Kethiri R. Reddy

Synthesis and activity of carbazole derivatives against Mycobacterium tuberculosis

Infecting one-third of the world’s inhabitants, Mycobacterium tuberculosis (MTB) is deemed a serious public health concern. Failure to follow the current regimen along with the HIV pandemic have led to the emergence of multiple drug-resistant tuberculosis (MDR-TB) strains. The pursuit of more efficacious drugs and prophylaxis is warranted. Findings of some naturally occurring carbazole alkaloids (Figure 1), exhibiting antituberculosis activity, have prompted us to explore further carbazole derivatives for structure–activity relationships. Clausine K or clauszoline J, a natural product isolated independently from several sources, was found to have weak antituberculosis activity (MIC of 100 mgmL 1 against the H37Ra strain). Ma et al. isolated micromeline from the stem bark of Micromelum hirsutum along with some known carbazole alkaloids, and found the MIC to be 31.5 mgmL 1 against M. tuberculosis H37Rv (selectivity index >3). [8] Based on these findings, we screened a series of carbazole alkaloids and derivatives for their in vitro anti-TB activity to find out whether the carbazole framework represents a novel antituberculosis scaffold. The intention of the present study was to identify potent anti-TB active carbazoles and to establish preliminary structure–activity relationships (SAR). Compounds 4a–i were purchased from Sigma Aldrich; 4 j–v and 8–15 were prepared using either the iron-mediated or the palladium-catalyzed approach previously developed by our group (Schemes 1 and 2, Table 1). An electrophilic aromatic substitution of the tricarbonyliron-cyclohexadienylium salts 1 and the arylamines 2 affords functionalized tricarbonyliron complexes 3. The oxidative cyclization of the tricarbonyliron complexes 3 furnishes substituted carbazole derivatives 4. In another approach, the palladium(0)-catalyzed amination of aryl

Transition metals in organic synthesis - Part 83#: Synthesis and pharmacological potential of carbazoles

A series of carbazole derivatives with promising pharmacological properties has been prepared using either an iron-mediated or a palladium-catalyzed synthetic approach. The carbazole alkaloids carbazoquinocin C, carbazomadurin A and B, epocarbazolin A and B, neocarazostatin B, and carquinostatin A are antioxidants acting as free-radical scavengers. Thus, they represent potential lead compounds for the development of novel drugs against diseases initiated by oxygen-derived free radicals. Initiated by the first naturally occurring carbazole alkaloids with antituberculosis (anti-TB) activity, clausine K and micromeline, a study on the structure–activity relationships for anti-TB-active carbazole derivatives has been carried out. The 6-oxygenated carbazoles glycozoline and glycozolinine show antibiotic activity towards several microorganisms. The 7-oxygenated carbazole siamenol exhibits anti-HIV activity.

First enantioselective total synthesis of neocarazostatin B, determination of its absolute configuration and transformation into carquinostatin A

The first enantioselective total synthesis of neocarazostatin B, the determination of its absolute configuration and transformation into carquinostatin A are described.

Anionic (4 2) cycloaddition reactions of dihydropyrazolin-5-one dienolate with dienophiles: a novel approach for substituted and fused indazolones

Dihydropyrazolin-5-one dienolate 2 generated by deprotonation of 2,3-dimethyl-4-formyl-1-phenylpyrazolin-5-one (4-formylantipyrine) is shown to be an efficient anionic pyrazolone α-oxy-o-quinodimethane analog, which undergoes facile cycloaddition with a variety of dienophiles to give substituted indazolones in good yields after dehydration–dehydrogenation of cycloadducts.

Chapter 5 - Chemistry of Carbazole Alkaloids

Publisher Summary The chapter presents a discussion on the chemistry of carbazole alkaloids and summarizes the different synthetic methods. The application of several procedures to the total synthesis of natural products is also discussed. The chapter discusses synthesis of carbazoles by deoxygenation of nitrobiphenyls, synthesis of carbazoles from azidobiphenyls, synthesis of carbazoles by cyclization of 2,2’-diaminobiphenyls, synthesis of carbazoles by cyclization of arylhydrazones, and so on. Cadogan developed a similar deoxygenative cyclization using refluxing triethylphosphite as solvent, and this method remained as the most common procedure for this conversion, which tolerates a variety of substituents on the o-nitrobiphenyls to afford diverse, functionalized carbazole derivatives. The widely accepted mechanism for this transformation involves exhaustive deoxygenation to a singlet nitrene that undergoes a downstream C–H insertion. The preparation of the hydrazone required in the Borsche method was accomplished very conveniently using the Japp–Klingemann reaction. The reaction uses formylcyclohexanone and a diazotized aromatic amine for the synthesis of hydrazone. This chapter also includes a discussion on the total synthesis of simple tricyclic carbazoles and on the tricyclic carbazoles substituted either at the C-ring or at the 9(N)-of the carbazole nucleus.

Chapter 2 - Occurrence, Isolation, and Structure Elucidation

Publisher Summary The chapter presents a study on the occurrence, isolation, and structure elucidation of carbazole alkaloids. A large number of carbazole alkaloids have been isolated from higher plants of the genera Murraya, Glycosmis, and Clausena, all belonging to the family Rutaceae (subtribe Clauseninae, tribe Clauseneae, subfamily Aurantioideae). The occurrence of carbazole alkaloids in these three genera of the Rutaceae is of chemotaxonomic importance and justifies their classification as an independent subtribe. Various monomeric and also bis-carbazole alkaloids, formed by the combination of two of the monomeric units, have been reported from the genus Murraya. The chapter presents information on the natural sources of carbazole alkaloids. Carbazole and various alkylcarbazoles have also been obtained from other sources, such as coal tar, petroleum oil, soil humus, the polluted atmosphere of industrial areas, as well as cigarette smoke. Among the large number of carbazole alkaloids that have been isolated from M. koenigii are also many 2-oxygenated derivatives. The higher plants of the genus Murraya (family Rutaceae), which are trees growing in Southern Asia, are the major source of 1-oxygenated carbazole alkaloids. Clausenapin was isolated from the leaves of C. heptaphylla. Although ekeberginine is an alkaloid closely related structurally to indizoline, it was isolated from two different sources, the stem bark of Ekebergia senegalensis (Meliaceae) and the combined extracts of the stem bark and roots of C. anisata.

Biogenesis of Carbazole Alkaloids

Publisher Summary The chapter presents a study on biogenesis of carbazole alkaloids. A closer examination of all the carbazole alkaloids isolated and studied so far presents several interesting biogenetic features of these molecules. The most important one is the origin of the indole nucleus and of the ring A. With some rare exceptions, the alkaloids having an extra methyl group (or its equivalent) at the 3-position are isolated from higher plants, whereas the others are obtained from several different sources. Based on their natural occurrence, the carbazole alkaloids isolated to date were classified under these two main categories, and their biosyntheses is discussed consequently. The chapter discusses some of the biosynthetic pathways based on rational, delineated proposals. The chapter discusses carbazole alkaloids from higher plants and other sources. The occurrence of 3-methylcarbazole and its oxidative congeners 3-formylcarbazole and methyl carbazole-3-carboxylate, from the taxonomically related genera Murraya, Clausena, and Glycosmis of the family Rutaceae, sub-family Aurantoidae, of higher plants, provides clear evidence for the in vivo oxidation of the methyl group in 3-methylcarbazole. This was supported by the photochemical oxidation of the 3-methyl group of carbazole alkaloids. All of the biogenetic proposals of the carbazole alkaloids isolated from other sources have indicated L-tryptophan has a progenitor. The occurrence of pityriazole, along with malasseziazoles A, B, and C, in the same source—namely, cultures of the human pathogenic yeast Malassezia furfur, indicates a common biogenesis among these structurally diverse carbazole derivatives.

Cuprous bromide-promoted cyclization of ketene N,S-acetals with prop-2-ynyl bromide: synthesis of regiospecifically substituted and annelated 3-acyl(or nitro)-5-methyl pyrroles

Acyclic 10a–h and cyclic 14a–b acyl and nitroketene 12a–bN,S-acetals undergo facile cuprous bromide induced cyclization with prop-2-ynyl bromide to afford 1-substituted-3-acyl(or nitro)-5-methyl-2-(methylsulfanyl)pyrroles 11a–h and 13a–b and the corresponding annelated analogues 15a–b in good yields.