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.

Superior laryngeal nerve block with in-line lignocaine nebulization for awake extubation response.

Background and Aims: Tracheal extubation is associated with various undesirable hemodynamic and airway responses. Various drugs are used effectively to curb these responses. But these drugs have limitations and produce side effects. Hence, the study was planned to assess the effects of superior laryngeal nerve block with inline lignocaine nebulization on awake extubation responses to suggest an alternative. The aim of this study was to assess the effect of bilateral superior laryngeal nerve block with inline lignocaine nebulization on awake extubation responses. Material and Methods: A study was conducted in 35 patients aged 18-60 years, posted for surgery less than 3 h under general anesthesia. The hemodynamic responses like heart rate, arterial blood pressure, and mean arterial pressure were recorded preoperatively and at 1, 5, and 10 min postextubation. Undesirable respiratory responses like bucking, severity of sore throat, and cough response were also assessed. Repeated measures analysis of variance followed by the Tukey HSD test was used to find the significance of hemodynamic parameters. Qualitative data were expressed as percentages. Results: Decrease in Systolic Blood Pressure, Diastolic Blood Pressure and Mean Arterial Pressure was statistically significant at 5 mins (T2) and 10 mins (T3) postextubation as compared to baseline (T0). No cough was observed postextubation in 80% patients while 20% had mild Grade 1 cough. Conclusion: Superior laryngeal nerve block with in-line lignocaine nebulization for awake extubation is effective in curbing the haemodynamic and respiratory responses of extubation.

Physics-informed machine learning: case studies for weather and climate modelling.

Machine learning (ML) provides novel and powerful ways of accurately and efficiently recognizing complex patterns, emulating nonlinear dynamics, and predicting the spatio-temporal evolution of weather and climate processes. Off-the-shelf ML models, however, do not necessarily obey the fundamental governing laws of physical systems, nor do they generalize well to scenarios on which they have not been trained. We survey systematic approaches to incorporating physics and domain knowledge into ML models and distill these approaches into broad categories. Through 10 case studies, we show how these approaches have been used successfully for emulating, downscaling, and forecasting weather and climate processes. The accomplishments of these studies include greater physical consistency, reduced training time, improved data efficiency, and better generalization. Finally, we synthesize the lessons learned and identify scientific, diagnostic, computational, and resource challenges for developing truly robust and reliable physics-informed ML models for weather and climate processes. This article is part of the theme issue 'Machine learning for weather and climate modelling'.

Synthesis of an Oxathiolane Drug Substance Intermediate Guided by Constraint-Driven Innovation.

A new route was developed for construction of the oxathiolane intermediate used in the synthesis of lamivudine (3TC) and emtricitabine (FTC). We developed the presented route by constraining ourselves to low-cost, widely available starting materials-we refer to this as supply-centered synthesis. Sulfenyl chloride chemistry was used to construct the framework for the oxathiolane from acyclic precursors. This bond construction choice enabled the use of chloroacetic acid, vinyl acetate, sodium thiosulfate, and water to produce the oxathiolane.

Access to a Stereoisomer Library of Solomonamide Macrocycles.

In an attempt towards understanding stereo-structure activity relationships (SSARs), we have prepared eight possible stereoisomers of solomonamide macrocycles, in particular, by changing the stereochemical pattern of non-peptide fragment AHMOA. Here, we have demonstrated different ways to construct three contiguous chiral centers present in solomonamide B macrocycle using substrate/reagent-controlled methods. These methods involve Brown crotylation, NHK reaction and Evans aldol addition as key steps to synthesize key non-peptide fragment. Further, these non-peptide fragments were converted to their corresponding macrocycles via ligand-free intramolecular Heck reaction.

An innovative modified feeding appliance for an infant with cleft lip and cleft palate: A case report.

Cleft lip and palate is one of the most common craniofacial anomalies of humans. A child born with cleft lip and palate may experience difficulties while feeding due to lack of seal of the oral cavity due to incomplete facial and palatal structures. Difficulty in feeding leads to inadequate nutrition and affects the health of the infant. Feeding difficulties should be assessed and intervened as early as possible, as they are an important aspect of the multidisciplinary team approach in the management of cleft lip and palate. Feeding appliance is a favorable feeding option in these infants as it creates a separation between oral and nasal cavities and thus helps in creating a negative intraoral pressure during suckling. This case report represents a fabrication of feeding appliance for a 2-day-old neonate born with cleft lip and palate, using copper wire as a retainer for the appliance.

Discovery of Potent and Selective A2A Antagonists with Efficacy in Animal Models of Parkinson's Disease and Depression.

Adenosine A2A receptor (A2AAdoR) antagonism is a nondopaminergic approach to Parkinson's disease treatment that is under development. Earlier we had reported the therapeutic potential of 7-methoxy-4-morpholino-benzothiazole derivatives as A2AAdoR antagonists. We herein described a novel series of [1,2,4]triazolo[5,1-f]purin-2-one derivatives that displays functional antagonism of the A2A receptor with a high degree of selectivity over A1, A2B, and A3 receptors. Compounds from this new scaffold resulted in the discovery of highly potent, selective, stable, and moderate brain penetrating compound 33. Compound 33 endowed with satisfactory in vitro and in vivo pharmacokinetics properties. Compound 33 demonstrated robust oral efficacies in two commonly used models of Parkinson's disease (haloperidol-induced catalepsy and 6-OHDA lesioned rat models) and depression (TST and FST mice models).

Total Synthesis of the Marine Natural Product Solomonamide B Necessitates Stereochemical Revision.

The first total synthesis of the proposed structure of solomonamide B has been achieved. However, the (1)H and (13)C NMR spectral data of the synthesized compound was not exactly matching with that of the natural solomonamide B. This prompted us to revise the originally proposed structure, in particular, the stereochemistry of the nonpeptide part, which was confirmed by its total synthesis. During the course of the synthesis, we have developed an interesting hydroxy group directed Wacker oxidation of internal olefins in a macrocyclic setting.

Breaking and making of olefins simultaneously using ozonolysis: application to the synthesis of useful building blocks and macrocyclic core of solomonamides.

A simple and practical one-pot, two-directional approach to access olefinic esters through simultaneous breaking and making of olefins using ozonolysis of alkenyl aryl selenides is disclosed. The scope of the method with a variety of examples is demonstrated, and the end products obtained here are useful building blocks. As a direct application of the present method, the macrocyclic core of potent anti-inflammatory natural cyclic peptides, solomonamides, is synthesized.

One-pot quadruple/triple reaction sequence: a useful tool for the synthesis of natural products.

Multiple reactions in one pot has always been a useful technique for synthetic organic chemists, as it can minimizes solvent usage, time and the number of purification steps when compared to individual multi-step syntheses. In line with this, here in this perspective we discuss a one-pot quadruple/triple reaction sequence comprising an enyne ring-closing metathesis/cross-metathesis/Diels-Alder/aromatization for the synthesis of natural products setting.

Total synthesis of Deoxy-solomonamide B by mimicking biogenesis.

A total synthesis of Deoxy-solomonamide B was accomplished starting from tryptophan in an efficient manner by mimicking the proposed biogenetic route. The present synthesis utilizes a crotylation, oxidative cleavage of the indole moiety, and macrolactamization as key steps. The use of the indole nucleus as a masked anthranilic acid unit paves the way for the easy synthesis of related macrocycles and natural products where the ortho-acyl aniline moiety is embedded into them, which otherwise is difficult to synthesize.

Total synthesis of an anticancer norsesquiterpene alkaloid isolated from the fungus Flammulina velutipes.

The first total synthesis of a norsesquiterpene alkaloid (R)-8-hydroxy-4,7,7-trimethyl-7,8-dihydrocyclopenta[e]isoindole-1,3(2H,6H)-dione, isolated from the mushroom-forming fungus Flammulina velutipes, in both racemic and enantiomeric pure forms, is reported. The (-)-enantiomer of the natural product has been synthesized from the D-(-)-pantolactone chiral pool. The synthesis features a one-pot, three-step reaction sequence comprising an enyne RCM/Diels-Alder/aromatization to construct the desired indane skeleton present in the natural product. Our synthesis further confirms the assigned structure and absolute configuration of the natural product.

Labial ankyloglossia associated with oligodontia: a case report.

Developmental disturbances of the tongue (aglossia, macroglossia, microglossia, and ankyloglossia) can adversely affect the development of the surrounding structures including the palate, alveolar process, and teeth. These developmental disturbances impair functions such as mastication, speech, and swallowing. Ankyloglossia is of various types and may be associated with other syndromic features like cleft palate. We report a rare type of non-syndromic ankyloglossia associated with missing of the permanent anterior tooth.

Studies toward the synthesis of potent anti-inflammatory peptides solomonamides A and B: synthesis of a macrocyclic skeleton and key fragment 4-amino-6-(2'-amino-4'-hydroxyphenyl)-3-hydroxy-2-methyl-6-oxohexanoic acid (AHMOA).

A first synthetic effort toward total synthesis of highly potent solomonamides is disclosed. An efficient strategy to synthesize this class of compounds, along with the synthesis of a core macrocycle (shown in red) and the key fragment AHMOA, is described.

Diet and nutritional status of rural preschool children in Punjab.

OBJECTIVE: To assess diet and nutritional profile of rural preschool children of Punjab. STUDY DESIGN: Multistage random sampling method was adopted by following probability proportion to population size (PPS). SUBJECT: Four hundred households (HH) were covered in each district of Punjab for socio-economic and demographic information. All the available individuals from these HHs were included for anthropometry and clinical examination. Every fourth household was covered for 24-hour recall method of diet survey (individual dietary intake). RESULTS: At the state level, the intake of macro and micronutrient rich foods such as cereals, pulses and green leafy vegetables, milk and milk products and fats and oils were lower than the RDI among preschool children. Except for protein, calcium and thiamine, the mean intake of all the nutrients was lower than the recommended level. About a half of the preschool children (50.3%) were undernourished (> 2SD weight for age); 60% were stunted (> 2SD height for age) and 12% were wasted (> 2SD weight for height). The extent of undernutrition and stunting was lower than that reported for the country. There was significant variation in the prevalence of severe stunting between the districts (p < 0.001), with the highest being observed in the Rupnagar (55%) and the lowest in Hoshiarpur and Sangrur (30% each). CONCLUSION: Despite, the reported high rates of economic growth and food production in the state, a higher proportion of preschool children were consuming diets, which are inadequate with respect to energy, fat, iron, riboflavin, vitamin A and vitamin C. The prevalence of undernutrition was high as was found in other states.