Synthesis, biological activity and docking calculations of bis-naphthoquinone derivatives from Lawsone.

Some metabolic enzyme inhibitors can be used as Multi-target-Directed-Ligands (MTDL) in Medicinal chemistry therefore, synthesis and determination of alternative inhibitors are essential. In this study, novel bis-napthoquinone derivatives (5a-o) were synthesized through a multi-component cascade reaction of two molecules of 2-hydroxy-1,4-naphthoquinone with an aromatic aldehyde in basic media using triethylamine as a catalyst. This novel heterocyclic derivatives (5a-o) are applied to inhibit the carbonic anhydrase (hCA I and hCA II) isoform in low levels of nano molecules with Ki values exist between 4.62 ± 1.01 to 70.45 ± 9.03 nM for hCA I and for hCA II which is physiologically dominant Kis values are in the range of 5.61 ± 1.04 to 73.26 ± 10.25 nM. Further these novel derivatives (5a-o) efficiently inhibit AChE with Ki values in the range of 0.13 ± 0.02 to 3.16 ± 0.56 nM. The compounds are also applied for BChE with Ki values varying between 0.50 ± 0.10 to 9.23 ± 1.15 nM. For α-glycosidase, the most efficient Ki values of 5e and 5f are 76.14 ± 9.60 and 95.27 ± 12.55 nM respectively. Finally, molecular docking calculations against enzymes (acetylcholinesterase, butyrylcholinesterase, and the human carbonic anhydrase I and II) are compared using biological activities of heterocyclic derivatives. After these calculations, an ADME/T analysis is performed to study the future medicinal use of heterocyclic derivatives from lawsone.

Xanthenone-based hydrazones as potent α-glucosidase inhibitors: Synthesis, solid state self-assembly and in silico studies.

Xanthenone based hydrazone derivatives (5a-n) have been synthesized as potential α-glucosidase inhibitors. All synthesized compounds (5a-n) are characterized by their FTIR, 1H NMR, 13C NMR and HRMS, and in case of 5g also by X-ray crystallographic technique. The compounds unveiled a varying degree of α-glucosidase inhibitory activity when compared with standard acarbose (IC50 = 375.38 ±â€¯0.12 µM). Amongst the series, compound 5l (IC50 = 62.25 ±â€¯0.11 µM) bearing a trifluoromethyl phenyl group is found to be the most active compound. Molecular modelling is performed to establish the binding pattern of the more active compound 5l, which revealed the significance of substitution pattern. The pharmacological properties of molecules are also calculated by MedChem Designer which determines the ADME (absorption, distribution, metabolism, excretion) properties of molecules. The solid state self-assembly of compound 5g is discussed to show the conformation and role of iminoamide moiety in the molecular packing.

Effective plant-endophyte interplay can improve the cadmium hyperaccumulation in Brachiaria mutica.

Soil contamination due to cadmium (Cd) is a ubiquitous environmental problem for which inexpensive remediation alternatives are required. Phytoaccumulation, the use of plants to extract and accumulate heavy metals from the contaminated environment, is such an alternative. In this study, we aimed at establishing effective plant-bacteria interplay between Brachiaria mutica and Cd-resistant endophytic bacteria eventually leading to improved phytoremediation. B. mutica was grown in a Cd-contaminated soil and inoculated with three Cd-tolerant endophytic bacteria individually as well as in combination. Plant physiological parameters, biomass production, bacterial colonization, and Cd-accumulation were observed at four different Cd exposures, i.e., 100, 200, 400 and 1000 mg kg-1 of soil. The combined application of endophytic bacteria was more effective as compared to their individual applications at all concentrations. Nevertheless, highest performance of consortium was seen at 100 mg Cd kg-1 of soil, i.e., root length was enhanced by 46%, shoot length by 62%, chlorophyll content by 40%, and dry biomass by 64%; which was reduced with the increase in Cd concentration. The bacterial population was highest in the root interior followed by rhizosphere and shoot interior. Concomitantly, plants inoculated with bacterial consortium displayed more Cd-accumulation in the roots (95%), shoots (55%), and leaves (44%). Higher values of BCFroot (> 1), and lower values for BCFshoot and TF (< 1) indicates capability of B. mutica to accumulate high amounts of Cd in the roots as compared to the aerial parts. The present study concludes that plant-endophyte interplay could be a sustainable and effective strategy for Cd removal from the contaminated soils.

Pyrazole derivatives of pyridine and naphthyridine as proapoptotic agents in cervical and breast cancer cells.

Cancer is one of the leading causes of death worldwide. The increasing prevalence and resistance to chemotherapy is responsible for driving the search of novel molecules to combat this disease. In search of novel compounds with pro-apoptotic potential, pyrazolo-pyridine and pyrazolo-naphthyridine derivatives were investigated against cervical cancer (HeLa) and breast cancer (MCF-7) cells. The anti-proliferative activity was determined through the MTT assay. Potent compounds were then analyzed for their cytotoxic and apoptotic activity through a lactate dehydrogenase assay and fluorescence microscopy after propidium iodide and DAPI staining. Flow cytometry was used to determine cell cycle arrest in treated cells and pro-apoptotic effect was verified through measurement of mitochondrial membrane potential and activation of caspases. Compounds 5j and 5k were found to be most active against HeLa and MCF-7 cells, respectively. G0/G1 cell cycle arrest was observed in treated cancer cells. Morphological features of apoptosis were also confirmed, and an increased oxidative stress indicated the involvement of reactive oxygen species in apoptosis. The compound-DNA interaction studies demonstrated an intercalative mode of binding and the comet assay confirmed the DNA damaging effects. Finally, potent compounds demonstrated a decrease in mitochondrial membrane potential and increased levels of activated caspase-9 and -3/7 confirmed the induction of apoptosis in treated HeLa and MCF-7 cells. The present work concludes that the active compounds 5j and 5k may be used as lead candidates for the development of lead drug molecules against cervical and breast cancer.

Multicomponent synthesis of pyrido[2,3-b]pyrazine derivatives: electrochemical DNA sensing, nonlinear optical properties and biological activity.

We synthesized novel pyrido[2,3-b]pyrazin based heterocyclic compounds (4-7) and their chemical structures were ascertained by spectral techniques (NMR, FT-IR). Besides experimental investigation, density functional theory (DFT) computations with B3LYP/6-31G(d,p) level of theory were executed to obtain spectroscopic and electronic properties. Nonlinear optical (NLO) properties, frontier molecular orbitals (FMOs), UV-visible, vibrational analysis, natural bond orbitals (NBOs), transition density matrix (TDM) and density of states (DOS) analyses of molecules (4-7) were accomplished at B3LYP/6-31G (d,p) level. Global reactivity parameters (GRPs) were correlated with the band gap (Egap) values; compound 7 with lower Egap (3.444 eV), exhibited smaller value of hardness (1.722 eV) with greater softness value (0.290 eV-1). The dipole moment (µ), average polarizability 〈α〉, first (ßtot) and second 〈γ〉 hyper-polarizabilities were calculated for compounds (4-7). Compound 7 showed less Egap, highest absorption wavelength and remarkable NLO response. The highest 〈α〉, ßtot and 〈γ〉 values for compound 7 were observed as 3.90 × 10-23, 15.6 × 10-30 and 6.63 × 10-35 esu, respectively. High NLO response revealed that pyrido[2,3-b]pyrazin based heterocyclic compounds had very remarkable contributions towards NLO technological applications. Further compounds (4-7) are utilized for the first time in electrochemical sensing of DNA, in vitro antioxidant and antiurease activity.

Synthesis, spectroscopic, SC-XRD/DFT and non-linear optical (NLO) properties of chromene derivatives.

In the present study, we reported the efficient synthesis of novel, heterocyclic, coumarin-based pyrano-chromene derivatives, 2-amino-8-methyl-5-oxo-4-[2-(2-oxo-2H-chromen-3-ylmethoxy)-phenyl]-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (4a) and 2-amino-8-methyl-5-oxo-4-[2-(2-oxo-2H-chromen-3-ylmethoxy)-phenyl]-4H,5H-pyrano[3,2-c]chromene-3-carboxylic acid methyl ester (4b). The chemical structures of synthesized compounds were resolved by employing various spectroscopic techniques like UV-Vis, FT-IR, 1H & 13C NMR, and single crystal X-ray diffraction (SC-XRD) analysis. The compounds; 4a and 4b, with appealing π-bonded skeleton were further analyzed in terms of their electronic and structural aspects using an integral approach of density functional theory (DFT) and time-dependent DFT (TD/DFT). The methodology: M06-2X/6-31G(d,p) level of theory was applied to compare their experimental data with theoretical outcomes using quantum chemical analysis. The frontier molecular orbitals (FMOs) study revealed that, 4a possesses a low band gap (5.168 eV) as compared to 4b (6.308 eV). Global reactivity parameters were associated with E gap values as 4a, with the lowest band gap showed the smaller value of hardness (0.094 eV) and a larger value of softness (5.266 eV). The non-linear optical (NLO) insight exhibited that, the average polarizability 〈α〉 and second hyperpolarizability (γ tot) were observed in 4a as 6.77005 × 10-23 and 0.145 × 104 esu, respectively. Overall, the computational studies suggest that the investigated compounds have distinct NLO properties.

Naphthyridine derived colorimetric and fluorescent turn off sensors for Ni2+ in aqueous media.

Highly selective and sensitive 2,7-naphthyridine based colorimetric and fluorescence "Turn Off" chemosensors (L1-L4) for detection of Ni2+ in aqueous media are reported. The receptors (L1-L4) showed a distinct color change from yellow to red by addition of Ni2+ with spectral changes in bands at 535-550 nm. The changes are reversible and pH independent. The detection limits for Ni2+ by (L1-L4) are in the range of 0.2-0.5 µM by UV-Visible data and 0.040-0.47 µM by fluorescence data, which is lower than the permissible value of Ni2+ (1.2 µM) in drinking water defined by EPA. The binding stoichiometries of L1-L4 for Ni2+ were found to be 2:1 through Job's plot and ESI-MS analysis. Moreover the receptors can be used to quantify Ni2+ in real water samples. Formation of test strips by the dip-stick method increases the practical applicability of the Ni2+ test for "in-the-field" measurements. DFT calculations and AIM analyses supported the experimentally determined 2:1 stoichiometries of complexation. TD-DFT calculations were performed which showed slightly decreased FMO energy gaps due to ligand-metal charge transfer (LMCT).

Regioselective, one-pot, multi-component, green synthesis of substituted benzo[c]pyrazolo[2,7]naphthyridines.

An efficient and environmentally benign synthetic protocol has been developed for the synthesis of benzo[c]pyrazolo[2,7]naphthyridine derivatives through regioselective multi-component "on-water" reaction of isatin, malononitrile and 3-aminopyrazole. The Knoevenagel condensation of isatin with malononitrile resulted in the formation of arylidene, which subsequently underwent Michael addition with 3-aminopyrazole followed by basic hydrolysis, cyclization, decarboxylation and aromatization to give the target naphthyridines in good to excellent yields. The one-pot multi-component protocol was also employed to obtain the said naphthyridines in a lower yield (10-15%) than obtained by basic hydrolysis of spiro-intermediates. The present study shows attractive features such as the use of water as a green solvent, short reaction time, reduced waste products and transition metal free C-C and C-N bond formation. The structures of the synthesized derivatives were established through FTIR, 1H-NMR, 13C-NMR spectroscopy and ESI-mass spectrometry.

Synthesis, Characterization, and In Silico Studies of Novel Spirooxindole Derivatives as Ecto-5'-Nucleotidase Inhibitors.

Ecto-5'-nucleotidase (ecto-5'-NT, CD73) inhibitors are promising drug candidates for cancer therapy. Traditional efforts used to inhibit the ecto-5'-nucleotidase have involved antibody therapy or development of small molecule inhibitors that can mimic the acidic and ionizable structure of adenosine 5'-monophosphate (AMP). Herein, we report an efficient, environment friendly route for the synthesis of non-nucleotide based small molecules, i.e., substituted spirooxindole derivatives 9a-9l and investigated their inhibitory potential on human and rat recombinant ecto-5'-nucleotidase isozymes. These attempts have resulted in the identification of compound 9f (IC50 = 0.15 ± 0.02 µM) inhibitor on h-ecto-5'-NT which showed 280-fold higher inhibition and compound 9h (IC50 ± 0.19 ± 0.03 µM) on r-ecto-5'-NT with 406-fold enhanced inhibition than reference standard sulfamic acid. Moreover, in silico studies were carried out to assess binding interactions of potent compounds within enzyme active sites and demonstrated excellent correlation with the experimental findings.

Thiazolidines: Potential anti-viral agents against avian influenza and infectious bronchitis viruses.

Viral outbreaks are a common cause of morbidity and mortality in livestock and human populations. Lack of good vaccines and poor control measures along with natural viral genetic drifting and shifting are the common causes of new viral strains and outbreaks. The current study reports the synthesis of some 2-aryl substituted thiazolidine-4-carboxylic acids 1a-h and their 3-acetyl 2a and 3-benzoyl derivatives 3a. Two important poultry viruses: Avian influenza virus (AIV; A/Chicken/Italy/1994/H9N2) and infectious bronchitis virus (IBV) were selected, grown in 9-11 days old chicken embryonated eggs , and subjected to in ovo anti-viral assays. Most of the synthesized compounds were found active against AIV subtype H9N2 and IBV. In the case of AIV, the best results were attained for compound 1d which showed an IC50 value of 3.47 µM, while IBV 1c showed IC50 value of 4.10 µM. The lower IC50 values of these compounds correlate with the high potency of these compounds, especially in comparison with control groups. The standard drugs amantadine and ribavarin were used as positive controls in the case of AIV and IBV, respectively. Better results were obtained with 2-aryl substituted thiazolidine-4-carboxylic acids 1a-h compared to their N-acylated derivatives 2a and 3a against both viruses. In conclusion, this preliminary data support the idea that thiazolidine carboxylic acids could be used as anti-viral drugs against AIV and IBV infections.

A facile and concise route to (hydroxybenzoyl)pyrido[2,3-d]pyrimidine heterocycle derivatives: synthesis, and structural, spectral and computational exploration.

In this work, we report the efficient synthesis of novel (hydroxybenzoyl)pyrido[2,3-d]pyrimidine heterocycle derivatives: 6-(2-hydroxy-5-methylbenzoyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (6a), 6-(5-fluoro-2-hydroxybenzoyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (6b), 6-(5-ethyl-2-hydroxybenzoyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (6c) and 6-(2-hydroxy-5-isopropylbenzoyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (6d). The chemical structures of the title compounds were ascertained by spectral techniques including 1H, 13C NMR, UV-visible and FT-IR spectroscopy as well as single-crystal X-ray diffraction analysis. Additionally, density functional theory (DFT) and time-dependent (TD-DFT) computation were adopted to analyze the electronic structures of 6a-d. Compounds 6a-d were computed in the ground state for FT-IR spectroscopic and natural bond orbital (NBO) analysis by DFT/B3LYP with the 6-311+G(d,p) basis set. UV-vis spectroscopic and HOMO and LUMO energy values for 6a-d were determined via TD-DFT/B3LYP with the 6-311+G(d,p) basis set. The optimized geometric parameters, UV-vis findings, and vibrational frequencies indicate good consistency with the experimental data. NBO analysis was conducted to explore the interactions and charge transfer among different orbitals in the title compounds. The HOMO and LUMO band gap (ΔE) values for 6a-d were found to be 3.93, 3.91, 4.10 and 3.91 eV, respectively. Molecular electrostatic potential (MEP) analysis explored the reactivity of the title compounds by predicting their nucleophilic as well as electrophilic sites.