Syntheses of 1,5-Benzothiazepines-Part XXXI: Syntheses and Antimicrobial Studies of 10-Substituted-7- (monochlorophenyl/dichlorophenyl)-6H-6a,7-dihydro-6-phenyl[1]benzopyrano[3,4-c]-[1,5]benzothiazepines

Abstract

Two flavindogenides, 3-(2-chlorobenzylidene)-flavanone and 3-(2,4-dichloro- benzylidene)-flavanone reacted with six 5-substituted-2-aminobenzenethiols, the substituents being fluoro, chloro, bromo, methyl, methoxyl, and ethoxyl, to give respective 12 new compounds, 10-substituted-7-(2-chlorophenyl/2,4-dichlorophenyl)- 6H-6a,7-dihydro-6-phenyl[1]benzopyrano[3,4?c][1,5]benzothiazepines (5a–l) in 60–70% yields. The products were characterized on the basis of microanalytical data for elements and IR, ¹ H, and ¹³ C NMR and mass spectral studies. All the synthesized compounds were evaluated for their antimicrobial activity against the bacteria,Escherichia coli and GFC,and the fungi,Aspergillus niger, Aspergillus flavus,and Curvularia lunata.     

The Mechanism of Thionyl Chloride Reaction with Dialkyl Alkylphosphonothionate Using 31 P NMR

Based on 31 P NMR studies of thionyl chloride reaction with dialkyl alkylphosphonothionates, a method for preparation of alkylphosphonic dichloride has been investigated. A mechanism via intermediacy of ester chloride is suggested.     

Substituted Diorganotin(IV) O,O’-Alkylene Dithiophosphates: Synthesis and Spectral Aspects

Six new substituted diphenyltin(IV) O,O′-alkylene dithiophosphates, (C₆H₅)₂Sn(X)S(S) POGO [G = —CH₂C(CH₃)₂CH₂—, X = Cl (1), SCN (3), ClO₄ (5); G = —CH₂C (C₄H₉)(C₂H₅)CH₂—, X = Cl (2), SCN (4), ClO₄ (6)], were synthesized by the reaction of the corresponding ammonium salts of the O,O’-alkylene dithiophosphates with an appropriate organotin(IV) chloride. The compounds were characterized on the basis of elemental and spectral analyses (ESI mass spectrometry, IR, ¹H, ¹³C, ³¹P, and ¹¹⁹Sn NMR). The presence of a four-coordinated Sn atom and monodentate O,O’-alkylene dithiophosphate moiety in compounds 1–4 as well as bidentate O,O’-alkylene dithiophosphate unit in compounds 5,6 is established.     

Synthesis and Characterization of Dichlorotin(IV)trithiophosphates and Their Adducts with Nitrogen Donor Bases

Abstract

Dichlorotin(IV)trithiophosphates [(RO)P(S)S ₂ ]SnCl ₂ were prepared by the reaction of methanolic solution of SnCl ₄ and dipotassium salt of trithiophosphates in a 1:1 molar ratio and their adducts [(RO)P(S)S ₂ ]SnCl _2.N ₂ C ₁₂ H ₈ and [(RO)P(S)S ₂ ]SnCl _2.N ₂ C ₁₀ H ₈ were prepared by the reaction of methanolic solution of [(RO)P(S)S ₂ ]SnCl ₂ and N-donor bases in a 1:1 molar ratio. These newly synthesised derivatives have been characterized by elemental analysis; molecular weight measurements; and IR, ¹³ C, ³¹ p and ¹¹⁹ Sn NMR spectral studies. Coordination number of four and six was suggested for dichlorotin (IV)trithiophosphates and their adducts with N-donor bases respectively.     

Flow Through Diffusion Cell Method: A Better Approach to Study Drug Release Behavior as Compared to Traditional Dissolution Test Method

Co‐polymeric hydrogels consisting of N‐vinyl‐2‐pyrrolidone (NVP) and acrylic acid (AAc) were synthesized and evaluated for release of a model drug, i.e., vitamin B₁₂. Release studies in simulated gastric fluid (pH 1.2) and intestinal fluid (pH 7.4), at 37°C, showed the hydrogels to be pH sensitive. An in vitro release study by ‘traditional dissolution test’ (TDT) showed that percent drug released from the hydrogel was nearly 8.6±2.1 and 83.2±4.8 in the media of pH 1.2 and 6.8, respectively. However, in order to incorporate in vivo GI conditions such as acidic pH and high water content in the stomach, low water content and the presence of a semi–solid mass in the large intestine, a new test model, called flow through diffusion cell (FTDC) was also used. The two approaches yielded almost different release profiles. The gels were characterized by thermogravimetric analysis and FTIR spectroscopy.     

Feasibility of Polyvinyl Alcohol as a Transdermal Drug Delivery System for Terbutaline Sulphate

A series of terbutaline sulphate drug incorporated polyvinyl alcohol (PVA) matrix films were produced by the solvent evaporation method. The effect of xanthan gum and plasticizers (propylene glycol and dibutyl phthalate) on the rate and amount of drug diffusion from PVA membrane across the hydrated cellophane membrane has been evaluated, using an open glass diffusion‐tube. The obtained films were clear, smooth and flexible having sufficient mechanical strength. The mechanical performance of the dry PVA films with xanthan gum and plasticizers were also ascertained. Polyvinyl alcohol‐xanthan gum blends showed a high rate of drug release compared to that of polyvinyl alcohol film alone. Among the two plasticizers employed, propylene glycol showed better permeability. Among different formulations studied, the formulation PVA/xanthan gum/propylene glycol (F7) was found to be an optimized composition for efficient transdermal delivery of the model drug, terbutaline sulphate. The mechanism of drug diffusion has been evaluated using the Peppas model. Stability studies carried out on polymer‐drug formulations revealed that the drug is stable at 40°C and 75% RH for a period of 6 weeks.     

Dynamic Release of Propranolol HCl from Cationic Ion–Exchanger–Loaded Calcium Alginate Beads

The dynamic release of drug propranolol HCl from the propranolol HCl–resin complex (PRC) loaded calcium alginate beads has been studied in the buffer media of pH 1.2 at the physiological temperature 37°C. The PRC encapsulated beads demonstrated nearly 58.04% release while naked PRC particles released 98.00% drug in 24 h in the gastric fluid. The amount of drug released was found to increase with and decrease in the amount of sodium alginate in the beads. Similarly, with the increase in the amount of entrapped PRC particles within the beads, the quantity of drug released was also observed to increase. The degree of crosslinking of beads also affected the release kinetics. Interestingly, the release from naked PRC particles followed ‘first‐order’ kinetics while PRC particles, entrapped in calcium–alginate beads, exhibited ‘diffusion controlled’ release behavior as indicated by liner nature of fractional release vs. √t plot.     

Molecular Modeling and 3D-QSAR Studies in 2-Aziridinyl-and 2,3-Bis(Aziridinyl)-1,4-Naphthoquinonyl Sulfonate and Acylate Derivatives as Potential Antimalarial Agents

Abstract

Malaria is still continuing to be one of the most dreadful diseases of the tropical countries particularly due to the development of resistance to the existing antimalarials. From observed, antimalarial activity of 2-aziridinyl- and 2,3-bis(aziridinyl)-1,4-naphthoquinonyl sulfonate and acylate derivatives acting through redox cycling mechanism, molecular modeling and three dimensional-quantitative structure activity relationship (3D-QSAR) studies have been carried out on a set of 63 compounds to identify important pharmacophors. Among several 3D-QSAR models generated, three models with correlation coefficient r > 0.82, match > 0.60 and chance = 0.00 have shown two common biophoric sites: one being the oxygen atom at position 1 of the naphthoquinone ring in terms of π-population, charge and electron donating ability while the second being the center of the phenyl ring in terms of its 6π-electrons. In addition to these sites, the models also share two common secondary sites: one positively contributing H-acceptor site while the second site contributing negatively in terms of steric refractivity. All these models showed good agreement between the experimental, calculated and predicted antimalarial activities.     

Synthesis of Some Novel bis‐Spiro[indole‐pyrazolinyl‐thiazolidine]‐2,4′‐diones

The reaction of 1H‐indol‐2,3‐diones with 1,6‐dibromohexane has resulted in the formation of new 1H‐indol‐2,3‐diones‐1,1′‐(1,6‐hexanediyl)bis in quantitative yields. These compounds have been used for the synthesis of novel [3′‐(2,3‐dimethyl‐5‐oxo‐1‐phenyl‐3‐pyrazolin‐4‐yl)spiro[3H‐indol‐3,2′‐thiazolidine]‐2,4′‐dione]‐1,1′‐(1,6‐hexanediyl)bis via bis Schiff's bases, [3‐(2,3‐dimethyl‐5‐oxo‐1‐phenyl‐3‐pyrazolin‐4‐yl) imino‐1H‐indol‐2‐one]‐1,1′‐(1,6‐hexanediyl)bis.     

Aerobic Iron‐Based Cross‐Dehydrogenative Coupling Enables Efficient Diversity‐Oriented Synthesis of Coumestrol‐Based Selective Estrogen Receptor Modulators

An iron‐based cross‐dehydrogenative coupling (CDC) approach was applied for the diversity‐oriented synthesis of coumestrol‐based selective estrogen receptor modulators (SERMs), representing the first application of CDC chemistry in natural product synthesis. The first stage of the two‐step synthesis of coumestrol involved a modified aerobic oxidative cross‐coupling between ethyl 2‐(2,4‐dimethoxybenzoyl)acetate and 3‐methoxyphenol, with FeCl₃ (10 mol %) as the catalyst. The benzofuran coupling product was then subjected to sequential deprotection and lactonization steps, affording the natural product in 59 % overall yield. Based on this new methodology other coumestrol analogues were prepared, and their effects on the proliferation of the estrogen receptor (ER)‐dependent MCF‐7 and of the ER‐independent MDA‐MB‐231 breast cancer cells were tested. As a result, new types of estrogen receptor ligands having an acetamide group instead of the 9‐hydroxyl group of coumestrol were discovered. Both 9‐acetamido‐coumestrol and 8‐acetamidocoumestrol were found more active than the natural product against estrogen‐dependent MCF‐7 breast cancer cells, with IC₅₀ values of 30 and 9 nM , respectively.