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Abstract

ABSTRACT This dissertation comprises of three chapters: The work described in this dissertation involves the design, synthesis, and biological evaluation of novel bi-heterocyclic molecules on soluble support using focused microwave irradiation. In Chapter 1, section A, we report the design of an efficient liquid-phase method for the parallel synthesis of substituted benzimidazolylbenzoxazols using focused microwave irradiation and subsequent bioactivity. A key step in this approach involves the attachment of 4-hydroxy-3- nitrobenzoic acid to polymer immobilized o-phenylenediamine. Mild acidic conditions then promote a ring closure and subsequent reduction to form substituted benzimidazole derivative. The so formed benzimidazole derivatives underwent efficient ring closure with various alkyl, aralkyl, aryl, heteroaryl and unsaturated isothiocyanates to generate the benzimidazolylbenzoxazols. The derived polymer-bound compounds were finally cleaved from the support with KCN in methanol at room temperature resulted in the generation of molecular library with two points of structural diversity (Section A). Interestingly, all the members of the molecular library exhibited moderate to high inhibition against VEGFR-3. This novel synthetic methodology offers an easy access to benzimidazolylbenzoxazols on soluble polymeric support, from which a new class of anti-cancer drugs may be developed. xii N N R1 O O NH2 F R2 O R2 1. PTSA, Toluene 2. KCN/MeOH N N R1 O O N R2 R2 N N R1 NH HN O O O R2 6 examples 80-99% ee O O NH2 NH R1 PEG 2 O HO NO2 F HCl.H2N R2 O O + Section B involves the focused microwave irradiation to a multistep synthetic sequence of reactions designed to generate benzimidazolyl quinoxalinones using a soluble polymer support. They were obtained by the ipso-fluoro (SNAr) displacement of the immobilized ortho-nitro fluoro benzimidazoles with chiral alpha amino esters under microwave irradiation. When subjected to neutral reduction, intermediate chiral organic-polymer conjugates underwent a spontaneous intramolecular ring closure. Cleavage of the polymer support, at room temperature did not cause any significant racemization resulting in the generation of a chiral molecular library with two points of structural diversity (Section B). Section C involves the synthesis of Benzazepines, the subject of our interest having sevenmembered aza-heterocyclic ring fusing aromatic unit, are of considerable interest owing to their varied biological activities. Polymer anchored 3-amino-4-fluorophenyl benzimidazole derivatives underwent intramolecular cyclisation with 1,3-disubstituted 2-butenone to generate the polymer anchored benzazepine derivatives. Subsequent cleavage from polymer support results the formation of architecturally diverse seven member heterocyclic molecules (Section C). xiii O HO ABz O OTBDMS P O O O T O O O O NC + O DMTO ABz O OTBDMS P O O O T O P O NC NC O N 5'-OHABz o=pTo=pABz o=pT-3'-O-Lev In chapter 2, we have developed a general procedure for the solution-phase synthesis of chimeric oligonucleotides (oNA) analogues using readily available phosphoramidite reagents with 2+2 and 3+3 protocol. The key feature of this method is using the solution-phase phosphoramidite procedure to assemble linear oligonucleotide sequences and sequential removal of 3΄ levulinyl group as well as 5΄ dimethoxytrityl group without the contamination of n−1 or shorter failures. This methodology offers an easy access to the scale up synthesis of oligonucleotides for clinical as well as commercial purposes. In Chapter 3, of section A, approaches towards the synthesis of 2-(substituted amino) benzimidazoles derivatives under focused microwave irradiation are described. Ionic liquid were employed as soluble support. Ionic liquid bound 4-fluoro-3-nitro benzoic acid underwent nucleophillic substitution reaction with various primary amines which after reduction and subsequent cyclisation with various isothiocyanates generates the desired compounds in high purity and yields. In the same way an alternative strategy on ionic liquid support for the parallel synthesis of thioanlogues of benzoxazol derivatives under focused microwave irradiation. Herein, we have replaced the NH group of R2 in chapter 1 of section A with sulphur analogues. A series of 16 member library were successfully synthesized with two structural variability present on benzoxazol moiety. xiv MW NH NHBOC OH O N + N OH BF4 - NH N N O O O O R1 R2 N N NHR2 R1 O O R2NCS N N R1 O O O N S R2 Section B develops the novel ionic-liquid supported synthetic protocol for hydantoin analogs tethered with azepino[4,5-b]indoles by the use of focused microwave irradiation. Ionic liquid bound tryptophan underwent Pictet-Spengler reaction and subsequent basification with various keto esters to generate the ionic liquid immobilized azepino[4,5-b]indoles. The so formed azepino[4,5-b]indole derivatives underwent cyclisation with various isocyanates to generate the three dimensional molecular architecture in traceless fashion (Section B).