Synthesis of novel flavones and isoflavones

The primary aim of this project is to synthesize new heterocyclic compounds derived from flavones and isoflavones and thereby, to investigate various methodologies for their synthesis.The biflavonoid, dependensin was a major focus of our study since the benzopyrano[4,3-b]benzopyran ring system present in the natural product was unique and hence, desirable for biological applications. We targeted the acid-catalyzed reactions of 5-methoxy-, 6-methoxy- and 7-methoxyflavenes and found the dimerization to be dependent on the position of the methoxy substituent in the flavene ring. A series of benzopyrano[4,3-b]benzopyrans was generated from the acid-catalyzed reactions of 7-methoxyflavenes and 5,7,8-trimethoxyflavenes.Interestingly, the acid-catalyzed reactions attempted on 5-methoxy- and 6-methoxyflavenes were found to undergo dimerization differently to yield a novel range of biflavonoids containing the tetrahydrochromeno[2,3-b]chromene ring system. A plausible mechanism for the observed rearrangement has also been proposed. The effect of various acids used as catalysts on the dimerization reactions has been evaluated and discussed in this thesis.Similarly, the acid-catalyzed dimerization reactions on isoflavanols and their corresponding isoflavenes were studied in depth and dimerization was found to be dependent on the presence of electron rich substituents in ring B of the isoflavanols and also in performing the reaction in very cold conditions. A probable rationale to this rearrangement has been described.The widespread applications of Mannich bases in medicinal chemistry are noteworthy. Hence, another part of the project was to study the Mannich reactions on flavones using various primary and secondary amines, aminals and amino acids and to probe into the regioselectivity and chemoselectivity of the products obtained. The key point of interest to note was the site of activation in the flavone ring, which was C5 in 6-hydroxyflavones and C8 in 7-hydroxyflavones. The primary amines yielded benzoxazines whereas the secondary amines, aminals and amino acids yielded simple Mannich bases. Further, the benzoxazines were found to undergo cleavage to generate the corresponding simple Mannich bases.Our research group has previously worked on the synthesis of a series of 4-arylflavans and 4-arylisoflavans, but however, there are no reports on the synthesis of 4-arylazaflavans in the literature. Hence, 4-arylazaflavans were synthesized via the acid-catalyzed reactions of azaflavanols with nucleophiles such as naphthol and dimethoxyphenol, whereas 4-heteroarylazaflavans were obtained using heterocycles such as furan, indoles and isoflavenes.Attempts were made to synthesize the corresponding azaflavenes with the primary aim on subjecting them to acid-catalyzed dimerization reactions similar to the flavenes. However, the dominant product isolated was the corresponding quinoline in all cases. Several experiments were conducted in order to oxidize the 4-arylazaflavans to the corresponding quinolines. The optimum conditions were achieved with the use of iodine as catalyst. This introduces a new strategy to the synthesis of 2,4-disubstituted quinolines

Synthesis and antimycobacterial evaluation of newer 1-cyclopropyl-1,4-dihydro-6-fluoro-7-(substituted secondary amino)-8-methoxy-5-(sub)-4-oxoquinoline-3-carboxylic acids

Thirty-four newer 1-cyclopropyl-1,4-dihydro-6-fluoro-7-(substituted secondary amino)-8-methoxy-5-(sub)-4-oxoquinoline-3-carboxylic acids were synthesized from 1,2,3,4-tetrafluoro benzene and evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant M. tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC2) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase. Among the synthesized compounds, 7-(1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinolin-2(1H)-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylic acid (13n) was found to be the most active compound in vitro with MIC of 0.16 and 0.33 μM against MTB and MDR-TB, respectively. In the in vivo animal model 13n decreased the bacterial load in lung and spleen tissues with 2.54 and 2.92 - log10 protections, respectively, at the dose of 50 mg/kg body weight. Compound 13n also inhibited the supercoiling activity of mycobacterial DNA gyrase with IC50of 30.0 μg/ml

Synthesis and antimycobacterial evaluation of newer 1-cyclopropyl-1,4-dihydro-6-fluoro-7-(substituted secondary amino)-8-methoxy-5-(sub)-4-oxoquinoline-3-carboxylic acids

Thirty-four newer 1-cyclopropyl-1,4-dihydro-6-fluoro-7-(substituted secondary amino)-8-methoxy-5-(sub)-4-oxoquinoline-3-carboxylic acids were synthesized from 1,2,3,4-tetrafluoro benzene and evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant M. tuberculosis (MDR-TB) and Mycobacterium smegmatis $(MC^2)$ and also tested for the ability to inhibit the supercoiling activity of DNA gyrase. Among the synthesized compounds, 7-(1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinolin-2(1H)- l)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylic acid (13n) was found to be the most active compound in vitro with MIC of 0.16 and 0.33 \mu M against MTB and MDR-TB, respectively. In the in vivo animal model 13n decreased the bacterial load in lung and spleen tissues with 2.54 and 2.92 - log10 protections, respectively, at the dose of 50 mg/kg body weight. Compound 13n also inhibited the supercoiling activity of mycobacterial DNA gyrase with $IC_{50}$ of 30.0 \mu g/ml

Synthesis and biological activity of novel bis-indole inhibitors of bacterial transcription initiation complex formation

The increasing resistance of bacteria against clinically approved antibiotics is resulting in an alarming decrease in therapeutic options for today's clinicians. We have targeted the essential interaction between bacterial RNA polymerase and σ⁷⁰/σ^A for the development of lead molecules exhibiting a novel mechanism of antibacterial activity. Several classes of structurally related bis-indole inhibitors of bacterial transcription initiation complex formation were synthesized and their antimicrobial activities were evaluated. Condensation of indole-7- and indole-2-carbohydrazides with 7- and 2-trichloroacetylindoles or indole-7- and indole-2-glyoxyloyl chlorides resulted in the successful synthesis of 7,7′-, 2,2′-, 2,7′- and 3,2′-linked bis-indole derivatives with –CO–NH–NH–CO– and –CO–CO–NH–NH–CO– linkers. Indole-7-glyoxyloyl chlorides were reacted with hydrazine hydrate in different ratios to afford respective –CO–CO–NH–NH–CO–CO– bis-indole or hydrazide derivatives. The resulting compounds were found to be active against the β′-CHσ⁷⁰/σ^A_2.2 interaction in ELISA assays and inhibited the growth of both Gram-positive and Gram-negative bacteria. Structure–activity relationship (SAR) studies were performed in order to identify the structural features of the synthesized inhibitors required for biological activity