Comprehensive Study on Solomonamides: Total Synthesis, Stereochemical Revision, and SAR Studies toward Identification of Simplified Lead.

Solomonamides, a pair of macrocyclic peptide natural products originating from marine sources, have garnered significant attention within the synthetic community owing to their marked anti-inflammatory efficacy and intricate molecular architectures. In this paper, we present a very detailed investigation into solomonamides, including the challenges associated with the total synthesis, the evolution of our synthetic strategies, structural reassignment, synthesis of all possible stereoisomeric macrocycles, biological assessment, structure-activity relationship (SAR) studies, etc. Within the ambit of this total synthesis, diverse strategies for macrocyclization were rigorously explored, encompassing the Friedel-Crafts acylation, cyclization involving the aniline NH2 moiety, macrolactamization utilizing Gly-NH2, and Heck macrocyclization methodologies. In addition, an array of intriguing chemical transformations were devised, including but not limited to photo-Fries rearrangement, Wacker oxidation, ligand-free Heck macrocyclization, oxidative cleavage of indole, synthesis of contiguous stereocenters via substrate/reagent-controlled protocols, and simultaneous making and breaking of olefinic moieties. The findings of this investigation revealed a structurally simplified lead compound. Remarkably, the lead compound, while possessing structural simplification in comparison to the intricate solomonamide counterparts, demonstrates equipotent in vivo anti-inflammatory efficacy.

Efficient Image De-Noising Technique Based on Modified Cuckoo Search Algorithm.

The image restoration has emerged as a very vital investigation technique in the domain of the image processing. The underlying motive behind the image restoration is devoted to the augmentation of the perceived visual impact of image so as to make it almost identical to the original image. A host of exploration approaches are now in vogues which are intended to steer clear of the noise, thereby regaining the images with original quality. In our earlier research, two distinct noise elimination methods like the (OGHP) and SURE shrinkage were effectively employed for the purpose of denoising, though the relative PSNR and SSIM efficiencies did not come up to the desired level. In the innovative approach envisaged in the document, at the outset, the noise is included by means of two processes like the salt and pepper and impulse noise. Subsequently, the pre-processing methods are performed with the able assistance of two novel filters such as the adaptive median filter and adaptive fuzzy switching. Thereafter, the preprocessed image is furnished to the succeeding function of noise elimination like the (OGHP) and SURE shrinkage. In the course of the OGHP noise elimination technique, the GHP constraints are optimized by employing the Cuckoo Search Algorithm. Thereafter, the noise-eliminated image is effectively estimated with the help of the Discrete Wavelet Transform (DWT). The consequential noiseless images are subjected to the image restoration procedure by efficiently employing the AGA approach. The cheering performance outcomes chant the success stories of the novel image restoration method, highlighting its superlative efficiency. Moreover, the efficacy of the innovative approach is assessed by means of a set of noise-polluted images and contrasted with the modern noiseless image restoration technique.

Synthesis, biological evaluation and docking studies of silicon incorporated diarylpyrroles as MmpL3 inhibitors: An effective strategy towards development of potent anti-tubercular agents.

Growing global demand for new molecules to treat tuberculosis has created an urgent need to develop novel strategies to combat the menace. BM212 related compounds were found to be potent anti-TB agents and they inhibit mycolic acid transporter, MmpL3, a known potent drug target from Mycobacterium tuberculosis. In order to enhance their inhibitory potency, several silicon analogues of diarylpyrroles related to BM212 were designed, synthesized, and evaluated for anti-tubercular activities. In Alamar blue assay, most of the silicon-incorporated compounds were found to be more potent than the parent compound (BM212), against Mycobacterium tuberculosis (MIC = 1.7 µM, H37Rv). Docking results from the crystal structure of MmpL3 and silicon analogues as pharmacophore model also strongly correlate with the biological assays and suggest that the incorporation of silicon in the inhibitor scaffold could enhance their potency by stabilizing the hydrophobic residues at the binding pocket. The best docking hit, compound 12 showed an MIC of 0.1 µM against H37Rv with an acceptable in vitro ADME profile and excellent selectivity index. Overall, the present study indicates that, the designed silicon analogues, especially compound 12 could be a good inhibitor for an intrinsically flexible drug-binding pocket of MmpL3 and has potential for further development as anti-tubercular agents.

Application of Vinamidinium Salt Chemistry for a Palladium Free Synthesis of Anti-Malarial MMV048: A "Bottom-Up" Approach.

MMV390048 (1) is a clinical compound under investigation for antimalarial activity. A new synthetic route was developed which couples two aromatic fragments while forming the central pyridine ring over two steps. This sequence takes advantage of raw materials used in the existing etoricoxib supply chain and eliminates the need for palladium catalysts, which were projected to be major cost-drivers.

A concise route to MK-4482 (EIDD-2801) from cytidine.

A two-step route to MK-4482 (EIDD-2801, 1) was developed consisting of an esterification and hydroxamination of cytidine. The selective acylation and direct amination eliminate the need for protecting and activating groups and proceed in overall yield of 75%, a significant advancement over the reported yield of 17%. The step count is reduced from five transformations to two, and expensive uridine is replaced with the more available cytidine.

Role of a moderately halophilic bacterial consortium in the biodegradation of polyaromatic hydrocarbons.

Polycyclic aromatic hydrocarbons are ubiquitous pollutants in the environment, and most high molecular weight PAHs cause mutagenic, teratogenic and potentially carcinogenic effects. While several strains have been identified that degrade PAHs, the present study is focused on the degradation of PAHs in a marine environment by a moderately halophilic bacterial consortium. The bacterial consortium was isolated from a mixture of marine water samples collected from seven different sites in Chennai, India. The low molecular weight (LMW) PAHs phenanthrene and fluorine, and the high molecular weight (HMW) PAHs pyrene and benzo(e)pyrene were selected for the degradation study. The consortium metabolized both LMW and HMW PAHs. The consortium was also able to degrade PAHs present in crude oil-contaminated saline wastewater. The bacterial consortium was able to degrade 80% of HMW PAHs and 100% of LMW PAHs in the saline wastewater. The strains present in the consortium were identified as Ochrobactrum sp., Enterobacter cloacae and Stenotrophomonas maltophilia. This study reveals that these bacteria have the potential to degrade different PAHs in saline wastewater.

Repurposing Ivacaftor for treatment of Staphylococcus aureus infections.

Drug repurposing of non-antimicrobials is a novel method to augment a seriously depleted drug pipeline for targeting drug-resistant pathogens. This article highlights the potent antimicrobial activity of Ivacaftor against Staphylococcus aureus, including vancomycin- and other multidrug-resistant strains. The potent activity of Ivacaftor in vivo is also demonstrated in a murine neutropenic thigh infection model. Taken together, these results support the potential of Ivacaftor as an antimicrobial agent for the treatment of staphylococcal infections.

Anaerobic digestion of tannery soak liquor with an aerobic post-treatment.

The leather industry occupies a place of prominence in the Indian economy due to its massive potential for employment, growth and exports. The potential environmental impact of tanning is significant. This study focuses on tannery soak liquor, generated by the soaking of hides and skins, which is characterised by high organic load and high salinity. For these reasons, the soak liquor should be segregated and pre-treated separately before being mixed with the composite wastewater, made of all other streams mixed together. The anaerobic digestion of tannery soak liquor was studied using a UASB. COD removal reached 78% at an OLR of 0.5 kg COD m(-3) d(-1), a HRT of 5 days and a TDS concentration of 71 gl(-1). The combination of the UASB with an aerobic post-treatment enhanced the performance of the overall wastewater treatment process and the COD removal efficiency of the combined anaerobic/aerobic treatment system reached 96%. However, for effective operation, the system had to be operated at very low OLRs, which affects the economic viability of such a process.

Impact of heavy metal toxicity and constructed wetland system as a tool in remediation.

The objective of this review is to throw light upon the global concern of heavy metal-contaminated sites and their remediation through an ecofriendly approach. Accumulated heavy metals in soil and water bodies gain entry through the food chain and pose serious threat to all forms of life. This has engendered interest in phytoremediation techniques where hyperaccumulators are used. Constructed wetland has a pivotal role and is a cost-effective technique in the remediation of heavy metals. Metal availability and mobility are influenced by the addition of chelating agents, which enhance the availability of metal uptake. This review helps in identifying the critical knowledge gaps and areas to enhance research in the future to develop strategies such as genetically engineered hyperaccumulators to attain an environment devoid of heavy metal contamination.

Halophilic biological treatment of tannery soak liquor in a sequencing batch reactor.

Hypersaline wastewater (i.e. wastewater containing more than 35 gl(-1) total dissolved solids (TDS)) is generated by various industrial activities. This wastewater, rich in both organic matter and TDS, is difficult to treat using conventional biological wastewater treatment processes. Among the industries generating hypersaline effluents, tanneries are prominent in India. In this study, tannery wastewater from soak pit was treated in a lab-scale SBR for the removal of organic matter. The characterisation of the soak liquor showed that this effluent is biodegradable, though not easily, and highly variable, depending on the origin and the nature of the hides. TDS was in the range of 21-57 gl(-1) and COD was in the range of 1.5-3.6 gl(-1). This soak liquor was biologically treated in an aerobic sequencing batch reactor seeded with halophilic bacteria, and the performance of the system was evaluated under different operating conditions with changes in hydraulic retention time, organic loading rate and salt concentration. The changes in salinity appeared to affect the removal of organic matter more than the changes in hydraulic retention time or organic loading rate. Despite the variations in the characteristics of the soak liquor, the reactor achieved proper removal of organic matter, once the acclimation of the microorganisms was achieved. Optimum removal efficiencies of 95%, 93%, 96% and 92% on COD, PO4 3-, TKN and SS, respectively, could be reached with 5 days hydraulic retention time (HRT), an organic loading rate (OLR) of 0.6 kg COD m(-3)d(-1) and 34 g NaCl l(-1). The organisms responsible for nitrogen removal appeared to be the most sensitive to the modifications of these parameters.

Degradation of non-phenolic beta-o-4 lignin substructure model compounds by Acinetobacter sp.

Acinetobacter sp. utilized non-phenolic beta-o-4-model compounds, 2-methoxy-4-formylphenoxyacetic acid and veratrylglycerol-beta-guaiacyl ether (VGE) as sole carbon source. Vanillin, vanillic acid, protocatechuic acid and catechol were detected in the 2-methoxy-4-formylphenoxyacetic acid amended culture. Veratryl alcohol, veratraldehyde, veratric acid, vanillic acid, protocatechuic acid, catechol and guaiacol were identified from veratrylglycerol-beta-guaiacyl ether culture. Acinetobacter sp. produced catechol 1,2-dioxygenase and protocatechuate 3,4-dioxygenase that cleaved catechol and protocatechuic acid, respectively.

Differential crosstalk between estrogen receptor (ER)alpha and ERbeta and the thyroid hormone receptor isoforms results in flexible regulation of the consensus ERE.

Crosstalk between nuclear receptors is important for conversion of external and internal stimuli to a physiologically meaningful response by cells. Previous studies from this laboratory have demonstrated crosstalk between the estrogen (ER) and thyroid hormone receptors (TR) on two estrogen responsive physiological promoters, the preproenkephalin and oxytocin receptor gene promoter. Since ERalpha and ERbeta are isoforms possessing overlapping and distinct transactivation properties, we hypothesized that the interaction of ERalpha and beta with the various TR isoforms would not be equivalent. To explore this hypothesis, the consensus estrogen response element (ERE) derived from the Xenopus vitellogenin gene is used to investigate the differences in interaction between ERalpha and beta isoforms and the different TR isoforms in fibroblast cells. Both the ER isoforms transactivate from the consensus ERE, though ERalpha transactivates to a greater extent than ERbeta. Although neither of the TRbeta isoforms have an effect on ERalpha transactivation from the consensus ERE, the liganded TRalpha1 inhibits the ERalpha transactivation from the consensus ERE. In contrast, the liganded TRalpha1 facilitates ERbeta-mediated transactivation. The crosstalk between the TRbeta isoforms with the ERalpha isoform, on the consensus ERE, is different from that with the ERbeta isoform. The use of a TRalpha1 mutant, which is unable to bind DNA, abolishes the ability of the TRalpha1 isoform to interact with either of the ER isoforms. These differences in nuclear receptor crosstalk reveal an important functional difference between isoforms, which provides a novel mechanism for neuroendocrine integration.

Isoform specificity for oestrogen receptor and thyroid hormone receptor genes and their interactions on the NR2D gene promoter.

Oestrogens are critical for the display of lordosis behaviour and, in recent years, have also been shown to be involved in synaptic plasticity. In the brain, the regulation of ionotropic glutamate receptors has consequences for excitatory neurotransmission. Oestrogen regulation of the N-methyl-d-aspartate receptor subunit 2D (NR2D) has generated considerable interest as a possible molecular mechanism by which synaptic plasticity can be modulated. Since more than one isoform of the oestrogen receptor (ER) exists in mammals, it is possible that oestrogen regulation via the ERalpha and ERbeta isoforms on the NR2D oestrogen response element (ERE) is not equivalent. In the kidney fibroblast (CV1) cell line, we show that in response to 17beta-oestradiol, only ERalpha, not ERbeta, could upregulate transcription from the ERE which is in the 3' untranslated region of the NR2D gene. When this ERE is in the 5' position, neither ERalpha nor ERbeta showed transactivation capacity. Thyroid hormone receptor (TR) modulation of ER mediated induction has been shown for other ER target genes, such as the preproenkephalin and oxytocin receptor genes. Since the various TR isoforms exhibit distinct roles, we hypothesized that TR modulation of ER induction may also be isoform specific. This is indeed the case. The TRalpha1 isoform stimulated ERalpha mediated induction from the 3'-ERE whereas the TRbeta1 isoform inhibited this induction. This study shows that isoforms of both the ER and TR have different transactivation properties. Such flexible regulation and crosstalk by nuclear receptor isoforms leads to different transcriptional outcomes and the combinatorial logic may aid neuroendocrine integration.

Crosstalk between oestrogen receptors and thyroid hormone receptor isoforms results in differential regulation of the preproenkephalin gene.

Nuclear receptors are ligand-activated transcription factors, which have the potential to integrate internal metabolic events in an organism, with consequences for control of behaviour. Previous studies from this laboratory have shown that thyroid hormone receptor (TR) isoforms can inhibit oestrogen receptor (ER)alpha-mediated induction of preproenkephalin (PPE) gene expression in the hypothalamus. Also, thyroid hormone administration inhibits lordosis, a behaviour facilitated by PPE expression. We have examined the effect of multiple ligand-binding TR isoforms on the ER-mediated induction of the PPE gene in transient transfection assays in CV-1 cells. On a natural PPE gene promoter fragment containing two putative oestrogen response elements (EREs), both ER alpha and beta isoforms mediate a four to five-fold induction by oestrogen. Cotransfection of TR alpha 1 along with ER alpha inhibited the ER alpha transactivation of PPE by approximately 50%. However, cotransfection with either TR beta 1 or TR beta 2 expression plasmids produced no effect on the ER alpha or ER beta mediated induction of PPE. Therefore, under these experimental conditions, interactions with a single ER isoform are specific to an individual TR isoform. Transfection with a TR alpha 1 DNA-binding mutant could also inhibit ER alpha transactivation, suggesting that competition for binding on the ERE may not be the exclusive mechanism for inhibition. Data with the coactivator, SRC-1, suggested that coactivator squelching may participate in the inhibition. In dramatic contrast, when ER beta is cotransfected, TR alpha 1 stimulated ER beta-mediated transactivation of PPE by approximately eight-fold over control levels. This is the first study revealing specific interactions among nuclear receptor isoforms on a neuroendocrine promoter. These data also suggest that the combinatorics of ER and TR isoforms allow multiple forms of flexible gene regulations in the service of neuroendocrine integration.

Estrogens, brain and behavior: studies in fundamental neurobiology and observations related to women's health.

Mechanisms and consequences of the effects of estrogen on the brain have been studied both at the fundamental level and with therapeutic applications in mind. Estrogenic hormones binding in particular neurons in a limbic-hypothalamic system and their effects on the electrophysiology and molecular biology of medial hypothalamic neurons were central in establishing the first circuit for a mammalian behavior, the female-typical mating behavior, lordosis. Notably, the ability of estradiol to facilitate transcription from six genes whose products are important for lordosis behavior proved that hormones can turn on genes in specific neurons at specific times, with sensible behavioral consequences. The use of a gene knockout for estrogen receptor alpha (ERalpha) revealed that homozygous mutant females simply would not do lordosis behavior and instead were extremely aggressive, thus identifying a specific gene as essential for a mammalian social behavior. In dramatic contrast, ERbeta knockout females can exhibit normal lordosis behavior. With the understanding, in considerable mechanistic detail, of how the behavior is produced, now we are also studying brain mechanisms for the biologically adaptive influences which constrain reproductive behavior. With respect to cold temperatures and other environmental or metabolic circumstances which are not consistent with successful reproduction, we are interested in thyroid hormone effects in the brain. Competitive relations between two types of transcription factors - thyroid hormone receptors and estrogen receptors have the potential of subserving the blocking effects of inappropriate environmental circumstances on female reproductive behaviors. TRs can compete with ERalpha both for DNA binding to consensus and physiological EREs and for nuclear coactivators. In the presence of both TRs and ERs, in transfection studies, thyroid hormone coadministration can reduce estrogen-stimulated transcription. These competitive relations apparently have behavioral consequences, as thyroid hormones will reduce lordosis, and a TRbeta gene knockout will increase it. In sum, we not only know several genes that participate in the selective control of this sex behavior, but also, for two genes, we know the causal routes. Estrogenic hormones are also the foci of widespread attention for their potential therapeutic effects improving, for example, certain aspects of mood and cognition. The former has an efficient animal analog, demonstrated by the positive effects of estrogen in the Porsolt forced swim test. The latter almost certainly depends upon trophic actions of estrogen on several fundamental features of nerve cell survival and growth. The hypothesis is raised that the synaptic effects of estrogens are secondary to the trophic actions of this type of hormone in the nucleus and nerve cell body.

Plasmid-mediated degradation of hydroxylated, methoxylated, and carboxylated benzene derivatives in Moraxella sp.

Chemical industries produce wastewater that contains large amount of aromatic substances including chlorinated compounds. Moraxella sp. isolated from a petroleum refinery unit efficiently used a variety of benzene derivatives bearing hydroxyl, methoxyl, carboxyl, and chloro- groups as the sole carbon source. The isolate harbored two plasmids of high mobility that are responsible for the utilization of these substrates.

Characterization of chicken riboflavin carrier protein gene structure and promoter regulation by estrogen.

The chicken riboflavin carrier protein (RCP) is an estrogen induced egg yolk and white protein. Eggs from hens which have a splice mutation in RCP gene fail to hatch, indicating an absolute requirement of RCP for the transport of riboflavin to the oocyte. In order to understand the mechanism of regulation of this gene by estrogen, the chicken RCP gene including 1 kb of the 5' flanking region has been isolated. Characterization of the gene structure shows that it contains six exons and five introns, including an intron in the 5' untranslated region. Sequence analysis of the 5' flanking region does not show the presence of any classical, palindromic estrogen response element (ERE). However, there are six half site ERE consensus elements. Four deletion constructs of the 5' flanking region with varying number of ERE half sites were made in pGL3 basic vector upstream of the luciferase-coding region. Transient transfection of these RCP promoter deletion constructs into a chicken hepatoma cell line (LMH2A) showed 6-12-fold transcriptional induction by a stable estrogen analogue, moxesterol. This suggests that the RCP gene is induced by estrogen even in the absence of a classical ERE and the half sites of ERE in this promoter may be important for estrogen induction

Bioremediation of oil sludge-contaminated soil.

Bioremediation has become an important method for the restoration of oil-polluted environments by the use of indigenous or selected microbial flora. Several factors such as aeration, use of inorganic nutrients or fertilizers and the type of microbial species play a major role in the remediation of oil-contaminated sites. Experiments were undertaken for bioremediation of oil sludge-contaminated soil in the presence of a bacterial consortium, inorganic nutrients, compost and a bulking agent (wheat bran). Experiments were conducted in glass troughs for the 90-day period. Bulked soil showed more rapid degradation of oil compared to all other amendments. During the experimental period, wheat bran-amended soil showed 76% hydrocarbon removal compared to 66% in the case of inorganic nutrients-amended soil. A corresponding increase in the number of bacterial populations was also noticed. Addition of the bacterial consortium in different amendments significantly enhanced the removal of oil from the petroleum sludge from different treatment units.

Utilization of petroleum hydrocarbons by Pseudomonas fluorescens isolated from a petroleum-contaminated soil.

A strain of Pseudomonas fluorescens, isolated from petroleum hydrocarbon-contaminated soil was examined for its ability to utilize a variety of hydrocarbon substrates. Surface tension measurements indicated the production of biosurfactant during the microbial degradation of hydrocarbon. The organism utilized both short and long chain n-alkanes. It emulsified a number of aliphatic and aromatic hydrocarbons.

Degradation of labelled lignins and veratrylglycerol-beta-guaiacyl ether by Acinetobacter sp.

Acinetobacter sp. evolved 14CO2 from 14C-(ring)DHP lignin and 14C-teakwood lignin. Veratrylglycerol-beta-guaiacyl ether, a lignin model compound with beta-o-4 linkage was cleaved by Acinetobacter sp. Veratrylglycerol-beta-guaiacyl ether into 2(o-methoxyphenoxy) ethanol and veratrylalcohol 2(o-methoxyphenoxy) ethanol was degraded to guaiacol and then to catechol whereas veratrylalcohol was converted to veratraldehyde, veratric acid, vanillic acid, protocatechuic acid and catechol. Both catechol 1,2-dioxygenase and protocatechuate 3,4-dioxygenase were detected in veratrylglycerol-beta-guaiacyl ether grown cultures.