methylphenyl) sulfonyl]amino}-N-(un/substituted-phenyl) acetamides as α-glucosidase and acetylcholinesterase inhibitors and their in silico study

The aim of the present research work was to investigate the enzyme inhibitory potential of some new sulfonamides having benzodioxane and acetamide moieties. The synthesis was started by the reaction of N-2,3-dihydrobenzo[1,4]-dioxin-6-amine (1) with 4-methylbenzenesulfonyl chloride (2) in the presence of 10% aqueous Na2CO3 to yield N-(2,3-dihydrobenzo[1,4]-dioxin-6-yl)-4-methylbenzenesulfonamide (3), which was then reacted with 2-bromo-N-(un/substituted-phenyl)acetamides (6a-l) in DMF and lithium hydride as a base to afford various 2-{2,3-dihydro-1,4-benzodioxin-6-yl[(4-methylphenyl)sulfonyl] amino}-N-(un/substituted-phenyl)acetamides (7a-l). All the synthesized compounds were characterized by their IR and 1 H-NMR spectral data along with CHN analysis data. The enzyme inhibitory activities of these compounds were tested against -glucosidase and acetylcholinesterase (AChE). Most of the compounds exhibited substantial inhibitory activity against yeast -glucosidase and weak against AChE. The in silico molecular docking results were also consistent with in vitro enzyme inhibition data

Reverse-phase chromatographic determination and intrinsic stability behavior of 5-[(4-chlorophenoxy)methyl]-1,3,4-oxadiazole-2-thiol

The study describes the development and preliminary validation of a simple reverse phase chromatographic method for determination of a novel drug candidate, 5-[(4-chlorophenoxy)methyl]-1,3,4-oxadiazole-2-thiol (OXCPM), in bulk and stressed solution, in order to find out the intrinsic stability behavior of the compound. Isocratic elution was carried out at a flow rate of 1.0 mL min–1 through a Promosil C18 column maintained at 25 °C, using the mobile phase comprising acetonitrile and aqueous o-H3PO4 (pH 2.67) (1:1, V/V). Detection was performed at 258 nm. The response of the detector was linear in a concentration range of 1.25–50.00 µg mL–1 with the correlation coefficient of 0.9996 ± 0.0001. Cumulative intra-day, inter-day and inter-instrument accuracy (99.5 ± 1.0, 100.2 ± 1.0 and 100.3 ± 0.4 %, resp.) with RSD less than 5 % indicated that the method was accurate and precise. The resolution and selectivity factor (>2 and >1, resp.), particularly in copper metal- and dry-heat-stress solutions, depicted the selectivity of the method. OXCPM remained stable under hydrolytic (acidic and neutral pH, ≤ 37 °C), photolytic and moist heat stress conditions. Under alkaline conditions (hydrolytic and photolytic), polar products were formed and eluted very fast through the column (tR < 3.75 min). At room temperature, the compound was susceptible to oxidation by hydrogen peroxide and transition metals. The ionogram of most of the stress solutions indicated the presence of a product having m/z 256, which may be a result of N- or S- methylation or -SH oxidation. The results of the study indicate that the method is selective, sensitive and suitable to be used for determination of OXCPM in bulk and under stress conditions

2-Amino-1,3-benzothia­zol-3-ium dihydrogen phosphate

The cation of the title compound, C7H7N2S+·H2PO4 −, is almost planar (r.m.s deviation = 0.017 Å for all non-H atoms). In the crystal structure, the cations and anions are connected by N—H⋯O and O—H⋯O hydrogen bonds, with π–π stacking inter­actions between neighbouring 1,3-thia­zole and benzene rings [centroid–centroid distance = 3.5711 (11) Å], forming a three-dimensional network

Synthesis of 2-{[5-(aralkyl/aryl)-1,3,4-oxadiazol-2- yl]sulfanyl}-N-(4-methyl-1,3-thiazol-2-yl)acetamides: Novel bi-heterocycles as potential therapeutic agents

Purpose: To evaluate the therapeutic potential of new bi-heterocycles  containing a 1,3-thiazole and 1,3,4-oxadiazole in the skeleton against Alzheimer's disease and diabetes, supported by in-silico study. Methods: The synthesis was initiated by the reaction of 4-methyl- 1,3-thiazol-2-amine (1) with bromoacetyl bromide (2) in aqueous basic medium to obtain an electrophile,2-bromo-N-(4-methyl-1,3- thiazol- 2-yl)acetamide (3). In parallel reactions, a series of carboxylic acids, 4a-r, were converted through a sequence of three steps, into respective 1,3,4-oxadiazole heterocyclic cores, 7a-r, to utilize as nucleophiles. Finally, the designed molecules, 8a-r, were synthesized by coupling 7a-r individually with 3 in an aprotic polar solvent. The structures of these bi-heterocycles were elucidated by infrared (IR), electron ionization-mass spectrometry (EI-MS), proton nuclear magnetic resonance (1H-NMR) and carbon nuclear magnetic resonance (13C-NMR). To evaluate their enzyme inhibitory potential, 8a-r were screened against acetylcholinesterase (AChE), but brine shrimp lethality bioassay.Results: The most active compound against AChE was 8l with half-maximal inhibitory concentration (IC50) of 17.25 ± 0.07 μM. Against BChE, the highest inhibitory effect was shown by 8k (56.23 ± 0.09 μM). Compound 8f (161.26 ± 0.23μM) was recognized as a fairly good inhibitor of urease. In view of its inhibition of α-glucosidase, 8o (57.35 ± 0.17μM) was considered a potential therapeutic agent.Conclusion: The results indicate that some of the synthesized products with low toxicity exhibit notable enzyme inhibitory activity against selected enzymes compared with the reference drug, and therefore, are of potential therapeutic interestKeywords: 4-Methyl-1,3-thiazol-2-amine,1,3,4-Oxadiazole,  Cholinesterases, α-Glucosidase, Urease, Brine shrim

Antimicrobial potential of alkaloids and flavonoids extracted from Tamarix aphylla leaves against common human pathogenic bacteria

Background: Alkaloids and flavonoids are secondary metabolites extracted from different medicinal plants. Tamarix aphylla a traditionally valuable medicinal plant; was used for the extraction of alkaloids and flavonoids in order to evaluate their antibacterial activity.Methodology: The leaves of the plant were collected from district Kohat, Pakistan, and their alkaloids and flavonoids were extracted with ethanol and methanol, respectively. Four bacteria i.e. Gram positive (Staphylococcus aureus) and Gram negative (Escherichia coli, Salmonella typhi and Pseudomonas aeruginosa) were selected for the biological screening of these phyto-constituents.Results: The concentration of alkaloids was found to be more in the leaves of Tamarix aphylla than flavonoids. The extracted phytochemicals showed varied inhibition zones against tested bacterial isolates. Alkaloids showed highest inhibitory activity against Staphylococcus aureus (14±0.6 mm) followed by Pseudomonas aeruginosa (13±0.7 mm). Conversely, flavonoids showed the highest inhibitory affect against Salmonella typhi (17±0.7 mm) followed by Staphylococcus aureus (14±0.7 mm). However, both extracts showed the lowest inhibitory effects against Escherichia coli.Conclusions: It was concluded that the alkaloids and flavonoids from Tamarix aphylla leaves have antimicrobial potential against common human bacterial pathogens. However, flavonoids were found to be more active phytochemical against tested bacterial strains as compared to alkaloids.Keywords: Kohat; Medicinal plants; Phytochemical screening; In-vitro activity; Bacterial strains

S-Alkylated/aralkylated 2-(1H-indol-3-yl-methyl)-1,3,4- oxadiazole-5-thiol derivatives. 2. Anti-bacterial, enzymeinhibitory and hemolytic activities

Purpose: To evaluate the antibacterial, enzyme-inhibitory and hemolytic activities of Salkylated/aralkylated 2-(1H-indol-3-ylmethyl)-1,3,4-oxadiazole-5-thiol  derivatives.Methods: Antibacterial activities of the compounds were evaluated using broth dilution method in 96 well plates. Enzyme inhibitory activities assays were investigated against α-glucosidase, butyrylcholinesterase (BchE) and lipoxygenase (LOX) using acarbose, eserine and baicalien as reference standards, respectively. A mixture of enzyme, test compound and the substrate was incubated and variation in absorbance noted before and after incubation. In tests for hemolytic activities, the compounds were incubated with red blood cells and variations in absorbance were used as indices their hemolytic activities.Results: The compounds were potent antibacterial agents. Five of them exhibited very good antibacterial potential similar to ciprofloxacin, and had minimum inhibitory concentrations (MIC) of at least 9.00 ± 4.12 μM against S. aureus, E.coli, and B. subtilis. One of the compounds had strong enzyme inhibitory potential against α-glucosidase, with IC50 of 17.11 ± 0.02 μg/mL which was better than that of standard acarbose (IC50 38.25 ± 0.12 μg/mL). Another compound had 1.5 % hemolytic activity. Conclusion: S-Alkylated/aralkylated 2-(1H-indol-3-ylmethyl)-1,3,4-oxadiazole-5-thiol deviratives with valuable antibacterial, anti-enzymatic and hemolytic activities have been successfully synthesized. These compounds may be useful in the development of pharmaceutical products.Keywords: 2-(1H-Indol-3-ylmethyl)-1,3,4-oxadiazole-5-thiol derivatives, Enzyme inhibition, Antibacterial activity, Hemolytic activity, Molecular dockin

Evaluating the antidiabetic and antioxidant properties of 5- benzyl-1,3,4-oxadiazole-2-thiol

Purpose: To evaluate 5-Benzyl-1,3,4-oxadiazole-2-thiol (OXPA) for antidiabetic and antioxidant properties. Methods: Antidiabetic activity was evaluated using three in vitro models, glucose uptake by yeast cells, alpha amylase inhibition assay and hemoglobin glycosylation inhibition assays. Antioxidant potential was determined by DPPH radical scavenging, reducing power and lipid peroxidation assays. Results: OXPA showed antidiabetic activity in all the three models. The activity of the compound was comparable with that of metronidazole in glucose uptake by yeast cells, but the alpha amylase inhibition activity of the compound was slightly lower than that of acarbose, whereas the hemoglobin glycosylation inhibition activity of the compound was higher than that of vitamin E. DPPH free radical and hydrogen peroxide scavenging activity of the compound was comparable with that of vitamin C. In reducing power assay, the activity of the compound was lower than that of vitamin C (p &gt; 0.05). Conclusion: The results of antidiabetic and antioxidant activity indicate that OXPA may be a drugcandidate for treating both diabetes and its associated oxidative stress