Synthetic access to thiolane-based therapeutics and biological activity studies.

Secondary metabolites isolated from bioactive extracts of natural sources iteratively pioneer the research in drug discovery. Modern medicine is often inspired by bioactive natural products or the bio-functional motifs embedded in them. One of such consequential bio-functional motifs is the thiolane unit. Thiolane-based bioactive organic compounds have manifested a plethora of astonishing biological activities such as anti-viral, anti-cancer, anti-platelet, α-glucosidase inhibition, anti-HIV, immunosuppressive and anti-microbial activities which renders them excellent candidates in drug discovery. Hence, to scale up the accessibility of thiolane-based therapeutics its chemical syntheses is essential and in addition; a sneak peek in its biosynthesis would give a perspective for developing biomimetic syntheses. This review highlights the development of important thiolane-based therapeutics such as (i) Nuphar sesquiterpene thioalkaloids (ii) Thiosugar sulphonium salts from Salacia sp. (iii) Albomycins (iv) Thiolane-based therapeutics from Allium sp. (v) 4'-thionucleosides summarizing various synthetic strategies, biosynthesis and biological activity studies, covering literature till 2021. We anticipate that this review will inspire chemists and biochemists to take up the challenges encountered in the synthesis and development of thiolane-based therapeutics.

Next generation quorum sensing inhibitors: Accounts on structure activity relationship studies and biological activities.

Bacterial resistance is a growing threat which represents major scourge throughout the world. The suitable way to control the present critical situation of antimicrobial resistance would be to develop entirely novel strategies to fight antibiotic resistant pathogens such as quorum sensing (QS) inhibitors or its combination with antibiotics. Anti QS agents can eliminate the QS signals and put the barrier in bio-film formation, consequently, bacterial virulence will be reduced without causing drug-resistance to the pathogens. Among the various anti QS agents identified, especially those of natural origin, furanones or acylatedhomoserine lactones (AHLs) are most popular. Semi-synthetic and synthetic inhibitors have shown greatest potential and have inspired chemists to design synthetically modified QS inhibitors with lactone moiety. This review focuses on anti QS agents (bio-film inhibitors) of both natural and synthetic origins. Further, the synthesis, structure activity relationship and anti QS activity covering literature from 2015 till March 2020 has been discussed.

Asymmetric Synthesis of (-)-6'-ß-Fluoro-aristeromycin via Stereoselective Electrophilic Fluorination.

(-)-6'-ß-Fluoro-aristeromycin (2), a potent inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase, has been synthesized via stereoselective electrophilic fluorination followed by a purine base build-up approach. Interestingly, purine base condensation using a cyclic sulfate resulted in a synthesis of (+)-5'-ß-fluoro-isoaristeromycin (2a). Computational analysis indicates that the fluorine atom controlled the regioselectivity of the purine base substitution.

Quick Identification of Piperidine Alkaloid from Roots of Grewia nervosa and Their Glucosidase Inhibitory Activity.

Grewia nervosa is a herbal plant used in traditional medicine for different purposes. Bioassay-guided chemical fractionation of G. nervosa roots resulted in an identification of two known and one new compound, namely microgrewiapine A, homomicrogrewiapine, and N-methylmicrocosamine, respectively. Their structures were determined using combination of LC/HR-MS, 1 H-NMR, and IR spectral analyses and followed by comparison with those reported in the literature. The problematic separation of these alkaloids on traditional column chromatography (Silica gel, Octadecyl silane, Sephadex) was resolved by using HPLC. Structurally similar compounds from the piperidine family have been characterized by using HR-MS analysis in combination with NMR data of crude samples. The major constituent i.e. N-methylmicrocosamine isolated from the butanol fraction of methanol root extract (MRE) was found to possess the dose dependent α-glucosidase inhibition activity with an IC50 value of 53.40 µm. Furthermore, N-methylmicrocosamine showed maximum α-glucosidase inhibition of 97.48 ± 0.7% at 107.5 µm, which is approximately 1.3 × 103 fold higher than the activity shown by acarbose (97.72% inhibition at 61.95 mm), a standard anti-diabetic drug available commercially. This work also reports the in vitro α-glucosidase inhibitory activity of the major alkaloids isolated from G. nervosa for the first time.

Quick elucidation of cyclodepsipeptide sequence from sacoglossan Elysia grandifolia using electrospray ionisation-tandem mass spectrometry.

Butanol fraction of sacoglossan Elysia grandifolia was investigated for identifying peptides using electrospray ionisation-tandem mass spectrometry (ESI-MS/MS). Without prior isolation, the structural determination is achieved on the basis of mass fragmentation pattern and comparison with the previously established data. The ESI-MS of the fraction in the positive ion mode gave clusters of singly and doubly charged molecular ion peaks. The ESI-MS spectrum showed peaks for the presence of the peptides kahalalides F, G, R and S reported earlier. In addition, it also showed molecular ion peaks at m/z 1557.8 [M+H]+ and doubly charged ions at m/z 779.4 [M+2H]2+, 790.4 [M+Na]2+ and 796.4 [M+K]2+. The MS/MS at m/z 779.4 [M+2H]+2 at collision energy 40 V obtained series of b and y fragment ions. The MS/MS spectrum showed identical fragment ion y6 at m/z 643 which revealed that cyclic part is identical with kahalalide F, R and S. Careful examination of the fragment ions b1 to b7 with their corresponding y fragment ions y12 to y6, respectively and by comparison of MS/MS pattern of kahalalide S, established that proline can be replaced by tyrosine amino acid residue. The mass difference between b4 ( m/z 511) and b5 ( m/z 674) is equal to 163 which is equivalent to mass residue of tyrosine. Their y fragment ions also quickly helped in fixing the puzzle. This resulted in the identification of the peptide sequence cyclo-[Val-(5-MeHex-Val-Thr-Val-Val-Tyr-Lys-Ile)Thr-Ile-Val-Phe-Dhb)] for the new cyclodepsipeptide, kahalalide Z3. Thus, ESI-MS/MS has set a trend in quick identification of new marine molecules.

Enhanced photocatalytic degradation of Amaranth dye on mesoporous anatase TiO2: evidence of C-N, N[double bond, length as m-dash]N bond cleavage and identification of new intermediates.

The photocatalytic degradation mechanism of Amaranth, a recalcitrant carcinogenic azo dye, was investigated using mesoporous anatase TiO2 under sunlight. Mesoporous anatase TiO2 of a high photocatalytic activity has been synthesized using a sol-gel method and its photocatalytic activity for the degradation of Amaranth dye has been evaluated with respect to Degussa P25. The effect of bi-dentate complexing agents like oxalic acid, ethylene glycol and urea on the surface properties of TiO2 catalyst has been investigated using TG-DTA, FTIR, HR-TEM, SAED, PXRD, EDS, UV-DRS, PL, BET N2 adsorption-desorption isotherm studies and BJH analysis. The influence of catalyst properties such as the mesoporous network, pore volume and surface area on the kinetics of degradation of Amaranth as a function of irradiation time under natural sunlight has been monitored using UV-Vis spectroscopy. The highest rate constant value of 0.069 min-1 was obtained for the photocatalytic degradation of Amaranth using TiO2 synthesized via a urea assisted sol-gel synthesis method. The effect of the reaction conditions such as pH, TiO2 concentration and Amaranth concentration on the photodegradation rate has been investigated. The enhanced photocatalytic activity of synthesized TiO2 in comparison with P25 is attributed to the mesoporous nature of the catalyst leading to increased pore diameter, pore volume, surface area and enhanced charge carrier separation efficiency. New intermediates of photocatalytic degradation of Amaranth, namely, sodium-3-hydroxynaphthalene-2,7-disulphonate, 3-hydroxynaphthalene, sodium-4-aminonaphthalenesulphonate and sodium-4-aminobenzenesulphonate have been identified using LC-ESI-MS for the very first time, providing direct evidence for simultaneous bond cleavage pathways (-C-N-) and (-N[double bond, length as m-dash]N-). A new plausible mechanism of TiO2 catalysed photodegradation of Amaranth along with the comparison of its toxicity to that of its degradation intermediates and products is proposed.

Fluorescence Turn-on Chemosensor for the Detection of Dissolved CO2 Based on Ion-Induced Aggregation of Tetraphenylethylene Derivative.

Herein, a sensitive fluorimetric assay for dissolved carbon dioxide (dCO2) was developed by using ion-induced self-assembly of a tetraphenylethylene derivative by taking advantage of its aggregation induced emission property. Chitosan, a commercially available polymer having amine functionality was utilized for the ion induced assay. In the presence of dCO2, the amine groups in the chitosan get protonated to convert neutral chitosan to a positively charged species, triggering negatively charged tetraphenylethene derivative (probe 1) to aggregate with it by electrostatic interaction. The aggregation causes intense blue fluorescence output from the system. The extent of the aggregation is reliant on the charge density of polymer, which is equivalent to dCO2 concentration. A linear relationship from 5 to 50 µM of dCO2, with a limit of detection of 5 × 10(-6) M (0.00127 hPa) was obtained. This is the first report for detecting dCO2 utilizing the AIE property.

Synthesis and photophysical characterization of quasi push-pull dicyanodibenzodioxins and their anti-tumor activity against glioma cell line C6.

Dibenzodioxins bearing multiple electron withdrawing groups were synthesized using a simple one-step methodology including examples of molecules possessing electron acceptor groups in both ends. As a consequence internal charge delocalization occurs and the optical spectra are found to be bathochromically shifted compared to similar examples known thus far. A theoretical analysis of the molecular orbitals reveals the origin of the peaks in the dibenzodioxin optical spectra. Select examples exhibit in vitro neuro-cytotoxicity against glioma cell line C6, a finding which enhances existing knowledge about the pharmacologically relevant structural motifs in dibenzodioxins.

Design and synthesis of marine natural product-based 1H-indole-2,3-dione scaffold as a new antifouling/antibacterial agent against fouling bacteria.

Marine organisms such as seaweeds, sponges and corals protect their own surfaces from fouling by their high anesthetic, repellant, and settlement inhibition properties. Within the marine ecosystem, evolution has allowed for the development of certain antifouling properties. Isatin is a biologically active chemical produced by an Alteromonas sp. strain inhibiting the surface of embryos of the cardiean shrimp Palaemon macrodectylus, which protect them from the pathogenic fungus Lagenidium callinectes. In present study, an antibacterial activity of isatin and its synthetic analogues were evaluated against different fouling bacteria in order to explore the structure activity relationships for the first time. The synthesized compounds along with parent isatin were tested against different ecologically relevant marine microorganisms by using the Kirby-Bauer disc diffusion method. Few synthetically modified isatin exhibited potent inhibitory activity at concentration of 2 µg/disc against Planococcus donghaensis, Erythrobacter litoralis, Alivibrio salmonicida, Vibrio furnisii. Overall, the modified analogues showed stronger activity than the parent marine natural product (isatin) and hence 1H-indole-2,3-dione scaffold has immense potential as future antibacterial/antifouling candidate.

Evaluation of single and joint effect of metabolites isolated from marine sponges, Fasciospongia cavernosa and Axinella donnani on antimicrobial properties.

The biochemical mechanisms that marine sponges have developed as a chemical defense to protect themselves against micro and subsequent macrobiofouling process might comprise a potential alternative for the preventing attack of biofilm forming bacteria. The present study investigated the antimicrobial activity of a series of major secondary metabolites isolated from the sponges Fasciospongia cavernosa and Axinella donnani against fouling bacteria. Secomanoalide (1), dehydromanoalide (2) and cavernosine (3) have been isolated from F. cavernosa. Their structures were determined by MS, (1)H NMR spectra analyses and by comparison with those reported in the literature. The most promising activity was exhibited by the metabolites from A. donnani, that is, cerebroside (5) against three strains Aeromonas hydrophila subsp. salmonicida A449 and Erythrobacter litoralis. Our investigation revealed that combined metabolites 1, 2 and 3 retained strong activity but individual metabolite had moderate activity indicating that activity probably results from synergistic interactions between multiple compounds. The antibacterial screening of compounds 3, 5 and synergistic effect of 1-3 against fouling bacteria has been studied for the first time. Further, isolation of manoalide related compounds and their synergistic screening can be accelerated for the development of new biofilm inhibitors.

Next generation biofilm inhibitors for Pseudomonas aeruginosa: Synthesis and rational design approaches.

The bacterial biofilms and the emergence of multiple drug resistance have become a major threat for current medical treatment of nosocomial infections. It has been estimated that about 65-80% of microbial infections in the developed countries are associated with biofilms. Given the prominence of biofilms in infectious diseases, increasing efforts toward the development of small molecules that will modulate bacterial biofilm development and maintenance is on the rise. Till date, marine natural products have shown a tremendous potential as pharma leads and also given new skeletons which would be used as biofilm/QS inhibitors. Medically relevant biofilm forming bacteria such as Pseudomonas aeruginosa which is most frequently isolated bacteria in nosocomial infection is believed to be a model organism for biofilm studies. Hence, in this review, we have highlighted the development of small molecules that inhibit and/or disperse bacterial biofilms of P. aeruginosa in particular. Additionally, the rational design approaches as well as synthetic methodologies along with biological studies has been accounted in this article.

Synthesis of (R)-norbgugaine and its potential as quorum sensing inhibitor against Pseudomonas aeruginosa.

(R)-Bgugaine is a natural pyrrolidine alkaloid from Arisarum vulgare, which shows antifungal and antibacterial activity. In this Letter, we have accomplished the simple synthesis of norbgugaine (demethylated form of natural bgugaine) employing Wittig olefination and cat. hydrogenation as the key steps and its biological studies are reported for the first time. The synthesized norbgugaine was evaluated for inhibition of quorum sensing mediated virulence factors (motility, biofilm formation, pyocyanin pigmentation, rhamnolipid production and LasA protease) in Pseudomonas aeruginosa wherein swarming motility is reduced by 95%, and biofilm formation by 83%.

Decreased expression of synapse-related genes and loss of synapses in major depressive disorder.

Previous imaging and postmortem studies have reported a lower brain volume and a smaller size and density of neurons in the dorsolateral prefrontal cortex (dlPFC) of subjects with major depressive disorder (MDD). These findings suggest that synapse number and function are decreased in the dlPFC of patients with MDD. However, there has been no direct evidence reported for synapse loss in MDD, and the gene expression alterations underlying these effects have not been identified. Here we use microarray gene profiling and electron microscopic stereology to reveal lower expression of synaptic-function­related genes (CALM2, SYN1, RAB3A, RAB4B and TUBB4) in the dlPFC of subjects with MDD and a corresponding lower number of synapses. We also identify a transcriptional repressor, GATA1, expression of which is higher in MDD and that, when expressed in PFC neurons, is sufficient to decrease the expression of synapse-related genes, cause loss of dendritic spines and dendrites, and produce depressive behavior in rat models of depression.

Fluorocyclopentenyl-cytosine with broad spectrum and potent antitumor activity.

On the basis of the potent biological activity of cyclopentenyl-pyrimidines, fluorocyclopentenyl-pyrimidines were designed and synthesized from D-ribose. Among these, the cytosine derivative 5a showed highly potent antigrowth effects in a broad range of tumor cell lines and very potent antitumor activity in a nude mouse tumor xenograft model implanted with A549 human lung cancer cells. However, its 2'-deoxycytidine derivative 5b did not show any antigrowth effects, indicating that 2'-hydroxyl group is essential for the biological activity.

Stereoselective synthesis of fluoro-homoneplanocin A as a potential antiviral agent.

Fluoro-homoneplanocin A (4) was synthesized from d-ribose, via the enyne ring-closing metathesis of 9, the stereoselective opening of epoxide 23a with fluoride, and a simultaneous oxidation-elimination reaction. The key intermediate 8 is expected to serve as a versatile intermediate for the synthesis of carbanucleosides.

Structure-activity relationships of truncated C2- or C8-substituted adenosine derivatives as dual acting A2A and A3 adenosine receptor ligands.

Truncated N(6)-substituted-4'-oxo- and 4'-thioadenosine derivatives with C2 or C8 substitution were studied as dual acting A(2A) and A(3) adenosine receptor (AR) ligands. The lithiation-mediated stannyl transfer and palladium-catalyzed cross-coupling reactions were utilized for functionalization of the C2 position of 6-chloropurine nucleosides. An unsubstituted 6-amino group and a hydrophobic C2 substituent were required for high affinity at the hA(2A)AR, but hydrophobic C8 substitution abolished binding at the hA(2A)AR. However, most of synthesized compounds displayed medium to high binding affinity at the hA(3)AR, regardless of C2 or C8 substitution, and low efficacy in a functional cAMP assay. Several compounds tended to be full hA(2A)AR agonists. C2 substitution probed geometrically through hA(2A)AR docking was important for binding in order of hexynyl > hexenyl > hexanyl. Compound 4g was the most potent ligand acting dually as hA(2A)AR agonist and hA(3)AR antagonist, which might be useful for treatment of asthma or other inflammatory diseases.

Total synthesis of (-)- and (+)-tedanalactam.

The first stereoselective route providing access to both enantiomers of tedanalactam, a naturally occurring piperidone, has been developed. The stereogenic centers were generated by the use of Sharpless asymmetric dihydroxylation. Tandem oxidation-Wittig reaction and one-pot deprotection, lactamization, and oxirane ring formation are the other key elements.

Tandem Wittig-ene reaction approach to kainic acid.

The first example of a tandem Wittig-intramolecular ene reaction approach and its application toward the synthesis of kainic acid is reported. The synthetic pathway involves conversion of prenyl bromide into phosphorane 3, followed by one-pot Wittig olefination and an ene reaction with glyoxalic acid to give the cis fused pyrrolidine skeleton of kainic acid.