Multiband LFM waveform generation and band-selection using stimulated Brillouin scattering.

Modern radar systems are designed to simultaneously serve multiple applications such as ranging, surveillance, imaging, or warfare, which necessitates operation at multiple carrier frequencies. Linear frequency modulated (LFM) signals are inherently capable of pulse compression leading to enhanced range resolution and good signal-to-noise ratios; therefore, they are widely employed in various radar applications. In this paper, a photonic-based generation scheme for carrier frequency multiplication of LFM waveforms up to a factor of four through a single dual-drive Mach-Zehnder modulator is proposed and experimentally demonstrated. The technique is employed to produce multiband LFM having wide-bandwidth chirps (500 MHz, 1 GHz) as well as narrow bandwidth chirps (10, 20 MHz) that are compatible with the intrinsic linewidth of stimulated Brillouin scattering (SBS). The frequency bands of the narrow bandwidth chirps are further selected through a frequency-agile Brillouin RF filter. The generated tupled chirped waveforms are at continuous multiples of the RF carrier frequency at 2, 4, 6, and 8 GHz, respectively, with the first three multiples having 10 MHz and the fourth multiple having 20 MHz chirp bandwidth. This scheme is also experimentally verified for generating different tupled products and respective filtering through SBS at multiples of 4 GHz up to 16 GHz, thereby verifying the system's agility and flexibility.

Insight into Structure Activity Relationship of DPP-4 Inhibitors for Development of Antidiabetic Agents.

This article sheds light on the various scaffolds that can be used in the designing and development of novel synthetic compounds to create DPP-4 inhibitors for the treatment of type 2 diabetes mellitus (T2DM). This review highlights a variety of scaffolds with high DPP-4 inhibition activity, such as pyrazolopyrimidine, tetrahydro pyridopyrimidine, uracil-based benzoic acid and esters, triazole-based, fluorophenyl-based, glycinamide, glycolamide, ß-carbonyl 1,2,4-triazole, and quinazoline motifs. The article further explains that the potential of the compounds can be increased by substituting atoms such as fluorine, chlorine, and bromine. Docking of existing drugs like sitagliptin, saxagliptin, and vildagliptin was done using Maestro 12.5, and the interaction with specific residues was studied to gain a better understanding of the active sites of DPP-4. The structural activities of the various scaffolds against DPP-4 were further illustrated by their inhibitory concentration (IC50) values. Additionally, various synthesis schemes were developed to make several commercially available DPP4 inhibitors such as vildagliptin, sitagliptin and omarigliptin. In conclusion, the use of halogenated scaffolds for the development of DPP-4 inhibitors is likely to be an area of increasing interest in the future.

Design, Synthesis, Molecular Docking, and Anticancer Evaluation of Pyrazole Linked Pyrazoline Derivatives with Carbothioamide Tail as EGFR Kinase Inhibitors.

BACKGROUND: The Epidermal Growth Factor Receptor (known as EGFR) induces cell differentiation and proliferation upon activation through the binding of its ligands. Since EGFR is thought to be involved in the development of cancer, the identification of new target inhibitors is the most viable approach, which recently gained momentum as a potential anticancer therapy. OBJECTIVE: To assess various pyrazole linked pyrazoline derivatives with carbothioamide for EGFR kinase inhibitory as well as anti-proliferative activity against human cancer cell lines viz. A549 (non-small cell lung tumor), MCF-7 (breast cancer cell line), SiHa (cancerous tissues of the cervix uteri), and HCT-116 (colon cancer cell line). METHODS: In vitro EGFR kinase assay, in vitro MTT assay, Lactate dehydrogenase release, nuclear staining (DAPI), and flow cytometry cell analysis. RESULTS: Compounds 6h and 6j inhibited EGFR kinase at concentrations of 1.66µM and 1.9µM, respectively. Furthermore, compounds 6h and 6j showed the most potent anti-proliferative results against the A549 KRAS mutation cell line (IC50 = 9.3 & 10.2µM). Through DAPI staining and phase contrast microscopy, it was established that compounds 6h and 6j also induced apoptotic activity in A549 cells. This activity was further confirmed by FACS using Annexin-V-FITC and Propidium Iodide (PI) labeling. Molecular docking studies performed on 6h and 6j suggested that the compounds can bind to the hinge region of ATP binding site of EGFR tyrosine kinase in a similar pose as that of the standard drug gefitinib. CONCLUSION: The potential anticancer activity of compounds 6h and 6j was confirmed and need further exploration in cancer cell lines of different tissue origin and signaling pathways, as well as in animal models of cancer development.

Recent advancement in the discovery and development of anti-epileptic biomolecules: An insight into structure activity relationship and Docking.

Although there have been many advancements in scientific research and development, the cause of epilepsy still remains an open challenge. In spite of high throughput research in the field of anti-epileptic drugs, efficacy void is still prevalent before the researchers. Researchers have persistently been exploring all the possibilities to curb undesirable side effects of the anti-epileptic drugs or looking for a more substantial approach to diminish or cure epilepsy. The drug development has shown a hope to medicinal chemists and researchers to carry further research by going through a substantial literature survey. This review article attempts to describe the recent developments in the anti-epileptic agents, pertaining to different molecular scaffolds considering their structure-activity relationship, docking studies and their mechanism of actions.

3'-(4-(Benzyloxy)phenyl)-1'-phenyl-5-(heteroaryl/aryl)-3,4-dihydro-1'H,2H-[3,4'-bipyrazole]-2-carboxamides as EGFR kinase inhibitors: Synthesis, anticancer evaluation, and molecular docking studies.

Pyrazoline-linked carboxamide derivatives were designed, synthesized, and evaluated for potential epidermal growth factor receptor (EGFR) kinase inhibition, anticancer activity, and apoptotic and cardiomyopathy toxicity. Compounds 6m and 6n inhibit EGFR kinase at a concentration of 6.5 ± 2.91 and 3.65 ± 0.54 µM, respectively. Some of these compounds showed effects on proliferation, which were also then evaluated against four different human cancer cell lines, that is, MCF-7 (breast cancer), A549 (non-small-cell lung tumor), HCT-116 (colon cancer), and SiHa cells (cancerous tissues of the cervix uteri). The results showed that certain synthetic compounds showed significant inhibitor activity; compounds 6m and 6n were more cytotoxic than doxorubicin against A549 cancer cells, with IC50 values of 10.3 ± 1.07 and 4.6 ± 0.57 µM, respectively. Additionally, compounds 6m and 6n induced apoptosis in A549 cancer cells, as evidenced by 4',6-diamidino-2-phenylindole (DAPI) staining and phase-contrast microscopy. Potency to induce apoptosis by compound 6n was further confirmed by fluorescence-activated cell sorting using Annexin V-FITC and propidium iodide labeling. Compound 6n showed normal cardiomyocytes with no marked sign of pyknotic nuclei in cardiomyopathy and also normal histological appearance of the renal cortex when compared with that of control. Results of molecular docking studies suggested that compounds 6m and 6n can bind to the hinge region of the adenosine triphosphate-binding site of EGFR kinase, like the standard drug erlotinib. Therefore, the present study suggests that compounds 6m and 6n have potent in vitro antitumor activities against the human non-small-cell lung tumor cell line A549, which can be further explored in other cancer cell lines and in animal studies.

Synthesis of 1,2-Fused Tricyclic Indoles via Cu-/Base-Mediated Hydroamination of Alkynes.

Synthesis of a variety of 1,2-fused tricyclic S-containing indoles is reported starting from indole sulfides tethered with terminal and internal alkynes via a key hydroamination step. Cu-catalyzed hydroamination reactions resulted in the exclusive formation of tricycles possessing an exocyclic methylene moiety, whereas base-mediated conditions led to thiazolo[3,2-a]indoles. Indole sulfides with internal alkyne functionality produced 2H-[1,3]thiazino[3,2-a]indoles under Cu-catalysis.

Recent advancement in the discovery and development of COX-2 inhibitors: Insight into biological activities and SAR studies (2008-2019).

Cyclooxygenase-2 is a very important physiological enzyme playing key roles in various biological functions especially in the mechanism of pain and inflammation, among other roles, making it a molecule of high interest to the pharmaceutical community as a target. COX 2 enzyme is induced only during inflammatory processes or cancer and reflects no role in the guarding stomach lining. Thus, selective COX-2 inhibition can significantly reduce the adverse effects including GI tract damage and hepatotoxic effects of traditional NSAIDs like aspirin, ibuprofen, etc. Recent developments on COX-2 inhibitors is primarily focused on improving the selectivity index of the drug towards COX-2 along with enhancing the potency of the drug by modifying the scaffolds of Coxibs currently in the market like Celecoxib, Indomethacin, Oxaprozin, etc. We have reported the progress on new COX-2 inhibitors in the last decade (2008-2019) focussing on five heterocyclic rings- Pyrazole, Indole, Oxazole, Pyridine and Pyrrole. The addition of various moieties to these core rings and their structure-activity relationship along with their molecular modelling data have been explored in the article. This review aims to aid medicinal chemists in the design and discovery of better COX-2 inhibitors constructed on these five heterocyclic pharmacophores.

One-pot mild and efficient synthesis of [1,3]thiazino[3,2-a]indol-4-ones and their anti-proliferative activity.

A base mediated environmentally benign one-pot efficient methodology has been developed for the synthesis of [1,3]thiazino[3,2-a]indol-4-ones using indoline-2-thiones and propiolate esters in aqueous medium. The conjugate addition of thiones first results in ethyl (3-(indol-2-yl)thio)acrylates in situ, which subsequently undergoes intramolecular cyclization to produce indole-fused thiazin-4-ones in good to excellent yields. The cytotoxic screening of the synthesized compounds using MTT assay revealed the anti-proliferative nature of these frameworks against triple negative breast cancer cell lines with the highest activity emanating from 4H-[1,3]thiazino[3,2-a]indol-4-one and 8-methyl-2-propyl-4H-[1,3]thiazino[3,2-a]indol-4-one compounds.

Au-Catalyzed Synthesis of Thiopyrano[2,3-b]indoles Featuring Tandem Rearrangement and Hydroarylation.

Gold(III)-catalyzed synthesis of 14-π electron heteroaromatic thiopyrano[2,3-b]indole is reported using conjugated enyne tethered indole sulfides, featuring skeletal rearrangement conjoined with intramolecular hydroarylation (via C3-H functionalization of the indole core) and oxidative aromatization. Subsequent Pd-catalyzed C-C coupling resulted in a 16-π electron heteroaromatic isothiochromeno[1,8,7-bcd]indole.

Synthesis of indole-annulated sulfur heterocycles using copper-catalysed C-N coupling and palladium-catalysed direct arylation.

A simple and efficient method for the synthesis of biologically relevant 5H-benzo[4,5][1,3]thiazino[3,2-a]indoles and 5,7-dihydroisothiochromeno[3,4-b]indoles has been developed via intramolecular copper catalysed Ullmann-type C-N coupling and palladium catalysed direct arylation from the corresponding precursors 2-(2-bromobenzylthio)-1H-indole and 2-(2-bromobenzylthio)-1-methyl-1H-indole, respectively, in good to excellent yields.

Synthesis and anti-cancer activity of 1,4-disubstituted imidazo[4,5-c]quinolines.

The synthesis and anti-cancer activity evaluation of fused imidazoquinoline compounds is reported in this paper. Yb(OTf)3 has been utilized as a catalyst for the synthesis of 1,4-diaryl substituted imidazo[4,5-c]quinolines via a modified Pictet-Spengler approach. The desired imidazole ring was synthesized from imines using TosMIC (toluenesulfonylmethyl isocyanide) and subsequently functionalized at the C-4 position yielding an imidazoquinoline skeleton. Importantly, the final step was carried out without the aid of any prefunctionalization to obtain the resultant compounds in good yields. The synthesized compounds, when screened for anti-cancer activity, revealed the highest activity with 4-(2-bromophenyl)-1-phenyl-1H-imidazo[4,5-c]quinoline (IC50: 103.3 µM).

Access to Substituted Dihydrothiopyrano[2,3-b]indoles via Sequential Rearrangements During S-Alkylation and Au-Catalyzed Hydroarylation on Indoline-2-thiones.

An efficient methodology for the synthesis of indole-fused dihydrothiopyrans has been developed from indoline-2-thiones. The protocol involves the synthesis of conjugated ene-yne-substituted indole-sulfides, a gold(III)-catalyzed rearrangement of the ene-yne side chain followed by intramolecular hydroarylation via C3-H functionalization of the indole core. This new synthesis of functionalized tricyclic indole derivatives through sequential rearrangements is quite general in nature.

Synthesis of 4-substituted oxazolo[4,5-c]quinolines by direct reaction at the C-4 position of oxazoles.

A facile synthesis of 4-aryl substituted oxazolo[4,5-c]quinolines has been described via a modified Pictet-Spengler method and using Cu(TFA)2 as a catalyst. The developed methodology directly functionalizes the C-4 position of oxazoles without the aid of any prefunctionalization, in the presence of the more reactive C-2 position in good yields. The versatility of the established method has been demonstrated by its application in the synthesis of 4-substituted oxazolo-[1,8]naphthyridine ring systems.

Bronsted acid-catalyzed rapid enol-ether formation of 2-hydroxyindole-3-carboxaldehydes.

A one-step Bronsted acid-catalyzed synthetic methodology leading to 3-(alkoxymethylene)indolin-2-ones was developed starting from easily accessible 2-hydroxyindole-3-carboxaldehydes. The procedure simply involves a treatment of differently substituted 2-hydroxyindole-3-carboxaldehydes with various alcohols (primary/secondary/tertiary/allyl/propargyl/benzyl) in the presence of a catalytic amount of Bronsted acids such as [Formula: see text]-toluenesulfonic acid and trifluroacetic acid. A series of 19 indolin-2-one-based enol-ethers were synthesized in excellent yields, which implies the general character of our methodology. The enol-ethers produced could be used as a useful building block for the synthesis of indole-based heterocycles.

A simple Cu-catalyzed coupling approach to substituted 3-pyridinol and 5-pyrimidinol antioxidants.

A convenient approach to 3-pyridinols and 5-pyrimidinols via a two-step Cu-catalyzed benzyloxylation/catalytic hydrogenation sequence is presented. The corresponding 3-pyridinamines and 5-pyrimidinamines can be prepared in an analogous sequence utilizing benzylamine in lieu of benzyl alcohol. The radical-scavenging ability of these derivatives are preliminarily explored and reveal that the increased acidities of the pyridinols and pyrimidinols render them susceptible to more significant kinetic solvent effects when compared to phenols.

Brassinin oxidase, a fungal detoxifying enzyme to overcome a plant defense -- purification, characterization and inhibition.

Blackleg fungi [Leptosphaeria maculans (asexual stage Phoma lingam) and Leptosphaeria biglobosa] are devastating plant pathogens with well-established stratagems to invade crucifers, including the production of enzymes that detoxify plant defenses such as phytoalexins. The significant roles of brassinin, both as a potent crucifer phytoalexin and a biosynthetic precursor of several other plant defenses, make it critical to plant fitness. Brassinin oxidase, a detoxifying enzyme produced by L. maculans both in vitro and in planta, catalyzes the detoxification of brassinin by the unusual oxidative transformation of a dithiocarbamate to an aldehyde. Purified brassinin oxidase has an apparent molecular mass of 57 kDa, is approximately 20% glycosylated, and accepts a wide range of cofactors, including quinones and flavins. Purified brassinin oxidase was used to screen a library of brassinin analogues and crucifer phytoalexins for potential inhibitory activity. Unexpectedly, it was determined that the crucifer phytoalexins camalexin and cyclobrassinin are competitive inhibitors of brassinin oxidase. This discovery suggests that camalexin could protect crucifers from attacks by L. maculans because camalexin is not metabolized by this pathogen and is a strong mycelial growth inhibitor.

Kinetic solvent effects on peroxyl radical reactions.

Kinetic solvent effects on peroxyl radical reactions are easily determined using a new peroxyester-based radical clock method.

Isosteric probes provide structural requirements essential for detoxification of the phytoalexin brassinin by the fungal pathogen Leptosphaeria maculans.

Brassinin is a plant defense metabolite with antimicrobial activity produced de novo by a variety of Brassica species in response to stress, that is, a phytoalexin. The inhibition of brassinin oxidase (BO), a brassinin-detoxifying enzyme produced by the phytopathogenic fungus Leptosphaeria maculans, is a target in our continuing search for novel crop protection agents. To probe the substrate specificity of BO, in particular the mechanism of the detoxification step, several analogues of brassinin, including functional group isosteres ((mono/dithio)carbamate, urea, and thiourea) and homologue methyl tryptaminedithiocarbamate, were investigated using fungal cultures and purified BO. It was concluded that the essential structural features of substrates of BO were: (i) an -NH at the (mono/dithio)carbamate, urea or thiourea group; (ii) a methylene bridge between indole and the functional group; (iii) a methyl or ethyl group attached to the thiol moiety of the (mono/di)thiocarbamate group. A general stepwise pathway for the oxidation of brassinin was proposed that accounts for the structural requirements of detoxification of brassinin analogues in L. maculans. All compounds that were BO substrates appeared to be oxidized in mycelial cultures to aldehydes, except for the two most polar compounds N'-(3-indolylmethyl)-N''-methylurea and methyl N'-(3-indolylmethyl)carbamate. The substrate specificity of BO suggests that selective inhibitors can be designed for the potential control of L. maculans.

Detoxification of the phytoalexin brassinin by isolates of Leptosphaeria maculans pathogenic on brown mustard involves an inducible hydrolase.

Brassinin is a phytoalexin produced by plants from the family Brassicaceae that displays antifungal activity against a number of pathogens of Brassica species, including Leptosphaeria maculans (Desm.) Ces. et de Not. [asexual stage Phoma lingam (Tode ex Fr.) Desm.] and L. biglobosa. The interaction of a group of isolates of L. maculans virulent on brown mustard (Brassica juncea) with brassinin was investigated. The metabolic pathway for degradation of brassinin, the substrate selectivity of the putative detoxifying hydrolase, as well as the antifungal activity of metabolites and analogs of brassinin are reported. Brassinin hydrolase activity was detectable only in cell-free homogenates resulting from cultures induced with brassinin, N'-methylbrassinin, or camalexin. The phytoalexin camalexin was a substantially stronger inhibitor of these isolates than brassinin, causing complete growth inhibition at 0.5mM.

Detection, characterization and identification of crucifer phytoalexins using high-performance liquid chromatography with diode array detection and electrospray ionization mass spectrometry.

We have analyzed 23 crucifer phytoalexins (e.g. brassinin, dioxibrassinin, cyclobrassinin, brassicanals A and C) by HPLC with diode array detection and electrospray ionization mass spectrometry (HPLC-DAD-ESI-MS) using both negative and positive ion modes. Positive ion mode ESI-MS appeared more sensitive than negative ion mode ESI-MS in detecting this group of compounds. A new HPLC separation method, new LC-MS and LC-MS(2) data and proposed fragmentation pathways, LC retention times, and UV spectra for selected compounds are reported.