Dimedone Annulated Multi-component Assembly Process (Mcap) An Expeditionary Approach Towards Synthesis And Biological Evaluation Of Six-membered Heterocylces And Enaminones

Ihsan, Ali (2014) Dimedone Annulated Multi-component Assembly Process (Mcap) An Expeditionary Approach Towards Synthesis And Biological Evaluation Of Six-membered Heterocylces And Enaminones. Doctoral thesis, University Of Peshawar, Peshawar.

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Abstract

Multicomponent reactions (MCRs) are convergent reaction, in which three or more substrates of variable complexity react to form a product, where basically all or most of atoms contribute to the newly formed product. The control of selectivity, for example chemo- and regioselectivities, is among the most important objectives in organic synthesis with special emphasis on six-membered functionalized heterocyclic frame work frequently available in a variety of antihypertensive and other drugs. For MCRs, the issue of selectivity is of particular significance due to the high probability of several potential parallel reaction pathways leading to different product classes. „h A piece of research findings presented in this dissertation refers to the development and standardization of dimedone annulated multi-component assembly process that has resulted into production of multi-functional six-membered aza- and oxa-heterocyclic compounds beside enaminones. „h This single-step multi-component assembly process offers a convenient route to generate structural diversity into heterocyclic frame work which may ensure interesting biological and pharmacological properties. „h Subsequently, these heterocyclic compounds and enaminones possessing interesting multi-functional motifs have been screened for different kinds of biological properties. As expected, majority of these compounds have exhibited interesting biological and pharmacological properties. „h Apparently, this synthetic protocol has been partially modified but otherwise derived from the well-known Hantzsch Condensation of four or three components (as the case may be) namely dimedone, appropriately substituted aromatic aldehyde, £]-keto ester and either a substituted 1,3-dicarbonyl system or ammonium acetate gives an easy excess to a diverse range of highly substituted six-membered aza- and/or oxa-heterocycles often known as polyhydroquinolines (PHQs) and xanthenes respectively. „h As regards optimization of experimental conditions for this protocol, choice of a suitable weak base or acid catalyst, appropriate protic solvent, mode of activation energy source such as heating or microwave irradiation beside adjustment of molar ration of dimedone to other partners remained the main players to control acceptable yields of the desired products.As far locally synthesized compounds, initially fifteen known PHQs derivatives besides five new compounds 2(a-t) have been obtained and fully characterized using morpholine and I2 /Al2O3 as a binary catalytic system under microwave irradiation (table 2.1). Furthermore, in order to further this synthetic scheme, compound 2a was structurally modified to hydrophobic alkyl ethers 3(a-c) through alkylation of phenolic component.„h Polyhydroacridines-1,8-diones (PHAs) unit is frequently available in previously reported anti-malarial, antibacterial and anticancer drugs. The reported synthetic protocol for these compounds was further modified using solid-phase synthetic process (tables 2.20 & 2.22) that involved green chemistry. Unlike reported compounds, these compounds 4(a-g) were tested for analgesic, anti-inflammatory and leishmanicidal activities but all remained inert to these assays. „h Substituted 1,4-dihydropyridine is an important class of anti-hypertensive drugs available in the market and several inconvenient methods of their synthesis are available in the literature. We have synthesized and carefully characterized these known compounds through a highly convenient and green protocol (table 2.16).This procedure involves microwave irradiation with shortest possible reaction time beside good to excellent isolated yields.„h Inspired by isolation in minute quantity of structurally interesting intermediate trapped during the synthesis of xanthenes 7(a-j) through a well-known Knoevenagel Condensation followed by Michael Addition reaction, it was extended to a series of such compounds 6(a-l) after modification in experimental conditions.Later on, these compounds were subjected to various biological assays as highlighted in the following paragraph.„h This part of the dissertation demands special attention because the intermediates trapped in the afore-mention procedure were subjected to cyclodehydration that resulted into the formation of substituted xanthenes 7(a-j) reported in table. 3.9.This protocol involves use of moderate recyclable acid catalyst Amberlite IR-120H, acetonitrile as highly coordinating organic solvent under reflux conditions.This procedure has £]-Enaminones are interesting synthetic intermediates and have been widely employed in organic synthesis. In particular, they have been used as synthons of a wide variety of bioactive heterocycles, as well as pharmaceutical compounds having diverse biological potential. Due to their wide range of activity and importance, several methods have been developed but inherit procedural demerits. We have modified the reported protocol using PPA-SiO2 as a catalyst under solvent free conditions and produced a series of functionalized £]-Enaminones 8(a-k), (table 4.3) by condensing dimedone with either substituted aromatic or aliphatic amines in variable isolated yields. Use of chiral aliphatic amines has resulted into a few novel chiral £]-Enaminones 8(g-j). Their biological studies are in process but cannot be included in the thesis at this stage. „h Part-B of the dissertation involves screening of the locally synthesized substituted and poly-functionalized six-membered heterocyclic compounds. Among them, polyhydroquinoline derivatives 2(a-p) were tested for anti-inflammatory, anti-epileptic, analgesic, cytotoxicity, and muscles relaxant activities, besides Protein Tyrosine Phosphatase 1B (PTP1B) inhibition. Based on computational study, compounds 2g (39.19¡Ó0.02), and 2m (37.42¡Ó0.04) exhibited significant PTP1B activities while compounds 2b, 2f, 2i, and 2n remained inactive „h As regards analgesic activity of PHQ derivatives 2(a-p) and 3(a-c) and, variable effects were observed. For instance, among the tested compounds, 3i, 3h, 2f and 2e demonstrated the maximum analgesic activity. Similarly, the above series 2(a-f) and 3(a-c) of synthetic compounds were tested for anti-inflammatory activity by employing carrageenan induced paw edema model. Among the tested compounds 2d, 3b and 2g exhibited significant anti-inflammatory. However, a moderate anti-inflammatory effect was observed with 3c and 2d, while rest of the compounds was devoid of anti-inflammatory potential. Surprisingly, none of these PHQs derivatives showed muscles relaxant, anti-epileptic and cytotoxicity activities.„h During the development and standardization of multi-component assembly process leading to the formation of six-membered heterocyclic compounds, an intermediate (4a)possessing interesting structural features was isolated. Later on, a series of these precursors 4(a-l) possessing variable substituents were synthesized and screened for cytotoxicity and leishmanicidal activities. Among the tested series 4(a-l), compounds 4(b-f) showed potent leishmanicidal activity against Leishmania major (DESTO) promastigotes, while the same series failed to reveal any cytotoxicity.„h Similarly, employing afore-mentioned one-step multi-component assembly process, another series 5(a-j) of six-membered oxa-heterocyclic compounds was synthesized and screened for cytotoxicity and leishmanicidal activities Among them compounds 5(b-f) exhibited potent leishmanicidal activity against Leishmania major (DESTO) promastigotes, while the same series did not show any cytotoxic effect.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: Evaluation, Dimedone, Biological, Annulated, Synthesis, Multi, Component Assembly Process, Enaminones, Expeditionary, Heterocylces
Subjects: Q Science > QD Chemistry
Depositing User: Muhammad Khan Khan
Date Deposited: 09 Sep 2016 10:43
Last Modified: 09 Sep 2016 10:43
URI: http://eprints.hec.gov.pk/id/eprint/1279

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