Showing papers by "Venkitasamy Kesavan published in 2018"
TL;DR: A highly enantioselective stereodivergent synthesis of 3-aminooxindole derivatives was accomplished via asymmetric Mannich reaction between 2-substituted benzofuran-3-one and isatin-derived ketimines using readily available cinchona-alkaloid derived organocatalysts.
Abstract: A highly enantioselective stereodivergent synthesis of 3-aminooxindole derivatives was accomplished via asymmetric Mannich reaction between 2-substituted benzofuran-3-one and isatin-derived ketimines. Both anti and syn-selective chiral 3,3-disubstituted amino oxindoles bearing two adjacent tetrasubstituted stereogenic centers with high yield and excellent enantioselectivities were obtained using readily available cinchona-alkaloid derived organocatalysts. The control experiment revealed that oxygen atom present in the benzofuran ring played an important role in switching diastereodivergence. The obtained Mannich product was further transformed into a biologically important 2,3-dihydrobenzofuran derivative having three contiguous stereocenters with no loss of enantioselectivity.
14 citations
TL;DR: Synthesis of drug conjugates with surfactants such as Tween-20 could open up new opportunities to improve the solubility of many drugs, reduce their toxicity and could possibly target the brain as polysorbates known to facilitate nanoparticulate systems to cross the blood-brain barrier.
Abstract: Background Amphotericin B (AmB), a polyene antibiotic used for the treatment of fungal and leishmanial infections is virtually insoluble in water and exhibits severe toxicity. AmB has been conjugated to various soluble polymers for improving its solubility and reducing its toxicity. Conjugating AmB to a polysorbate surfactant such as polyoxyethylene sorbitan monolaurate (Tween 20), was examined to improve its solubility and reduce its toxicity. Methods AmB was coupled to Tween 20 via carbamate linkage at 15 and 30 wt% concentrations in high yield by activating the hydroxyl groups of the surfactant using p- nitrophenyl chloroformate. The conjugates were characterized by using 1H NMR, IR, UV and HPLC analysis and were examined for their toxicity, and anti-fungal and anti-leishmanial activities in vitro. Results Tween-AmB conjugates were soluble to the extent of 10 mg/mL in water, showed improved critical micelle concentration in comparison with AmB, exhibited negligible hemolytic potential even at a concentration of 1000 µM and were not toxic against human embryonic kidney cell line (HEK293T) at similar concentrations. The conjugates showed potent anti-fungal activity against Candida albicans, Candida parapsilosis and Cryptococcus neoformans and anti-leishmanial activity against intramacrophage amastigotes of Leishmania donovani. Conclusions Tween 20 is a surfactant approved by the US FDA as an additive in food and pharmaceutical preparations. Synthesis of drug conjugates with surfactants such as Tween-20 could open up new opportunities to improve the solubility of many drugs, reduce their toxicity and could possibly target the brain as polysorbates known to facilitate nanoparticulate systems to cross the blood-brain barrier.
8 citations
TL;DR: The synthetic application of alkylated phenol derivatives were further demonstrated to biologically important new class of chromene fused spirooxindoles through intramolecular metal-free iodocyclization under mild reaction conditions with broad substrate scope in very good yields.
4 citations
05 Feb 2018
TL;DR: Water-soluble polymeric prodrugs of 2-PQ were synthesized for intravenous administration with the objective of treating patients having severe visceral leishmaniasis with recurrent vomiting, and the new compounds were less active compared to AmBisome® both in vitro and in vivo and the conjugates were not active.
Abstract: 2-n-propylquinoline (2-PQ) is a natural compound having interesting anti-leishmanial activities by the oral route but with a rapid elimination rate. 2-PQ is insoluble in water and therefore cannot be administered intravenously. In this study, water-soluble polymeric prodrugs of 2-PQ were synthesized for intravenous administration with the objective of treating patients having severe visceral leishmaniasis with recurrent vomiting. As 2-PQ has no functional groups for tethering onto a soluble polymer, two amine derivatives of 2-PQ, (E)-2-(3-(2-ammonioethoxy)-3-oxoprop-1-en-1-yl)quinolin-1-ium chloride (1) and (E)-2-(3-(2-ammonioethyl)amino)-3-oxoprop-1-en-1-yl)quinolin-1-ium chloride (2), were synthesized and characterized using 1H and 13C NMR, IR, and mass spectroscopy. Both compounds (1) and (2) were soluble in water. They were tethered onto oxidized polyglucose (PG) at ~ 20 wt% concentration via imine linkages susceptible to hydrolysis. In vitro release at 37 °C into phosphate buffer showed that around 75% of both the compounds was released in 24 h. The parent compounds and their conjugates were evaluated for their anti-leishmanial activity both in vitro, and in vivo in a Leishmania donovani/Balb/c mice model. In vitro, the most active compound was (1) with an IC50 value of 5.67 ± 0.0.44 μg/mL against axenic and 8.34 ± 0.74 μg/mL against intramacrophage amastigotes. In vivo, both compounds (1) and (2) were less active at a dose of 10 mg/kg body weight showing a reduction in parasite burden of 30.2 and 21.7% respectively. The conjugates of (1) and (2) with PG were inactive in vivo. Probably, much higher concentrations of the conjugates and prolonged treatment times are necessary for potential anti-leishmanial activity. 2-n-propylquinoline (2-PQ) is a natural compound having anti-leishmanial activities by the oral route but with a rapid elimination rate. 2-PQ is insoluble in water and therefore cannot be administered intravenously. As 2-PQ has no functional groups, two amine derivatives of 2-PQ were synthesized and conjugated to oxidized polyglucose. The parent compounds and their conjugates were evaluated for their anti-leishmanial activity both in vitro, and in vivo in a Leishmania donovani/Balb/c mice model. The new compounds were less active compared to AmBisome® both in vitro and in vivo and the conjugates were not active. Possibly, multiple injections and prolonged treatment durations are necessary for better in vivo response.
2 citations