Browsing by Author "Sakhuja, Rajeev"

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Additive-Driven Rhodium-Catalyzed [4+1]/[4+2] Annulations of N-Arylphthalazine-1,4-dione with α-Diazo Carbonyl Compounds
(ACS, 2018-09-05) Sakhuja, Rajeev
A Rh(III)-catalyzed strategy involving the [4+1] annulation of 2-arylphthalazine-1,4-diones with α-diazo carbonyl compounds was developed, accessing a series of unprecedented hydroxy-dihydroindazolo-fused phthalazines in good to excellent yields. By varying the additive, phthalazino-fused cinnolines were synthesized under Rh-catalyzed conditions via [4+2] annulation between the same starting materials. Notably, such two strategies showed a good functional group tolerance and high atom efficiency.
Amino acid appended cholic acid–azobenzene dyad: an effective & smart phase selective gelator for aromatic solvents
(RSC, 2016) Sakhuja, Rajeev
A series of amino acid appended cholic acid–azobenzene dyads have been synthesized and studied for their gelation behaviour. One of the L-alanine based dyads showed excellent gelation behaviour in a variety of solvents at room temperature with minimum gel concentration in the range 0.8% (w/v)–1.8% (w/v). The morphology of the stable gels indicated the formation of a lamellar or a dense sheet network in different solvents. Variable temperature 1H-NMR and FT-IR studies revealed an evident role of intermolecular hydrogen bonding in the self-assembly process. The photo-isomerization between the trans and cis forms of the azobenzene unit was established by UV-visible spectroscopy, and a comparison of 1H NMR and SEM images of the gel and sol forms. In addition, π → π stacking between phenyl groups of azobenzene might have provided an additional driving force for the formation of a dense three-dimensional network capable of phase selective gelation of aromatic solvents from a water/solvent mixture. This selective gelation of aromatic solvents remains unaffected even in the presence of the common salts usually present in water from different sources. The phase selective gelation ability of the dyad was successfully explored towards the removal of toxic fat-soluble rhodamine dye from water and selectively gelatinizing petrol and crude oil from an oil/water mixture at room temperature. Thus, these smart systems possess the potential to be used effectively in water purification and oil-spill remediation.
An Articulate Oxidative Transition-Metal-Free Homocoupling of Imidazo Heterocycles through C(sp2)–C(sp2) Bond Formation
(Wiley, 2017-03-13) Sakhuja, Rajeev
Direct oxidative homocoupling of 2-arylimidazo heterocycles was achieved by using a phenyliodine diacetate-mediated BF3·OEt2-accelerated protocol at room temperature. A series of biimidazo heterocycles were synthesized under ambient conditions without prior activation of the C(sp2)–H bond. The desired biimidazo heterocycles were also obtained by using catalytic amounts of iodobenzene and m-CPBA/AcOH in an organocatalytic fashion.
Aziridine based electrophilic handle for aspartic acid ligation
(RSC, 2018) Sakhuja, Rajeev; Bajaj, Kiran
A one-pot ligation strategy at aspartic acid junctions has been developed by successfully incorporating aziridin-2,3-dicarboxylate to the N-side of a peptide fragment, affording N-aziridine appended peptides, which were ligated in solution phase with a variety of small peptide thio acids to afford native peptides, following a ring-opening/peptidyl migration/desulfurization strategy. The reaction proceeds in a highly regiospecific manner, and provides short native peptides in good isolable yields. A variety of aspartame based peptides were synthesized to showcase the generality of this aziridine based ligation. Computational studies have also been performed to obtain insight about the reaction pathway.
Aziridine-Mediated Ligation at Phenylalanine and Tryptophan Sites
(Wiley, 2017-05-23) Sakhuja, Rajeev; Bajaj, Kiran
An efficient approach towards peptide synthesis that allows easy access to variety of small peptides via one-pot aziridine-mediated ligation/desulfurization strategy has been described. The protocol afforded a library of phenylalanine- and tryptophan-containing α-peptides in good yields by regioselective ring-opening of aziridine-3-aryl-2-carboxylates with peptide thioacids, followed by desulfurization.
Benzotriazole: Much More Than Just Synthetic Heterocyclic Chemistry
(Springer, 2016) Sakhuja, Rajeev
Benzotriazole could be considered as a premium synthetic auxiliary that has been extensively explored for the synthesis of natural and synthetic-based molecules of varied biological and pharmaceutical importance. Much more than heterocyclic compounds, its derivatives have exhibited outstanding properties in medicinal chemistry including anticancer, antifungal, antibacterial, antiviral, antiparasitic, and antioxidative activities. In addition, benzotriazole derivatives have found profound applications as corrosion inhibitors, UV filters, and materials for solar and photovoltaic cells. The aim of this review is to provide an overview of the applications of benzotriazole derivatives in medicinal chemistry and material sciences.
Bile-Acid-Appended Triazolyl Aryl Ketones: Design, Synthesis, In Vitro Anticancer Activity and Pharmacokinetics in Rats
(MDPI, 2021-09-17) Sakhuja, Rajeev; Mazumdar, Samrat; Chitkara, Deepak
A library of bile-acid-appended triazolyl aryl ketones was synthesized and characterized by detailed spectroscopic techniques such as 1H and 13C NMR, HRMS and HPLC. All the synthesized conjugates were evaluated for their cytotoxicity at 10 µM against MCF-7 (human breast adenocarcinoma) and 4T1 (mouse mammary carcinoma) cells. In vitro cytotoxicity studies on the synthesized conjugates against MCF-7 and 4T1 cells indicated one of the conjugate 6cf to be most active against both cancer cell lines, with IC50 values of 5.71 µM and 8.71 µM, respectively, as compared to the reference drug docetaxel, possessing IC50 values of 9.46 µM and 13.85 µM, respectively. Interestingly, another compound 6af (IC50 = 2.61 µM) was found to possess pronounced anticancer activity as compared to the reference drug docetaxel (IC50 = 9.46 µM) against MCF-7. In addition, the potent compounds (6cf and 6af) were found to be non-toxic to normal human embryonic kidney cell line (HEK 293), as evident from their cell viability of greater than 86%. Compound 6cf induces higher apoptosis in comparison to 6af (46.09% vs. 33.89%) in MCF-7 cells, while similar apoptotic potential was observed for 6cf and 6af in 4T1 cells. The pharmacokinetics of 6cf in Wistar rats showed an MRT of 8.47 h with a half-life of 5.63 h. Clearly, these results suggest 6cf to be a potential candidate for the development of anticancer agents
C--H Functionalization of Indazoles
(Wiley, 2022-11) Kumar, Anil; Sakhuja, Rajeev
The indazole is an important class of bicyclic nitrogen-containing heterocycle that forms the core structure of a large number of compounds with potential therapeutic value. Consequently, CH functionalization of this scaffold has been extensively explored using transition metal-catalyzed and metal-free CH functionalization strategies. This article provides a perspective on various strategies that have been developed to add a substituent on this heterocycle core and their appropriate coupling partners.
Carbene-Mediated Transformations of 1-(Benzylideneamino)benzimidazoles
(ACS, 2011-04-11) Sakhuja, Rajeev
Carbene-mediated transformations of N-(3-butylbenzimidazol-3-ium-1-yl)-1-arylmethanimine iodides with carbon disulfide and benzoyl isothiocyanate gave the corresponding NHC·CS2 betaines in 68−85% and benzoyl-[1-butyl-3-[(E)-(aryl)methyleneamino]benzimidazol-1-ium-2-carbothioyl]azanides, respectively, in 74−85% yields. However, reaction with excess isopropyl isothiocyanate in NaH/THF at room temperature yielded the 1-butyl-1′,3′-diisopropyl-3-[(E)-(aryl)methyleneamino]spiro[benzimidazole-2,5′-imidazolidine]-2′,4′-dithiones (74−77%).
The Chemistry of N-Hydroxyamidoximes, N-Aminoamidoximes, and Hydrazidines
(ACS, 2012-02-27) Sakhuja, Rajeev
N-Hydroxyamidoximes, N-aminoamidoximes, and hydrazidines belong to a class of compounds with the general formula RC═NX(NHY) where X = OH or NH2, Y = OH or NH2, and R is a linear side chain, carbocycle residue, or heterocycle residue. Their structures are similar to those of amidoximes and amidrazones, but they possess very different synthetic utility and pharmacological properties. There are several reviews published on the synthetic and biological applications of amidrazones and amidoximes. (1-8) However, a comprehensive review on the preparative methods, synthetic utility, and biological applications is missing for this class of compounds thus far. We now attempt to readdress the situation by providing a detailed compilation on the chemistry of N-hydroxyamidoximes, N-aminoamidoximes, and hydrazidines in terms of the structure, preparative methods, reactivity, and biological applications.
Clickable conjugates of bile acids and nucleosides: Synthesis, characterization, in vitro anticancer and antituberculosis studies
(Elsiever, 2018-11) Sakhuja, Rajeev
A series of clickable bile acid-nucleosides conjugates linked directly or via amino acid linker were synthesized, and characterized by spectroscopic techniques such as 1H NMR, 13C NMR, FT-IR, HRMS and HPLC. The synthesized compounds 6a–p were screened for their in vitro anticancer property against a panel of three cancer cell lines (PC-3, MCF-7, IMR-32). In addition, the synthesized derivatives were also tested for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC 27294 strain). Among the screened compounds, cholic acid-uridine clicked conjugate (6c), and cholic acid-uridine clicked conjugate liked via phenylalanine moiety (6m) were found to be most active against MCF-7 and IMR-32 exhibiting an IC50 value of 8.084 and 8.71 µM, respectively. The antimycobacterial study of the synthesized conjugates revealed all the conjugates to be active with MIC values in the range of 4.09–15.41 µM. Deoxycholic acid-adenosine clicked conjugate (6b) showed most promising antituberculosis property with MIC value of 4.09 µM. Most of the synthesized conjugates were found to be safe at 50 µM against normal human embryonic kidney (HEK 293 T) cell line.
Copper catalyzed direct aerobic double-oxidative cross-dehydrogenative coupling of imidazoheterocycles with aryl acetaldehydes: an articulate approach for dicarbonylation at C-3 position
(Elsiever, 2016-02) Kumar, Anil; Sakhuja, Rajeev
Direct aerobic oxidative cross-dehydrogenative coupling of aryl acetaldehydes at C-3 position of imidazoheterocycles via copper catalyzed reaction resulted in the synthesis of dicarbonylated imidazoheterocycles in 55–85% yields. The methodology provides a straightforward, high yielding and one-pot approach towards the synthesis of C-3 dicarbonylated imidazoheterocycles without prior activation of C(sp2)-H or a base. This also reports the first method of coupling of aryl acetaldehydes on imidazo[1,2-a]pyridine system via double-oxidative cross-dehydogenative process.
Copper-catalysed Csingle bondN/Csingle bondO coupling in water: a facile access to N-coumaryl amino acids and fluorescent tyrosine & lysine labels
(Elsiever, 2016-06) Bajaj, Kiran; Sakhuja, Rajeev
A mild, efficient, ligand free and environmentally benign approach towards the construction of sp2 C-sp3 N bond has been developed via copper catalysed Ullmann type of coupling between 4-chlorocoumarin with N-terminus unprotected amino acids in microwave-aqua conditions, yielding a series of N-coumaryl amino acids in good to excellent yields. Excellent photo-physical properties exhibited by these N-coumaryl amino acids and their chemical applicability as C-terminus coupling partners for N-terminus peptides make them potential fluorescent probes in labelling studies. The methodology was extended towards the Csingle bondO and Csingle bondN coupling for the synthesis of fluorescent coumaryl labelled tyrosine and lysine labels respectively. Application of coumaryl labelled tyrosine was further explored towards the synthesis of fluorescent labelled opioid tetrapeptide, Endomorphin-2 derivative.
Copper-catalysed Csingle bondN/Csingle bondO coupling in water: a facile access to N-coumaryl amino acids and fluorescent tyrosine & lysine labels
(Elsiever, 2016-06-22) Sakhuja, Rajeev; Bajaj, Kiran
A mild, efficient, ligand free and environmentally benign approach towards the construction of sp2 C-sp3 N bond has been developed via copper catalysed Ullmann type of coupling between 4-chlorocoumarin with N-terminus unprotected amino acids in microwave-aqua conditions, yielding a series of N-coumaryl amino acids in good to excellent yields. Excellent photo-physical properties exhibited by these N-coumaryl amino acids and their chemical applicability as C-terminus coupling partners for N-terminus peptides make them potential fluorescent probes in labelling studies. The methodology was extended towards the Csingle bondO and Csingle bondN coupling for the synthesis of fluorescent coumaryl labelled tyrosine and lysine labels respectively. Application of coumaryl labelled tyrosine was further explored towards the synthesis of fluorescent labelled opioid tetrapeptide, Endomorphin-2 derivative.
Design and synthesis of amino acid appended azo dye hybrid: Characterization, solvatochromic and quantum-chemical calculations using experimental and theoretical approach
(Elsiever, 2016-09) Sakhuja, Rajeev; Pant, Debi D.
Amino acid appended azobenzene hybrid was synthesized and characterized using Spectroscopic techniques like 1H NMR, 13C NMR, FT-IR and Mass spectrometry analysis and its optical properties were investigated using UV–vis absorption and fluorescence spectroscopy in solvents of different polarity. Based on solvent refractive index and relative permittivity, by using the theory of solvatochromism, the excited-state (μe) and ground-state (μg) dipole moments was determined for (E)-4-((4-(heptyloxy)phenyl)diazenyl)benzyl((benzyloxy)carbonyl)glycinate (Gly-Azo-O7) based on the variation of Stokes shift as an effect of various solvent's. A bathochromic shift observed in absorption and emission spectra with increasing solvent polarity, which implied that the transition involved is π → π*. The ground state and excited state dipole moments were also calculated and compared using experimental and DFT calculations.
Design and synthesis of spiro[indole-thiazolidine]spiro[indole-pyrans] as antimicrobial agents
(Elsiever, 2011-09-15) Sakhuja, Rajeev
A series of novel spiro[indole-thiazolidine]spiro[indole-pyran] derivatives were synthesized from N-(bromoalkyl)indol-2,3-diones via monospiro-bisindole intermediates; the two indole nuclei being connected via N–(CH2)n–N linker. Synthesized compounds were evaluated for their antimicrobial activities in vitro against three Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, and Staphylococcus epidermis), four Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, and Klebsiella pneumonia) as well as four fungi (Aspergillus niger, Aspergillus fumigatus, Aspergillus flavus, and Candida albicans) using Cup plate method. Bis spiro-indoles exhibited stronger antibacterial and antifungal efficiency than their corresponding mono spiro-indoles. Compound 10e, the most active derivative was shown to inhibit the growth of all bacterial strains and two fungal strains (A. niger and C. albicans)
Design, synthesis, antimicrobial, and DNA gyrase inhibitory properties of fluoroquinolone–dichloroacetic acid hybrids
(Wiley, 2019-10-17) Sakhuja, Rajeev
A series of new fluoroquinolone conjugates 8a–g and 9a–f were synthesized via benzotriazole-mediated synthetic approach with good yield and purity. Some of the synthesized analogs exhibited significant antibacterial properties against Escherichia coli and Staphylococcus aureus with potency higher than that of the parent drugs through in vitro standard bioassay procedure (conjugates 8c and 8d reveal antimicrobial properties with potency 1.9, 61.9, 20.7 and 2.4, 37.1, 8.3 folds relative to the parent antibiotic 6 against E. coli, S. aureus, and Enterococcus faecalis, respectively). The observed experimental data were supported by enzymatic DNA gyrase inhibitory property. Developed BMLR-QSAR model validates the observed experimental data and recognizes the parameters responsible for the enhanced antibacterial properties.
Detection of Hg2+ ions in aqueous medium using an indole-based fluorescent probe: Experimental and theoretical investigations
(Elsiever, 2017-12) Sakhuja, Rajeev; Pant, Debi D.
Mercury pollution is a widespread danger to human health and environment. Due to limitations associated with the existing Hg2+ chemosensors, development of new, efficient and selective chemosensors capable of sensing mercury ions in aqueous medium remains a demanding area of research. In this regard, an indole-based fluorescent probe has been synthesized and characterized by detailed spectroscopic analysis. The probe showed a high selectivity and sensitivity towards Hg2+ by giving significant fluorescence quenching over other tested cations in H2O/DMF (7:3, v/v) medium. The association constant (Ka) was 6.4 × 103 M− 1 between sensor and Hg2+. The detection limit of sensor to Hg2+ was found to be 0.143 μM (143 nM). The experimental results have been verified with Density Functional Theory.
Development of Isatin-Based Schiff Bases Targeting VEGFR-2 Inhibition: Synthesis, Characterization, Antiproliferative Properties, and QSAR Studies
(Wiley, 2022-05) Sakhuja, Rajeev
Three sets of isatin-based Schiff bases were synthesized utilizing the molecular hybridization approach. Some of the synthesized Schiff bases show significant to moderate antiproliferative properties against MCF7 (breast), HCT116 (colon), and PaCa2 (pancreatic) cancer cell lines with potency compared to reference drugs 5-fluorouracil (5-FU) and Sunitinib. Among all, compound 17 f (3-((1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)imino)-1-((1-(2-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-methylindolin-2-one) exhibits promising antiproliferative properties against the MCF7 cancer cell line with 2.1-fold more potency than Sunitinib. However, among all the synthesized compounds, three (5-methylisatin derivatives) were the most effective against HCT116 in comparison to 5-FU. Compound 17 f exhibited the highest anti-angiogenic effect on the vasculature as it significantly reduced BV from 43 mm to 2 mm in comparison to 5.7 mm for Sunitinib and flow cytometry supports the arrest of the cell cycle at G1/S phases. In addition, compound 17 f also showed high VEGFR-2 inhibition properties against breast cancer cell lines. Robust 2D-QSAR studies supported the biological data.
Effect of filler loading on the mechanical properties of crosslinked 1,2,3-triazole polymers
(Wiley, 2010-06-28) Sakhuja, Rajeev
The effect of filler loading on the mechanical properties of crosslinked triazole polymers obtained by polymerization of E300 dipropiolate (1) with diazide (2) obtained from tetraethylene glycol using tetraacetylene functionalized crosslinker (3) was studied systematically. Aluminum (10–14 μm) was used as the primary filler during the formulations; the effect of secondary fillers such as aluminum (<75 μm), NaCl (45–50 and 83–105 μm) was studied with the increase in the total filler loading. The modulus of the aluminum-filled crosslinked triazole polymers increases with the increase in the filler content while using either particle sized aluminum powder. The use of Al (particle size <75 μm) and NaCl (particle size 45–50 μm and 83–105 μm) as secondary or additional fillers while using aluminum (10–14 μm) as the main filler, has a diminishing effect on the modulus and strain of the crosslinked triazole polymers. Triazole polymers described herein have the ability to wet and adhere to large quantities of these inorganic salts and thus maintain mechanical properties of the composite comparable to typical polyurethane elastomeric matrices, regardless of the chemistry of the particulate filler, which imparts an important and necessary binder characteristic for energetic composites