الفهرس 
IntroductionOnly 14 pages are availabe for public view
 |  | from | 227 |  |  |
| | | from | 227 | | |
Abstract
This work aimed to the synthesis of some new angular benzochromene and benzochromenopyrimidine derivatives with anticipated pharmacological activities. The present work divided into three parts:Part 1: Synthesis and Reactions of Some New Angular Hydroxybenzo [f]chromene Derivatives In this part, we focused our study on benzo[f]chromene skeleton anchored to the enaminonitrile moiety as a synthon for various heterocyclic compounds with anticipated pharmacological activities. The compound, 2-amino-6-hydroxybenzo[f]chromene-3-carbonitrile, which was utilized as a good precursor, was synthesized via two different pathways. Firstly, the one-pot multicomponent reaction between 2,7-dihydroxynaphthalene, benzaldehyde and malononitrile in the presence of catalytic amount of piperidine as a convenient and high yielding method. The second pathway was pursued that included the domino Michael addition/cyclization reaction between 2,7-dihydroxynaphthalene and benzylidene malononitrile under the same reaction condition to afford the desired precursor. A series of coumarins were synthesized through the treatment of 2-amino-6-hydroxybenzo[f]chromene-3-carbonitrile with different reagents under various conditions including the oxidation, acidic hydrolysis and basic hydrolysis conditions. On the other hand, 2-amino-6-hydroxybenzo[f]chromene-3-carbonitrile was allowed to react with CS2 in the presence of potassium hydroxide to yield the chromeno[d]thiazine derivative. Also, the reaction of 2-amino-6-hydroxybenzo[f]chromene-3-carbonitrile with 2,5-dimethoxytetrahydrofuran in the presence of diluted acetic acid affording the uncommon N-benzochromenyl pyrrole derivative via Clauson-Kaas reaction. O-Allylation of the precursor hydroxybenzo[f]chromene derivative by using allyl bromide in the presence of anhydrous K2CO3 afforded the expected alloxylbenzo[f]chromene derivative. Moreover, treatment of 2-amino-6-hydroxybenzo[f]chromene-3-carbonitrile with the diazonium salts of aniline or 4-chloroaniline under coupling conditions afforded the corresponding aryl diazobenzochromene products. Part 2: Synthesis and Reactions of Some New Benzo[f]chromeno[2,3-d]pyrimidine Derivatives In this part, we synthesized the 4-oxobenzo[f]chromeno[2,3-d]pyrimidine from the previously prepared 2-amino-6-hydroxybenzo[f]chromene-3-carbonitrile through its treatment with acetic anhydride under vigorous heating to yield the corresponding benzo[f]chromeno[2,3-d]pyrimidine derivative. In our study, we utilized POCl3 as simple and efficient chlorinating agent under drastic basic conditions to synthesize the interesting chlorobenzo chromenopyrimidene derivative and its deacetylated compound from the precursor 4-oxobenzo[f]chromeno[2,3-d]pyrimidine. It was very interesting to finely tune the latter reaction conditions in order to get the corresponding chloropyrimidine in highly possible yields. The optimization scenario concluded to the use of POCl3 in the presence of six equivalents of DBU as efficient base to give the chlorobenzochromenopyrimidine derivative in 96% yield and in shorter time (1.5 hr). We studied the substitution chemistry of the chlorine atom in chlorobenzochromenopyrimidene through its treatment with different amines including primary and secondary amines via nucleophilic aromatic substitution reaction SNAr. In the presence of tertiary amines such as triethyl amine the deacetylation process occurred to yield the previously prepared deacetylated product after acidification with HCl. Herein, the compound N-(7-hydroxy-2-methyl-5-phenyl-5H-benzo[f]chromeno[2,3-d]pyrimidin-4-yl) hydrazine was utilized to construct different isolated and condensed heterocyclic nitrogenous systems. By the reaction with different aromatic aldehydes the corresponding aryl hydrazones were produced successfully. In addition, we utilized a classical condensation reaction of acetylacetone with N-(7-hydroxy-2-methyl-5-phenyl-5H-benzo[f]chromeno[2,3-d]pyrimidin-4-yl) hydrazine to afford the expected 4-(1-pyrazolyl)benzochromenopyrimidine derivative. On the other hand, we aimed to design and construct the interesting triazolobenzochromenopyrimidine via reaction of pyrimidinyl hydrazine precursor with DMF-DMA or formic acid to give the corresponding triazolopyrimidine in good yield without separation of any intermediate. Also the treatment of the pyrimidinyl hydrazine with acetic acid afforded the unexpected acetohydrazide derivative. We planned to construct another benzochromenopyrimidine skeleton via refluxing 2-amino-6-hydroxy-4-phenyl-4H-benzo[f]chromene-3-carbonitrile with formamide to give the corresponding 4-aminobenzochromenopyrimidine derivative. The coupling reaction of the phenolic moiety in the 4-aminobenzochromenopyrimidine with the previously prepared aryl or heteroaryl diazonium salts of different aromatic amines yielded the corresponding aryl and heteroaryl diazenyl benzochromenopyrimidine derivatives in good yields. The presence of the homoaryl phenolic moiety was invested to construct different multi-fused heterocyclic compounds. The furobenzo[f]chromenopyrimidine derivative was prepared via the treatment of 4 aminobenzochromenopyrimidine with chloroacetone to yield α-aryloxy acetone derivative that was easily cyclized to the target furobenzo[f] chromenopyrimidine derivative by heating with freshly prepared polyphosphoric acid (PPA). Moreover, reaction of 4-aminobenzochromenopyrimidine with ethyl chloroacetate yielded ethyl α-aryloxyacetate product which underwent the same cyclization protocol by treating with PPA to afford the corresponding angular furobenzochromenopyrimidine derivative.Part 3: Biological Evaluation and Computational Analysis The Antioxidant Activity
The synthesized naphthopyran derivatives were evaluated for their antioxidant activity by using ABTS method and L-Ascorbic acid as a reference antioxidant. Cyanodihydrocoumarin and acetohydrazide showed excellent antioxidant activity. Docking study of acetohydrazide indicated its vast selectivity as antioxidant lead.
The Antimicrobial Activity The prepared compounds were screened for their antimicrobial activity against different microbes using Streptomycin as standard antibiotic. The cyanodihydrocoumarin, 2o amine 17 and 4-aminobenzochromenopyrimidine revealed unique activity indices surpassing activity of the reference antibiotic Streptomycin. Docking study indicated that the 4-aminobenzochromenopyrimidine performed proper recognition at the binding sites with some crucial amino acids through strong hydrogen bond increasing the antibacterial and antifungal properties.