Gautam Panda

Synthetic Methodologies of Achiral Diarylmethanols, Diaryl and Triarylmethanes (TRAMs) and Medicinal Properties of Diaryl and Triarylmethanes-An Overview

The last decade has witnessed a high demand of various synthetic approaches towards bioactive achiral diarylmethanols, diaryl and triarylmethanes and the molecules derived thereof. Their biological and therapeutical relevancy in diverse areas such as antimicrobials, infectious, cardiovascular and nervous system disorders, genital tract diseases, estrogen related disorders and bone remodeling is quite well known. These small molecules have also been the starting materials for the development of a variety of pharmaceutically important compounds. Compounds belonging to this family have not only played a leading role in the development of small molecules as therapeutically useful compounds but also have become one of the mainstays for the development of organic synthesis. However, a comprehensive review which covers their synthesis as well as their biological activity is still lacking. (Two reviews cover the synthesis of chiral diarylmethanols through asymmetric aryl transfer, and three reviews cover the photochemical properties of triarylmethanes, bioconjugation, application of trityl ions and the use of triarylmethanes as dyes.) This review describes the synthesis as well as the biological activities of this group of molecules that came up in the last fifteen years (1995–2013). The current review will cover the various approaches followed for the synthesis of achiral diarylmethanols and the strategies followed for the synthesis of achiral diaryl as well as triarylmethanes. Finally, we will also cover the bioactivities of molecules containing the diaryl and triaryl methane core.

A new synthesis of corannulene

Flash vacuum pyrolysis of 2-substituted benzo[c]phenanthrene has been exploited as a pivotal step in a new, simple synthesis of the ‘bowl-shaped’ hydrocarbon corannulene 1.

Antiplasmodial Activity of [(Aryl)arylsulfanylmethyl]Pyridine

ABSTRACT A series of [(aryl)arylsufanylmethyl]pyridines (AASMP) have been synthesized. These compounds inhibited hemozoin formation, formed complexes (KD = 12 to 20 μM) with free heme (ferriprotoporphyrin IX) at a pH close to the pH of the parasite food vacuole, and exhibited antimalarial activity in vitro. The inhibition of hemozoin formation may develop oxidative stress in Plasmodium falciparum due to the accumulation of free heme. Interestingly, AASMP developed oxidative stress in the parasite, as evident from the decreased level of glutathione and increased formation of lipid peroxide, H2O2, and hydroxyl radical (·OH) in P. falciparum. AASMP also caused mitochondrial dysfunction by decreasing mitochondrial potential (ΔΨm) in malaria parasite, as measured by both flow cytometry and fluorescence microscopy. Furthermore, the generation of ·OH may be mainly responsible for the antimalarial effect of AASMP since ·OH scavengers such as mannitol, as well as spin trap α-phenyl-n-tertbutylnitrone, significantly protected P. falciparum from AASMP-mediated growth inhibition. Cytotoxicity testing of the active compounds showed selective activity against malaria parasite with selectivity indices greater than 100. AASMP also exhibited profound antimalarial activity in vivo against chloroquine resistant P. yoelii. Thus, AASMP represents a novel class of antimalarial.

Total Synthesis of (−)-Balanol, All Stereoisomers, Their N-Tosyl Analogues, and Fully Protected Ophiocordin: An Easy Route to Hexahydroazepine Cores from Garner Aldehydes

Total syntheses of (-)-balanol and all of its stereoisomers starting from easily available Garner aldehydes are described. Diastereoselective Grignard reactions on Garner aldehydes and ring-closing metatheses are the key steps for the construction of hexahydroazepine subunits. The benzophenone subunits were constructed through coupling of suitably functionalized aromatic aldehyde and bromo components. The synthetic route constitutes a convenient and scalable reaction sequence to generate all of the stereoisomers of balanol. The methodology is explored further for the synthesis of N-tosyl analogues of balanol and of fully protected ophiocordin.

Anti-tumor activity of a new series of benzoxazepine derivatives in breast cancer

A series of new benzoxazepine derivatives substituted with different alkoxy and aryloxy group were synthesized comprising synthetic steps of Mitsunobu reaction, lithium aluminum hydride (LAH) reduction, followed by debenzylation and finally intramolecular Mitsunobu cyclization. The new benzoxazepines specifically inhibited growth of breast cancer cell lines, MCF-7 and MDA-MB-231, but lack cytotoxicity to normal HEK-293 cells. The cell growth inhibition induced by the active compounds was due to cell cycle arrest at G(0)/G(1) phase. The active compound could cause significant reduction in tumor volume of MCF-7 xenograft tumor in nude mice model and their activity was comparable to that of tamoxifen citrate at 16mgkg(-1) dose at 30days of treatment. The identified most active compounds of the series have specific advantages as anti-cancer agent in breast cancer than tamoxifen.

Amino acid based enantiomerically pure 3-substituted benzofused heterocycles: A new class of antithrombotic agents

A diverse group of novel medium ring heterocycles derived from naturally abundant proteinogenic amino acids were evaluated for their potency towards antithrombotic activity. The more potent benzofused oxazepine and oxazocine scaffolds were diversified by incorporating different amino acids at the position number 3. Further the effect of ring size has also been taken into account and it was observed that the eight-membered oxazocines ane more potent compared to the corresponding oxazepines.

Regioselective Ring-Opening of Amino Acid-Derived Chiral Aziridines: an Easy Access to cis-2,5-Disubstituted Chiral Piperazines

An efficient four-step synthetic strategy for cis-2,5-disubstituted chiral piperazines derived from amino-acid-based aziridines is described. The key steps in this strategy are the highly regioselective boron trifluoride diethyl etherate (BF(3)·OEt(2))-mediated ring-opening of less-reactive N-Ts chiral aziridines by α-amino acid methyl ester hydrochloride followed by Mitsunobu cyclization. This protocol has been used in an attempt to construct the piperazine core framework of natural product (+)-piperazinomycin.

Scandium triflate-catalyzed one-pot domino approach towards general and efficient syntheses of unsymmetrical 9-substituted xanthene derivatives

A general and efficient one-pot cascade/tandem approach to synthesize unsymmetrical 9-aryl/heteroaryl xanthenes has been developed under extremely mild reaction conditions using 10 mol% Sc(OTf)(3) as a catalyst. This strategy has been further extended to synthesize 9-(thioaryl) xanthenes through tandem carbon-sulfur (C-S) and carbon-carbon (C-C) bond formation. Novel C-C and C-S bond cleavage promoted by Sc(OTf)(3) is also discussed during mechanistic investigation.

In vivo activity of thiophene-containing trisubstituted methanes against acute and persistent infection of non-tubercular Mycobacterium fortuitum in a murine infection model

OBJECTIVES Mycobacterium fortuitum causes opportunist non-tubercular infection in humans. Chronic infection of M. fortuitum has been clinically documented and requires prolonged chemotherapy. The objectives of this study were to characterize acute and persistent infection of M. fortuitum in a murine infection model and to screen thiophene-containing trisubstituted methanes active against both acute and persistent infection. METHODS A murine infection model of M. fortuitum was used. Bacillary count, bioluminescence, disease symptoms, host immune response, drug susceptibility and mortality were measured. Reactivation of persistent bacilli was induced by dexamethasone. Trisubstituted methanes containing thiophene rings were synthesized and screened in vitro by agar dilution and BACTEC assay and in mice. Cytotoxicity was tested with Vero monkey kidney cells using a resazurin assay. RESULTS The acute infection in mice was marked by a 3 log rise in viable counts, the appearance of disease symptoms and a rise in the Th1 immune response. Bacilli were susceptible to fluoroquinolones. This was followed by persistent infection, in which disappearance of disease symptoms, a decline in Th1 response and non-susceptibility to fluoroquinolones was observed. When the mice were immunocompromised on day 40 post-infection (persistent state) by dexamethasone, a rise in viable counts, symptoms and susceptibility to fluoroquinolones and a prominent Th1 response reappeared. Two lead compounds were found that cleared the mice of bacilli in acute infection and caused a 2.29-2.99 log reduction in cfu of persistent bacilli. CONCLUSIONS The study established acute and persistent infection in mice and identified two promising anti-M. fortuitum compounds with a selectivity index >10.

I2-mediated diversity oriented diastereoselective synthesis of amino acid derived trans-2,5-disubstituted morpholines, piperazines, and thiomorpholines.

Diastereoselective trans-2,5-disubstituted amino acids derived diverse morpholines, piperazines and thiomorpholines were prepared in 30 min-1 h with high yields through iodine-mediated 6-exotrig type cyclization from a single common synthetic intermediate. The displacement of iodine with hydride ion gave a methyl substituent at the 2-position of morpholines which provides an additional opportunity for diversity oriented nucleophilic substitution on the rings as well as incorporation of substituents at the 5-position from amino acids constituents.