Synthesis and reactions of 1-amino-1,5,6,10b-tetrahydroimidazo[2,1-a]isoquinolin-2(3H)-ones

1-Amino-1,5,6,10b-tetrahydroimidazo[2,1-a]isoquinolin-2(3H)-ones, as previously unknown ring-annelated isoquinolines with a 3-aminoimidazolidin-4-one scaffold, were selectively prepared upon reacting 2-carbamoylmethyl- or 2-ethoxycarbonylmethyl-3,4-dihydroisoquinolinium salts with hydrazine hydrate. Acylation of the primary amino group with benzoyl chlorides, followed by reductive ring cleavage of the annelated 4-imidazolidinone ring and final cyclodehydration of the N,N'-diacylhydrazines resulted in the synthesis of 1-methyl-2(5-aryl-[1,3,4]oxadiazol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolines which are of interest due to their potential use as bioisosteres of biologically active N-aryl-2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl) acetamides

N′-(3,5-Dibromo-2-hy­droxy­benzyl­idene)-4-nitro­benzohydrazide methanol monosolvate

The title compound, C14H9Br2N3O4·CH4O, was obtained as the product of the reaction of 3,5-dibromo­salicyl­aldehyde with 4-nitro­benzohydrazide in methanol. The benzohydrazide mol­ecule is nearly planar, with a maximum deviation of 0.126 (2) Å. The mean planes of the two benzene rings make a dihedral angle of 9.3 (3)°. Intra­molecular O—H⋯N and O—H⋯Br inter­actions are observed in the benzohydrazide mol­ecule. In the crystal, pairs of adjacent benzohydrazide mol­ecules are linked by two methanol mol­ecules through inter­molecular O—H⋯O and N—H⋯O hydrogen bonds, forming a dimer

2-Hydroxy-N-(4-Fluorobenzoyl)Benzohydrazide

2-Hydroxy-N-(4-fluorobenzoyl)benzohydrazide was synthesized in two steps using methyl salicylate as the starting material. The reaction took place via microwave-aided hydrazinolysis, followed by acylation using 4-fluorobenzoyl chloride at low temperature to yield the target compoun

Synthesis, spectral LFER and antimicrobial activities of some (E)-N׳-(1-(substituted phenyl)ethylidene)benzohydrazides

About eleven substituted (E)-N׳-(1-(substituted phenyl) ethylidene) benzo- hydrazides have been synthesized. They are characterized by their analytical, ultraviolet, infrared and NMR spectral data. The antibacterial and fungal activities of these chalcones have been evaluated

N′-(5-Bromo-2-hy­droxy­benzyl­idene)-4-nitro­benzohydrazide methanol monosolvate

In the title compound, C14H10BrN3O4·CH4O, the benzohydrazide mol­ecule is nearly planar [maximum deviation = 0.110 (2) Å]. The mean planes of the two benzene rings make a dihedral angle of 8.4 (3)°. In the benzohydrazide mol­ecule, there is an intra­molecular O—H⋯N hydrogen bond and the NH group is hydrogen bonded to the methanol solvent mol­ecule. In the crystal, inter­molecular O—H⋯O hydrogen bonds involving the methanol solvent mol­ecule link the benzohydrazide mol­ecules to form chains which propagate along the a axis

Synthesis and Molecular Docking Studies of N’-benzoylsalicylhydrazide derivatives as antituberculosis through InHA enzym inhibition

The specific aims of this study is to synthesize and to study the possible mechanism of N’-benzoylsalicylhydrazide derivatives as an antituberculosis agent through InhA (Enoyl acyl carrier protein reductase) inhibition using in silico method. Five analogues of N’-benzoylsalicylhydrazide were synthesized using microwave irradiation from methyl salicylate as starting material, which yielded 80-90% product on average. This indicates a considerable improvement in terms of effectivity and efficiency, compared to the more conventional method using reflux condition. Character-ization of the compounds were subsequently carried out by UV, FTIR, 1H-NMR, 13C-NMR spectroscopy, which confirmed that the compounds had been successfully synthesized. Ultimately, molecular docking was performed using Molegro Virtual Docker (MVD) on the active site of InhA enzyme to predict the activity of the compounds. The results showed that all compounds performed comparatively well against N-(4-Methylbenzoyl)-4-benzylpiperidine as the native ligand and also yielded lower docking score than isoniazide (INH). From this study it can be concluded that N’-benzoylsalicylhydrazide derivatives could be synthesized using microwave irradiation with good product yield and all of the synthesized analogues are suggested to possess antituberculosis activity via InhA enzyme inhibition. In vitro activity will have to be determined in the future to validate whether N’-benzoylsalicylhydrazide derivatives perform well as a potential antituberculosis agent

SYNTHESIS OF SOME NEW HETEROCYCLIC COMPOUNDS DERIVED FROM N-(Ñ-PHENYL GLYCYL) SACCHARIN AND STUDY THEIR BIOLOGICAL ACTIVITY

Objective: In the present work, a variety of new heterocyclic compounds namely aza-β- lactam, cyclicimides, 1,3-thiazole, and 1,2,4-triazole.Methods: Procedure includes the synthesis of aza-β- lactam, cyclic imides, 1,3-thiazole, and 1,2,4-triazole. The synthesis was carried out in eleven steps using N-(Ñ-substituted phenylglycyl) saccharin derivatives (1a,b) as a starting material and converted to benzoic acid derivatives (2a,b) and then to ester derivatives (3a,b), which finally convers to benzohydrazide derivatives (4a,b). The cyclization of (4a,b) with carbon disulfide and hydrazine hydrate (80%) in the presence of potassium hydroxide gives 1,2,4-triazole compounds (5a,b), and subsequently (5a,b) derivatives reacted with different aromatic aldehydes in the presence of few drops of glacial acetic acid to give Schiff bases (6a-f). Compounds (7a-b) was prepared by the reaction of compounds (4a,b) with chloroacetyl chloride. 1,3-thiazole derivatives (8a,b) were synthesized through the cyclization of compounds (7a,b) with thiourea. Schiff bases (9a-f) were obtained by condensation of (4a,b) with different aromatic aldehydes in the presence of few drops of glacial acetic acid. Aza-β-lactam compounds (10a-f) were prepared by the cycloaddition of Schiff-bases (9a-f) with phenyl isocyanate through [2+2] cycloaddition reaction. Reaction (4a,b) with various acid anhydrides in presence of acetic acid gave the corresponding cyclic imide (11a-f). The newly prepared.Results: The results showed that compounds (5a) and (10e) have a good activity against Gram-positive bacterium and no activity against Gram-negative bacterium, compared to standard drugs (ciprofloxacin and amoxicillin), while compounds (8a) and (6b) have a high activity against fungi, compared to standard drugs (metronidazole benzoate), and the other tested compounds have low-to-moderate activity.Conclusion: 1,2,4-triazole is a most potent assemblage of Gram-positive bacterium retardants and cyclic imides are a most potent assemblage of fungi retardants

Synthesis and Biological Evaluation of Benzimidazoles as Target for α-Glucosidase Inhibitors

Diabetes mellitus is rising globally touching more than 180 million people worldwide. This is prevailing mostly in type 2 diabetes and according to WHO report the incidence is likely to be more than doubled by 2030. α-glucosidase inhibitors work by reducing the amount of glucose that the intestines absorb from food. In our previous work, forty-five benzimidazoles analogues were studied using 3D QSAR, HQSAR, and Pharmacophore mapping and based on their results 60 compounds were designed. Docking studies of those designed compounds showed that most of the compounds are bonding with important amino acids LEU 520, ARG 335 and ASP 69 through hydrogen bonds and steric interaction. In this work, synthesis of eleven compounds was done on the basis of molecular docking studies. Compounds containing hydroxyl and alkyl groups (compound no. 3, 9 and 10) were found to be five to eight folds more active with IC90 values in the range of 6.02 ± 1.10 to 33.25 ± 1.20 µg/ml, in comparison with the standard drug, Acarbose (IC90= 290.55 ± 0.081 µg/ml). Thus, these compounds after the toxicity studies could be of therapeutic use in treating diabetes. Keywords: Acarbose, Alpha-glucosidase inhibition, Benzimidazoles, Docking, Molecular modelling, Post-prandial hyperglycemi

RATIONAL DESIGN, SYNTHESIS, AND CHARACTERIZATION OF NOVEL mPGES-1 INHIBITORS AS NEXT GENERATION OF ANTI-INFLAMMATORY DRUGS

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are currently widely used as fever and pain relief in patients with arthritis and other inflammatory symptoms. NSAIDs effect by inhibiting cyclooxygenase-1 (COX-1) and/or cyclooxygenase-2 (COX-2). COX isozymes (COXs) are key enzymes in the biosynthesis of prostaglandin H2 (PGH2) from arachidonic acid (AA). It is now clear that prostaglandin E2 (PGE2), one of the downstream products of PGH2, is the main mediator in both chronic and acute inflammation. Microsomal prostaglandin E synthase (mPGES-1) is the terminal enzyme of COX-2 in the PGE2 biosynthesis pathway. Different from other two constitutively expressed PGE2 synthase (PGES), mPGES-2 and cPGES, mPGES-1 is induced by pro-inflammatory stimuli and responsible for the production of PGE2 related to inflammation, fever and pain. For these reasons, selective inhibition of mPGES-1 is expected to suppress inflammation induced PGE2 production and, therefore, will exert anti-inflammatory activity while avoid the side effects of COXs inhibitors, such as gastrointestinal (GI) toxicity, and cardiovascular events. A combination of computational and experimental approaches was used to discovery mPGES-1 inhibitors with new scaffolds. The methods used include molecular docking, molecular dynamic simulation, molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculation, and in vitro activity assays. Our large-scale structure-based virtual screening was performed on compounds in the NCI libraries, containing a total of ~260,000 compounds. 7 compounds have been determined for their IC50 values (about 300 nM to 8000 nM). What’s more, these new inhibitors of mPGES-1 identified from virtual screening did not shown significant inhibition against COX isozymes even at substantially high concentrations (e.g. 100 µM). Rational methodology for drug design and organic synthesis were applied to generate three series of mPGES-1 inhibitors with different scaffolds. In total, about 200 compounds were synthesized and tested for their in vitro inhibition against human mPGES-1. Compounds with high potency against human mPGES-1 were further screened for their inhibition against mouse mPGES-1 and selectivity of human mPGES-1 over COXs. Several compounds were identified as submicromolar inhibitors against human mPGES-1 with high selectivity over COXs. In general, we have successfully identified a library of compounds as potent mPGES-1 inhibitors without significant inhibition against COXs. Structure information and in vitro activity evaluation data generated from the virtual screening and the library of compounds will be used to guide future design and synthesis of the mPGES-1 inhibitors