TMEDA-Catalyzed Regioselective Decarboalkoxy C-N Bond Formation: A Unified Direct Access to Indolo[2,1-a]isoquinoline and Dibenzopyrrocoline Alkaloids.

An unprecedented TMEDA-catalyzed, regioselective, decarboethoxy direct C-N coupling protocol towards the synthesis of dibenzopyrrocolines 17 a-i and 5,6-dihydroindolo[2,1-a]isoquinoline 15 a-f/18 a-c alkaloids via the identification of N,N,N',N'-tetramethylethylenediamine (TMEDA) as a homogeneous catalyst is reported. The transition-metal-free, TMEDA-catalytic novel protocol is operationally simple and showed a wide range of functional group tolerance and substrate compatibility. The gram-scale application and synthesis of naturally occurring Cryptaustoline (dibenzopyrrocoline) alkaloid, further highlights the importance and versatile nature of the developed protocol. This finding also offers a TMEDA-catalyzed direct synthesis of dibenzopyrrocolines and substituted 5,6-dihydroindolo[2,1-a]isoquinoline compounds in a one-pot. The probable reaction pathway involves the free-radical sequential approach via a single electron transfer (SET) mechanism.

Biological Evaluation in Resistant Cancer Cells and Study of Mechanism of Action of Arylvinyl-1,2,4-Trioxanes.

1,2,4-trioxane is a pharmacophore, which possesses a wide spectrum of biological activities, including anticancer effects. In this study, the cytotoxic effect and anticancer mechanism of action of a set of 10 selected peroxides were investigated on five phenotypically different cancer cell lines (A549, A2780, HCT8, MCF7, and SGC7901) and their corresponding drug-resistant cancer cell lines. Among all peroxides, only 7 and 8 showed a better P-glycoprotein (P-gp) inhibitory effect at a concentration of 100 nM. These in vitro results were further validated by in silico docking and molecular dynamic (MD) studies, where compounds 7 and 8 exhibited docking scores of -7.089 and -8.196 kcal/mol, respectively, and remained generally stable in 100 ns during MD simulation. Further experiments revealed that peroxides 7 and 8 showed no significant effect on ROS accumulations and caspase-3 activity in A549 cells. Peroxides 7 and 8 were also found to decrease cell membrane potential. In addition, peroxides 7 and 8 were demonstrated to oxidize a flavin cofactor, possibly elucidating its mechanism of action. In conclusion, apoptosis induced by 1,2,4-trioxane was shown to undergo via a ROS- and caspase-3-independent pathway with hyperpolarization of cell membrane potential.

Novel halogenated arylvinyl-1,2,4 trioxanes as potent antiplasmodial as well as anticancer agents: Synthesis, bioevaluation, structure-activity relationship and in-silico studies.

Herein, we have synthesized a series of lipophilic, halogenated-arylvinyl-1,2,4-trioxanes 8a-g (28 compounds) and assessed for their in vitro anti-plasmodial activity in Plasmodium falciparum culture using SYBRgreen-I fluorescence assay against chloroquine-resistant Pf INDO and artemisinin-resistant Pf Cam 3.1R539T (MRA-1240) strains. Alongside, the cell cytotoxic potential of 8a-g has also been determined against the HEK293 cell line in vitro. Out of twenty-eight halogenated-arylvinyl-1,2,4-trioxanes; ten analogues (8a2, 8a4, 8b2, 8b4, 8d4, 8e1, 8e2, 8e4,8f2, and 8g4) have shown potent in vitro antiplasmodial activity with IC50 < 27 nM (IC50 range = 4.48-26.58 nM). Also, the selectivity index (SI) for these ten analogues were found in the range of 72.00-3972.50 which indicates their selective potential towards Plasmodium cells. Results of the cell cycle stage specificity with two of the most potent compounds 8a4 {(IC50 = 4.48 nM; SI = 3972.50) more potent than chloroquine (IC50 = 546 nM; SI = 36.64) and artesunate (IC50 = 6.6 nM; SI = 4333.33)} and 8e2 (IC50 = 9.69 nM; SI = 1348) against Pf INDO indicated all three stages to be the target of the action of 8e2 while only rings and trophozoites appeared to be targeted by 8a4. Ring stage survival assay against artemisinin-resistant Pf Cam 3.1R539T indicated that 8a4 may be well suited to replace artemisinin from current ACTs which are experiencing in vivo delayed parasite clearance. With intraperitoneal (i.p.) and oral (p.o.) route at the dose of 50 mg/kg/day × 4 days; 8a4 has also shown 100% suppression of parasitemia in P. berghei ANKA infected Balb C mice. Further, the in vitro anticancer activity of 8a-g performed against human lung (A549) and liver (HepG2) cancer cell lines as also against immortalized normal lung (BEAS-2B) and liver (LO2) cell lines has revealed that most of the derivatives are endowed also with promising anticancer activity (IC50 = 0.69-15 µM; SI = 1.02-20.61) in comparison with standard drugs such as chloroquine (IC50 = 100 µM; SI = 0.03), artemisinin (IC50 = 100 µM), and artesunic acid (IC50 = 9.85 µM; SI = 0.76), respectively. All the derivatives have shown moderate anticancer activity against liver (HepG2) cancer cell lines. Arylvinyl-1,2,4-trioxanes 8f2 (IC50 = 0.69 µM; SI = 16.66), the most active compound of the series, has shown ∼145 fold more cytotoxic potential with higher selectivity in comparison to reference drugs chloroquine (IC50 = 100 µM; SI = 0.03) and artemisinin (IC50 = 100 µM), respectively against the lung (A549) cancer cell line. Finally, the in-silico docking studies of the potent halogenated 1,2,4-trioxanes along with reference drug molecules against epidermal growth factor receptor (EGFR; PDB ID: 1M17) have demonstrated the strong virtual interaction.

Organocatalyst in Direct C(sp2)-H Arylation of Unactivated Arenes: [1-(2-Hydroxyethyl)-piperazine]-Catalyzed Inter-/Intra-molecular C-H Bond Activation.

This article describes the identification of 1-(2-hydroxyethyl)-piperazine as a new, cost-effective, highly efficient organocatalyst, which promotes both inter- and intra-molecular direct C(sp2)-H arylations of unactivated arenes in the presence of potassium tert-butoxide. While the inter-molecular C-H arylation of unactivated benzenes with aryl halides (Ar-X; X = I, Br, Cl) toward biaryl syntheses underwent smoothly in the presence of only 10 mol % organocatalyst, the intra-molecular C-H arylation catalytic system composed of 40 mol % each of the catalyst and the additive (4-dimethylaminopyridine (DMAP)). The novel catalyst was also able to perform both inter- and intra-molecular direct arylations simultaneously in a single pot. The mechanistic studies confirmed the involvement of aryl radical anions and proceeded via a single-electron-transfer (SET) mechanism. The large substrate scope, high functional group tolerance, competition experiments, gram-scale synthesis, and kinetic studies further highlight the importance and versatile nature of the methodology as well as the compatibility of the new catalyst. To the best of our knowledge, this is the first report on any organocatalyst that reported detailed investigations of both inter- and intra-molecular direct C(sp2)-H arylations of unactivated arenes in a single representation.

Design, Synthesis, Structure-Activity Relationship and Docking Studies of Novel Functionalized Arylvinyl-1,2,4-Trioxanes as Potent Antiplasmodial as well as Anticancer Agents.

A novel series of synthetic functionalized arylvinyl-1,2,4-trioxanes (8 a-p) has been prepared and assessed for their in vitro antiplasmodial activity against the chloroquine-resistant Pf INDO strain of Plasmodium falciparum by using a SYBR green-I fluorescence assay. Compounds 8 g (IC50 =0.051 µM; SI=589.41) and 8 m (IC50 =0.059 µM; SI=55.93) showed 11-fold and >9-fold more potent antiplasmodial activity, respectively, as compared to chloroquine (IC50 =0.546 µM; SI=36.63). Different in silico docking studies performed on many target proteins revealed that the most active arylvinyl-1,2,4-trioxanes (8 g and 8 m) showed dihydrofolate reductase (DHFR) binding affinities on a par with those of chloroquine and artesunate. The in vitro cytotoxic potentials of 8 a-p were also evaluated against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS-2B) and liver (LO2) cell lines. Following screening, five derivatives viz. 8 a, 8 h, 8 l, 8 m and 8 o (IC50 =1.65-31.7 µM; SI=1.08-10.96) were found to show potent cytotoxic activity against (A549) lung cancer cell lines, with selectivity superior to that of the reference compounds artemisinin (IC50 =100 µM), chloroquine (IC50 =100 µM) and artesunic acid (IC50 =9.85 µM; SI=0.76). In fact, the most active 4-naphthyl-substituted analogue 8 l (IC50 =1.65 µM; SI >10) exhibited >60 times more cytotoxicity than the standard reference, artemisinin, against A549 lung cancer cell lines. In silico docking studies of the most active anticancer compounds, 8 l and 8 m, against EGFR were found to validate the wet lab results. In summary, a new series of functionalized aryl-vinyl-1,2,4-trioxanes (8 a-p) has been shown to display dual potency as promising antiplasmodial and anticancer agents.

Synthesis, Bioevaluation, Structure-Activity Relationship and Docking Studies of Natural Product Inspired (Z)-3-benzylideneisobenzofuran-1(3H)-ones as Highly Potent antioxidants and Antiplatelet agents.

For the first time, a series of highly potent natural product inspired substituted (Z)-3-benzylideneisobenzofuran-1(3H)-ones 28a-t, embraced with electron-withdrawing groups (EWG) and electron-donating groups (EDG) at site I and site II, were prepared and assessed for their in vitro antioxidant activities (DPPH free radical scavenging assay) and arachidonic acid (AA)-induced antiplatelet activities using ascorbic acid (IC50 = 4.57 µg/mL) and aspirin (IC50 = 21.34 µg/mL), as standard references, respectively. In this study, compounds 28f-g, 28k-l and 28q have shown high order of in vitro antioxidant activity. Infact, 28f and 28k were found to show 10-folds and 8-folds more antioxidant activity than ascorbic acid, respectively and was found to be the most active analogues of the series. Similarly, Compounds 28c-g, 28k-l, 28o and 28q-t were recognized as highly potent antiplatelet agents (upto 6-folds) than aspirin. Furthermore, in silico studies of the most active antioxidants 28f, 28k and 28l and very active antiplatelet molecules 28f, 28k, 28l and 28s were carrying out for the validation of the biological results. This is the first detailed study of the discovery of several (Z)-3-benzylideneisobenzofuran-1(3H)-ones as highly potent antioxidants and antiplatelet agents.

Artemisinin-derived antimalarial endoperoxides from bench-side to bed-side: Chronological advancements and future challenges.

According to WHO World Malaria Report (2018), nearly 219 million new cases of malaria occurred and a total no. of 435 000 people died in 2017 due to this infectious disease. This is due to the rapid spread of parasite-resistant strains. Artemisinin (ART), a sesquiterpene lactone endoperoxide isolated from traditional Chinese herb Artemisia annua, has been recognized as a novel class of antimalarial drugs. The 2015 "Nobel Prize in Physiology or Medicine" was given to Prof Dr Tu Youyou for the discovery of ART. Hence, ART is termed as "Nobel medicine." The present review article accommodates insights from the chronological advancements and direct statistics witnessed during the past 48 years (1971-2019) in the medicinal chemistry of ART-derived antimalarial endoperoxides, and their clinical utility in malaria chemotherapy and drug discovery.

Recent Developments in Natural Product Inspired Synthetic 1,2,4- Trioxolanes (Ozonides): An Unusual Entry into Antimalarial Chemotherapy.

According to WHO "World health statistics 2018", malaria alongside acute respiratory infections and diarrhoea, is one of the major infectious disease causing children's death in between the age of 1-5 years. Similarly, according to another report (2016) malaria accounts for approximately 3.14% of the total disease burden worldwide. Although malaria has been widely eradicated in many parts of the world, the global number of cases continues to rise due to the rapid spread of malaria parasites that are resistant to antimalarial drugs. Artemisinin (8), a major breakthrough in the antimalarial chemotherapy was isolated from the plant Artemisia annua in 1972. Its semi-synthetic derivatives such as artemether (9), arteether (10), and artesunic acid (11) are quite effective against multi-drug resistant malaria strains and are currently the drug of choice for the treatment of malaria. Inspite of exhibiting excellent antimalarial activity by artemisinin (8) and its derivatives, parallel programmes for the discovery of novel natural and synthetic peroxides were also the area of investigation of medicinal chemists all over the world. In these continuous efforts of extensive research, natural ozonide (1,2,4- trioxolane) was isolated from Adiantum monochlamys (Pteridaceae) and Oleandra wallichii (Davalliaceae) in 1976. These naturally occurring stable ozonides inspired chemists to investigate this novel class for antimalarial chemotherapy. The first identification of unusually stable synthetic antimalarial 1,2,4-trioxolanes was reported in 1992. Thus, an unusual entry of ozonides in the field of antimalarial chemotherapy had occurred in the early nineties. This review highlights the recent advancements and historical developments observed during the past 42 years (1976-2018) focusing mainly on important ventures of the antimalarial 1,2,4-trioxolanes (ozonides).

Ag2O nanoparticle-catalyzed substrate-controlled regioselectivities: direct access to 3-ylidenephthalides and isocoumarins.

Herein, we disclose the first example of an efficient, silver oxide nanoparticle-catalyzed, direct regioselective synthesis of 3-ylidenephthalides 11-16 and isocoumarins 17-20via sonogashira type coupling followed by substrate-controlled 5-exo-dig or 6-endo-dig cyclization reaction, respectively. This one pot coupling involves reaction of substituted 2-halobenzoic acid with meta/para-substituted and ortho-substituted terminal alkynes, which proceeded in a regioselective manner resulting in the formation of 3-ylidenephthalides or isocoumarins, respectively, in excellent yields (up to 95%) with complete Z-selectivity. This protocol features relatively broad substrate scope, mild conditions, operational simplicity, and is favourable with aromatic/alicyclic terminal alkynes. The competition experiments and gram-scale synthesis further highlight the importance and versatility of the methodology. The proposed mechanistic pathways illustrate that the regioselectivity is substantially being controlled by the substituent(s) present on the acetylenic phenyl ring.

New orally active diphenylmethyl-based ester analogues of dihydroartemisinin: Synthesis and antimalarial assessment against multidrug-resistant Plasmodium yoelii nigeriensis in mice.

A new series of ester analogues of artemisinin 8a-f, incorporating diphenylmethyl as pharmacologically privileged substructure, and 8g-j have been prepared and evaluated for their antimalarial activity against multidrug-resistant (MDR) Plasmodium yoelii nigeriensis in Swiss mice via oral route. These diphenylmethyl-based ester analogues 8a-f were found to be 2-4 folds more active than the antimalarial drugs ß-arteether 4 and artesunic acid 5. Ester 8a, the most active compound of the series, provided complete protection to the infected mice at 24 mg/kg × 4 days as well as 12 mg/kg × 4 days, respectively. In this model ß-arteether provided 100% and 20% protection at 48 mg/kg × 4 days and 24 mg/kg × 4 days, respectively.