Palladium-catalyzed regioselective synthesis of mono and bis(arylthiol) alkenes from propargyl carbonate and thiophenol.

A palladium catalyzed regioselective reaction of propargylic carbonate with thiophenols and benzene selenol is described. Atom-economic addition of thiols to propargylic carbonates provides an excellent opportunity for effective processes. The reaction proceeds via hydrothiolation to produce mono(arylthiol) alkenes and hydrothiolation followed by Tsuji-Trost type substitution to form bis(arylthiol) alkenes through single and double sequential attack by soft thio nucleophiles by control of the equivalence of thiophenols. This coupling reaction with good tolerance towards functional groups in both propargylic carbonates and thiols furnished a variety of highly functionalized alkenylation products in moderate to excellent yields via the formation of new C-S and C-Se bonds.

Metal-free thiolation of sulfonyl hydrazone with thiophenol: synthesis of 4-thio-chroman and diarylmethyl thioethers.

A simple, efficient, and transition metal-free approach was developed for accessing 4-thio-substituted chroman and diarylmethyl thioethers from sulfonyl hydrazones. This protocol provides straightforward access to a class of diarylmethane derivatives with good to excellent yields. This operationally simple protocol exhibited good tolerance for labile functional groups, providing biologically relevant chemical libraries. This safe and feasible route is applicable to the large-scale synthesis of 4-thio-substituted chromans, which are of great synthetic interest because of their further reaction potential.

A Tandem Semipinacol Rearrangement/Aldehyde Arylation or Alkylation of Trisubstituted 2,3-Epoxy Alcohols with Grignard Reagents for Functionalized 1,3-Diols.

A tandem semipinacol rearrangement/aldehyde arylation or alkylation reaction leading to formation of functionalized 1,3-diols bearing three consecutive tertiary stereocenters is identified from the reaction of various new trisubstituted 2,3-epoxy alcohols with numerous Grignard reagents. This reaction is useful for stereoselective construction of three consecutive tertiary stereocenters. The observed 1,3-diols exist in the anti configuration, which is confirmed by two-dimensional nuclear Overhauser effect spectroscopy, the crystal structure of acetonide of 1,3-diol analogue 3ai, and further density functional theory studies.

Transition metal-free, base mediated one-pot approach for the construction of the benzo[b][1,4,5]oxathiazepine 1-oxide core.

Herein, we have developed a base mediated, transition metal-free intermolecular epoxide ring opening by the nucleophilic attack of ortho-halogenated NH-sulfoximine followed by intramolecular aromatic nucleophilic substitution (SNAr) for the synthesis of separable diastereomers of selected benzo[b][1,4,5]oxathiazepine 1-oxides. Both C-N and C-O bonds are formed simultaneously in a single step. This strategy has a good substrate scope and requires simple reaction conditions (room temperature) and cost-effective reagents, and shows good applicability for accessing sulfoximine analogues of benzoxathiazepine 1-oxide like bioactive skeletons. The absolute configurations of the separable major isomer 4z (R,R), minor isomer 4z' (R,S) and single isomer 4r (R,R,S) were confirmed by 2D NMR. On the other hand, the relative configuration of 4q (S,R) was assigned by 2D NMR along with X-ray crystal data analysis.

Transition metal-free reductive coupling of allylic sulfonylhydrazones with aryl boronic acids for C(sp3)-C(sp2) bond formation.

The reductive coupling between allylic sulfonylhydrazones and aryl boronic acids gives 1,3-diarylpropene systems with good to excellent yields. Simple reaction conditions, high yields, and good functional group tolerance are the salient features of this reaction which takes place without using any transition-metal catalysts and an inert atmosphere. The substituents on aryl boronic acid or allylic sulfonylhydrazone play a role in the isomerization of the double bond. The 3,3-diphenylacrylaldehyde derived allylic sulfonylhydrazone gives almost exclusively a single isomer.

Synthesis, biological evaluation, Structure - Activity relationship studies of quinoline-imidazole derivatives as potent antimalarial agents.

In our efforts to identify novel chemical scaffolds for the development of antimalarial agents, a series of quinoline - imidazole hybrid compounds were synthesized and their blood-stage antimalarial activity was evaluated in both drug-sensitive and -multi drug-resistant (MDR) P. falciparum strains. The new analogs possess sub-micromolar activities against Plasmodium falciparum. Among all synthesized derivatives, 11(xxxii) exhibited significant antimalarial efficacy in-vitro against both CQ-sensitive (IC50-0.14 µM) and MDR strain (IC50- 0.41 µM) with minimal cytotoxicity and high selectivity. Structure-activity relationships revealed that Br and OMe substitutions on quinoline ring improved the antimalarial activity and selectivity index. The role of stereochemistry in the inhibitory activity was assessed by enantiomeric separation of a racemic mixture of 11(xxxii). The enantiomer (-)-11(xxxii) had potent antimalarial activity over the other isomer, with IC50 of 0.10 µM.

Preclinical pharmacokinetics, CYP phenotyping, and tissue distribution study of novel anti-breast cancer candidate S-011-1559.

S-011-1559 is a tyrosine-derived novel benzoxazine CDRI molecule targeted to the oestrogen-related receptor (ER-α/ß) modulator in breast cancer. To explore the pharmacokinetics of S-011-1559, a selective and sensitive bioanalytical method using LC-MS/MS was established and validated in different biological matrices of female rats.Blood-to-plasma ratio and plasma protein binding (PPB) of S-011-1559 were found to be <1 and >97% in both rats and humans, respectively. The human serum albumin (HSA) and alpha-1-acid glycoprotein (AAG) binding was found in the range of > 68 to 45% and >14% respectively. Half-life and intrinsic clearance by microsomal stability study were found to be 28.83 min and 0.05 mL/min/mg in rats, 78.35 min and 0.036 mL/min/mg in humans, respectively. The IC50 value of S-011-1559 against CYP isoforms was revealed to moderately inhibit CYP2D6 by a reversible non-competitive mechanism.Tissue distribution of S-011-1559 on single intravenous injection at 2 mg/kg was found in the order of C lungs > C mammary gland > C spleen > C heart > C kidney > C liver > C brain.The data from the present study provides crucial information about S-011-1559 for further development as a novel potential drug candidate in modulating ER-α/ß receptors of lung and breast neoplasia.

A Comparative Synthetic Strategy Perspective on α-Amino Acid- and Non-Amino Acid-Derived Synthons towards Total Syntheses of Selected Natural Macrolides.

Macrocyclic alkaloids (macrolides) and cyclopeptides have an immense range of applications in drug discovery research because of their natural abundance and potential biological and physicochemical properties. Presently, more than 100 approved drugs or clinical drug candidates contain macrocyclic scaffolds as the biologically active component. This review provides an interesting perspective about the use of amino acid-derived chiral pools versus other methods derived from miscellaneous synthons towards the total synthesis of non-peptidic macrolides. The synthetic routes and the key strategies involved in the total syntheses of ten natural macrolides have been discussed. Both the amino acid-derived and non-amino acid-derived synthetic routes have been illustrated to present a comparative study between the two approaches.

Synthesis of 2-methoxy-3-(thiophen-2-ylmethyl)quinoline containing amino carbinols as antitubercular agents.

We have designed and synthesized 2-methoxy-3-(thiophen-2-ylmethyl)quinoline containing amino carbinols as possible anti-tubercular agents to combat the disease. These molecules were synthesized by tethering amino ether linkage with hydroxyl group to diarylquinoline skeleton; hydroxyl and amine chains were engrafted on diaryl ring. They were evaluated against strain (H37Ra) of Mycobacterium tuberculosis and most of compounds showed in vitro antitubercular activity. Two compounds having diaryl quinoline hydroxyl amino ether scaffold and three compounds having diaryl amino alkyl carbinol core showed activities at 6.25 µg/mL. This study explores diaryl carbinol prototype as inhibitor against Mycobacterium tuberculosis.

Anti-cholinesterase hybrids as multi-target-directed ligands against Alzheimer's disease (1998-2018).

Alzheimer's disease (AD) is a genetically complex, progressive and irreversible neurodegenerative disorder of the brain which involves multiple associated etiological targets. The complex pathogenesis of AD gave rise to multi-target-directed ligands (MTDLs) principle to combat this dreaded disease. Within this approach, the design and synthesis of hybrids prevailed greatly because of their capability to simultaneously target the intertwined pathogenesis components of the disease. The hybrids include pharmacophoric hybridization of two or more established chemical scaffolds endowed with the desired pharmacological properties into a single moiety. In AD, the primary foundation of medication therapy and drug design strategies includes the inhibition of cholinesterase (ChE) enzymes. Hence the development of ChE inhibition based hybrids is the central choice of AD medicinal chemistry research. To illustrate the progress of ChE inhibition based hybrids and novel targets, we reviewed the medicinal chemistry and pharmacological properties of the multi-target molecules published since 1998-December 2018. We hope that this article will allow the readers to easily follow the evolution of this prominent medicinal chemistry approach to develop a more efficient inhibitor.

Diversity oriented synthesis of chromene-xanthene hybrids as anti-breast cancer agents.

A diverse library of chromene-xanthene hybrids were synthesized through intramolecular Friedel-Crafts reaction of the arenoxy carbinols. Examples include first incorporation of amino acid tyrosine into xanthene skeletons with polar functionalities. A careful structural evaluation revealed that tyrosine crafted chromene-xanthene hybrids exhibited good activities against breast cancer cell lines MCF-7, MDA-MB-231. The lead compound 16 displays significant cell cycle arrest at G1 phase and induces apoptosis in MDA-MB-231 cells.

Indium triflate catalysed 3-aza-Cope rearrangement of amino acid derived α,ß-unsaturated esters to alkylidene oxindoles.

The first examples of amino acid derived α,ß-unsaturated esters to Z-alkylidene oxindoles via 3-aza-Cope rearrangement using In(OTf)3 are reported.

Targeting progesterone metabolism in breast cancer with l-proline derived new 14-azasteroids.

Breast cancer cell proliferation is promoted by a variety of mitogenic signals. Classically estrogen is considered as most predominant mitogenic signal in hormone-dependent breast cancer and progesterone is primarily considered to have protective effect. However, it is suggested that some progesterone metabolite may promote breast cancer and progesterone metabolites like 5α-pregnane and 4-pregnene could serve as regulators of estrogen-responsiveness of breast cancer cells. Here, we estimated the potential of alternate targeting of breast cancer via progesterone signalling. l-Proline derived novel 14-azasteroid compounds were screened against MCF-7 and MDA-MB-231 cell lines using MTT assay. In silico studies, cell cycle, Annexin-V-FITC/PI, JC-1 mitochondrial assay, ROS analysis were performed to analyse the impact of hit compound 3b on breast cancer cells. Further, we analysed the impact of hit 3b on the progesterone, its metabolites and enzymes responsible for the conversion of progesterone and its metabolites using ELISA. Data suggests that compound 3b binds and down regulates of 5α-reductase by specifically inhibiting production of progesterone metabolites that are capable of promoting breast cancer proliferation, epithelial mesenchymal transition and migration. This study establishes the proof of concept and generation of new leads for additional targeting of breast cancer.

Synthesis of Hydroxysumanene and Substituent Effect of Hydroxy Group on Bowl Inversion Dynamics and Electronic Structure.

Hydroxysumanene was synthesized from acylsumanenes by Baeyer-Villiger oxidation. DFT calculation predicted the higher bowl inversion energy and deeper bowl structure of hydroxysumanene than those of pristine sumanene. The bowl inversion energy of hydroxysumanene was experimentally determined by 2D-EXSY NMR measurement as 21.2 kcal/mol. The energy was larger than that of pristine sumanene (20.3 kcal/mol), which agreed with the calculation result. Electrochemical measurement indicated the higher HOMO level of hydroxysumanene than that of sumanene, which confirmed the electron-rich character of the phenolic function in the bowl skeleton.

A rapid entry to amino acid derived diverse 3,4-dihydropyrazines and dihydro[1,2,3]triazolo[1,5-a]pyrazines through 1,3-dipolar cycloaddition.

An efficient, general and practical synthesis of diverse 3,4-dihydropyrazines, 6,7-dihydro-[1,2,3]triazolopyrazines and 7,8-dihydro-[1,2,3]triazolodiazepines through intramolecular 1,3-dipolar cycloaddition from amino acid derived common intermediates with high yields is described. Moreover, one-pot access to optically active 3-aryl substituted 6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazines in the palladium-copper co-catalytic system has also been achieved in this work. The easy substrate availability and operational simplicity make the process suitable for further exploration.

Synthesis of enantiomerically enriched indolines and tetrahydroisoquinolines from (S)-amino acid-derived chiral carbocations: an easy access to (3S,4R)-demethoxy-3-isopropyl diclofensine.

Enantiomerically enriched indolines and tetrahydroisoquinolines were synthesized within 5 min to 2 h in high yields from easily accessible (S)-amino acid derived chiral carbocations. The diastereoselective Friedel-Crafts reaction is promoted by a Lewis acid (AlCl3) offering trans-diastereoselectivity. The rate of the reaction and diastereoselectivity of the product are significantly influenced by steric hindrance of the amino acids substituents and aryl groups. The methodology can be applied for the synthesis of the enantiomerically enriched bioactive scaffold (3S,4R)-demethoxy-3-isopropyl diclofensine.

Amino acid chirons: a tool for asymmetric synthesis of heterocycles.

As a result of their easy availability in enantiomerically enriched form and their possession of synthetically transformable diverse functional groups, amino acids have been extensively used by synthetic organic and medicinal chemists as a chiral pool for access to heterocycles (monocycles, bicycles or polycycles, either bridged or fused). This review describes the syntheses of diverse asymmetric heterocycles with various membered rings (n = 3-9) followed by benzo or heteroannulated ones, for the period from 1996 to Dec. 2013. It details solution phase synthetic methodologies in which the naturally occurring α-amino acid is incorporated, totally or partially, into the final product.

Amino acids derived benzoxazepines: design, synthesis and antitumor activity.

Two series of new benzoxazepines substituted with different alkyl amino ethyl chains were synthesized comprising synthetic steps of inter and intramolecular Mitsunobu reaction, lithium aluminium hydride (LAH) reduction, debenzylation, bimolecular nucleophilic substitution (SN2) reaction. The present study investigates the effect of a tyrosine-based benzoxazepine derivative in human breast cancer cells MCF-7 and MDA-MB-231 and in breast cancer animal model. The anti-proliferative effect of 15a on MCF-7 cells was associated with G1 cell-cycle arrest. This G1 growth arrest was followed by apoptosis as 15a dose dependently increased phosphatidylserine exposure, PARP cleavage and DNA fragmentation that are hallmarks of apoptotic cell death. Interestingly, 15a activated components of both intrinsic and extrinsic pathways of apoptosis characterized by activation of caspase-8 and -9, mitochondrial membrane depolarization and increase in Bax/Bcl2 ratio. However, use of selective caspase inhibitors revealed that the caspase-8-dependent pathway is the major contributor to 15a-induced apoptosis. Compound 15a also significantly reduced the growth of MCF-7 xenograft tumors in athymic nude mice. Together, 15a could serve as a base for the development of a new group of effective breast cancer therapeutics.

Transition-Metal-Free Multicomponent Approach to the Regioselective Synthesis of Highly Substituted N-Alkylpyrazoles.

An efficient transition-metal-free multicomponent approach to the regioselective synthesis of highly substituted N-alkylpyrazoles through 1,6-addition of pyrazole (in situ generated from α,ß-unsaturated aldehyde and hydrazide) to para-Quinone Methides has been developed. The N-alkylpyrazole containing triarylmethanes having several heteroaryl rings (quinoline, pyridine, thiophene) at the central methine carbon atom was developed. This chemical process may be used for large-scale synthesis and provides a novel way to produce triarylmethanes with diverse functional groups.

A Synthetic Overview of Benzoxazines and Benzoxazepines as Anticancer Agents.

Benzoxazines and benzoxazepines are nitrogen and oxygen-containing six and seven-membered benzo-fused heterocyclic scaffolds, respectively. Benzoxazepines and benzoxazines are well-known pharmacophores in pharmaceutical chemistry, which are of significant interest and have been extensively studied because of their promising activity against various diseases including their wide range of anticancer activity. Several reports are known for synthesizing benzoxazine and benzoxazepine-based compounds in the literature. Herein this review provides a critical analysis of synthetic strategies towards benzoxazines and benzoxazepines along with various ranges of anticancer activities based on these molecules that have been reported from 2010 onwards. This review also focuses on the structure-activity relationship of the benzoxazine and benzoxazepine scaffolds containing bioactive compounds and describes how the structural modification affects their anticancer activity.