Ancient and Nonuniform Loss of Olfactory Receptor Expression Renders the Shark Nose a De Facto Vomeronasal Organ.

Cartilaginous fishes are renowned for a keen sense of smell, a reputation based on behavioral observations and supported by the presence of large and morphologically complex olfactory organs. At the molecular level, genes belonging to the four families coding for most olfactory chemosensory receptors in other vertebrates have been identified in a chimera and a shark, but it was unknown whether they actually code for olfactory receptors in these species. Here, we describe the evolutionary dynamics of these gene families in cartilaginous fishes using genomes of a chimera, a skate, a sawfish, and eight sharks. The number of putative OR, TAAR, and V1R/ORA receptors is very low and stable, whereas the number of putative V2R/OlfC receptors is higher and much more dynamic. In the catshark Scyliorhinus canicula, we show that many V2R/OlfC receptors are expressed in the olfactory epithelium in the sparsely distributed pattern characteristic for olfactory receptors. In contrast, the other three vertebrate olfactory receptor families are either not expressed (OR) or only represented with a single receptor (V1R/ORA and TAAR). The complete overlap of markers of microvillous olfactory sensory neurons with pan-neuronal marker HuC in the olfactory organ suggests the same cell-type specificity of V2R/OlfC expression as for bony fishes, that is, in microvillous neurons. The relatively low number of olfactory receptors in cartilaginous fishes compared with bony fishes could be the result of an ancient and constant selection in favor of a high olfactory sensitivity at the expense of a high discrimination capability.

Serotype and genomic diversity of dengue virus during the 2023 outbreak in Pakistan reveals the circulation of genotype III of DENV-1 and cosmopolitan genotype of DENV-2.

Dengue, a mosquito-borne viral disease, poses a significant public health challenge in Pakistan, with a significant outbreak in 2023, prompting our investigation into the serotype and genomic diversity of the dengue virus (DENV). NS-1 positive blood samples from 153 patients were referred to the National Institute of Health, Pakistan, between July and October 2023. Among these, 98 (64.1%) tested positive using multiplex real-time PCR, with higher prevalence among males (65.8%) and individuals aged 31-40. Serotyping revealed DENV-1 as the predominant serotype (84.7%), followed by DENV-2 (15.3%). Whole-genome sequencing of 18 samples (DENV-1 = 17, DENV-2 = 01) showed that DENV-1 (genotype III) samples were closely related (>99%) to Pakistan outbreak samples (2022), and approx. > 98% with USA (2022), Singapore and China (2016), Bangladesh (2017), and Pakistan (2019). The DENV-2 sequence (cosmopolitan genotype; clade IVA) shared genetic similarity with Pakistan outbreak sequences (2022), approx. > 99% with China and Singapore (2018-2019) and showed divergence from Pakistan sequences (2008-2013). No coinfection with dengue serotypes or other viruses were observed. Comparisons with previous DENV-1 sequences highlighted genetic variations affecting viral replication efficiency (NS2B:K55R) and infectivity (E:M272T). These findings contribute to dengue epidemiology understanding and underscore the importance of ongoing genomic surveillance for future outbreak responses in Pakistan.

National Comparison of Burnout for a Cohort of Surgical and Nonsurgical Female Trainees.

INTRODUCTION: Studies have shown that female physician trainees have an increased risk of burnout. We describe the current state of surgical and nonsurgical female trainee well-being and examine differences between surgical and nonsurgical specialties. METHODS: Survey responses were received from 1017 female identifying trainees from 26 graduate medical education institutions across the United States. These survey responses included demographic data and well-being measures. Specifically, burnout was assessed using the Maslach Burnout Inventory. Data were analyzed using Wilcoxon rank sum test, Fisher's exact test, and Pearson's Chi-squared test data with significance defined as a P < 0.05. This survey was reported in line with strengthening the reporting of cohort studies in surgery criteria. RESULTS: Nine-hundred ninety-nine participants completed the demographic and well-being section of the surveys and were included in analysis. Demographic data between the surgical versus nonsurgical group were similar, aside from surgeons being slightly older. Burnout was prevalent among all surveyed trainees with 63% scoring positive. Trainees also scored high in imposter syndrome and moral injury with low levels of self-compassion, although respondents also reported themselves flourishing. Surgical trainees scored higher than nonsurgical trainees in the personal accomplishment domain of burnout (P < 0.048). There was no difference between surgical and nonsurgical trainees in measures of the emotional exhaustion or depersonalization domains of burnout, or in impostor syndrome, self-compassion, moral injury, or flourishing. CONCLUSIONS: While personal accomplishment was noted to be higher in surgical trainees as compared to nonsurgical trainees, overall rates of burnout are high among both groups. Targeted interventions for well-being, such as coaching, can help decrease the levels of burnout experienced by female physician trainees and do not need to be specialty specific.

Genomic characterization of human respiratory syncytial virus circulating in Islamabad, Pakistan, during an outbreak in 2022-2023.

In this study, conducted at the National Institute of Health, Islamabad, during an outbreak of human respiratory syncytial virus (hRSV) from December 2022 to January 2023, the first whole-genome sequences of hRSV isolates from Islamabad, Pakistan, were determined. Out of 10 positive samples, five were sequenced, revealing the presence of two genotypes: RSV-A (GA2.3.5, ON1 strain) and RSV-B (GB5.0.5.a, BA-10 strain). A rare non-synonymous substitution (E232G) in G the protein and N276S in the F protein were found in RSV-A. In RSV-B, the unique mutations K191R, Q209R, and I206M were found in the F protein. These mutations could potentially influence vaccine efficacy and viral pathogenicity. This research underscores the importance of genomic surveillance for understanding RSV diversity and guiding public health responses in Pakistan.

Synthesis, Kinetics and Computational Explorations of 4-Phenylpiperazine Bearing N-(Aryl)-3-substituted-benzamides as Auspicious Tyrosinase Inhibitors.

In the aimed research study, a new series of N-(aryl)-3-[(4-phenyl-1-piperazinyl)methyl]benzamides was synthesized, which was envisaged as tyrosinase inhibitor. The structures of these newly designed molecules were verified by IR, 1H-NMR, 13C-NMR, EI-MS and CHN analysis data. These molecules were screened against tyrosinase and their inhibitory activity explored that these 3-substituted-benzamides exhibit good to excellent potential, comparative to the standard. The Kinetics mechanism was investigated through Lineweaver-Burk plots which depicted that molecules inhibited this enzyme in a competitive mode. Moreover, molecular docking was also performed to determine the binding interaction of all synthesized molecules (ligands) with the active site of tyrosinase enzyme and the results showed that most of the ligands exhibited efficient binding energy values. Therefore, it is anticipated that these molecules might serve as auspicious therapeutic scaffolds for treatment of the tyrosinase associated skin disorders.

Biochemical, Toxicological, and in Silico Aspects of Trillium govanianum Wall. ex D.Don (Trilliaceae): A Rich Source of Natural Bioactive Compounds.

Trillium govanianum is a high-value medicinal herb, having multifunctional traditional and culinary uses. The present investigation was carried out to evaluate the phytochemical, biological and toxicological parameters of the T. govanianum Wall. ex D. Don (Family: Trilliaceae) roots collected from Azad Kashmir, Pakistan. Phytochemical profiling was achieved by determining total bioactive contents (total phenolic and flavonoid contents) and UHPLC-MS analysis. For biological evaluation, antioxidant activities (DPPH, ABTS, FRAP, CUPRAC, phosphomolybdenum, and metal chelation assays) and enzyme inhibition activities (against AChE, BChE, glucosidase, amylase, and tyrosinase) were performed. Moreover, cytotoxicity was assessed against three human carcinoma cell lines (MDA-MB-231, CaSki, and DU-145). The tested extract was found to contain higher total phenolics (7.56 mg GAE/g dry extract) as compared to flavonoid contents (0.45 mg RE/g dry extract). Likewise, for the antioxidant activity, higher CUPRAC activity was noted with 39.84 mg TE/g dry extract values. In the case of enzyme assays, higher activity was pointed out against the cholinesterase, glucosidase and tyrosinase enzymes. The plant extract displayed significant cytotoxicity against the cell lines examined. Moreover, the in-silico studies highlighted the interaction between the important phytochemicals and tested enzymes. To conclude, the assessed biological activity and the existence of bioactive phytochemicals in the studied plant extract may pave the way for the development of novel pharmaceuticals.

Exploring the therapeutic potential of Derris elliptica (Wall.) Benth in Streptozotocin-Induced diabetic Rats: Phytochemical characterization and antidiabetic evaluation.

Derris elliptica (Wall.) Benth, a native medicinal plant, has been used to treat diabetes for centuries; however, comprehensive documentation of its bioactive constituents and therapeutic effectiveness is lacking. In this study, we investigated the phytochemical profile and antidiabetic potential of D. elliptica methanolic leaf extract (DEME) in diabetic Sprague Dawley rats induced with streptozotocin (STZ). In normal rats, acute oral toxicity evaluations were conducted, and in STZ-induced rats, antidiabetic properties were investigated. 14 days of oral administration of standard glibenclamide and the extract at 200 and 400 mg/kg body weight to diabetic rodents. Assessed parameters included blood glucose levels, alterations in body weight, biochemical markers, and histological analysis of the pancreas, liver, and kidney. Numerous phytoconstituents were uncovered through qualitative phytochemical assays, 1H NMR, and 1H-13C HSQC screening. Quercetin was identified by 1H NMR characterization, and a ceramide analogue compound was isolated and partially characterized by 1H NMR. There were no indications of toxicity or mortality. The treatment with DEME significantly (p < 0.001) decreased body weight and had a remarkable hypoglycemic effect. Both 200 mg/kg and 400 mg/kg extract concentrations decreased total cholesterol levels significantly (p < 0.01 and p < 0.05, respectively). In addition, glibenclamide and the 400 mg/kg dose of extract increased serum insulin levels substantially (p < 0.05) and decreased total bilirubin, lactic acid dehydrogenase, aspartate aminotransferase, and alanine aminotransferase levels. In addition to glibenclamide, treatment with DEME has exhibited cytoprotective effects and increased insulin secretion, thereby exerting a potent antihyperglycemic effect. These results suggest that D. elliptica may have therapeutic potential for the treatment of diabetes mellitus.

First report of coinfection and whole-genome sequencing of norovirus and sapovirus in an acute gastroenteritis patient from Pakistan.

Acute gastroenteritis is one of the most common diseases in infants and children in developing countries including Pakistan. In Pakistan, rotavirus (RVA) is known to contribute significantly to pediatric diarrheal illness, but the contribution of other viruses is still unclear. In the current study we have identified a case of mixed infection of norovirus (NoV) and sapovirus (SaV) in a 2-year-old child with acute gastroenteritis. The sample was initially processed for the detection of group A RVA through ELISA followed by NoV using RT-PCR assay. The sample tested positive for NoV RNA and was later subjected to whole-genome sequencing using meta-genome approach on Miseq (Illumina) platform. Sequencing results revealed GII.15 genotype of NoV that clustered with viruses from China and USA from 2017 to 2021. We also retrieved the complete genome of SaV (GI.1 genotype) from the same sample and phylogenetic analysis showed clustering with strains reported from Japan, South Korea, US, and Taiwan during 2012-2016. This is the first report from Pakistan that confirms coinfection of NoV and SaV and elucidates their whole genomes. We recommend initiation of NoV and SaV surveillance program to ascertain disease burden and explore genetic diversity, especially as RVA vaccines have been included in national immunization program.

Synthesis and Computational Exploration of Morpholine Bearing Halogenated Sulfonamides as Potential Tyrosinase Inhibitors.

In the presented work, a new series of three different 4-((3,5-dichloro-2-[(2/4-halobenzyl)oxy]phenyl)sulfonyl)morpholines was synthesized and the structure of these compounds were corroborated by 1 H-NMR & 13 C-NMR studies. The in vitro results established all the three compounds as potent tyrosinase inhibitors relative to the standard. The Kinetics mechanism plots established that compound 8 inhibited the enzyme non-competitively. The inhibition constants Ki calculated from Dixon plots for this compound was 0.0025 µM. Additionally, computational techniques were used to explore electronic structures of synthesized compounds. Fully optimized geometries were further docked with tyrosinase enzyme for inhibition studies. Reasonably good binding/interaction energies and intermolecular interactions were obtained. Finally, drug likeness was also predicted using the rule of five (RO5) and Chemical absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics. It is anticipated that current experimental and computational investigations will evoke the scientific interest of the research community for the above-entitled compounds.

Synthesis, Characterization, and Biological Evaluation of 2-(N-((2'-(2H-tetrazole-5-yl)-[1,1'-biphenyl]-4yl)-methyl)-pentanamido)-3-methyl Butanoic Acid Derivatives.

This study aimed to evaluate 2-(N-((2'-(2H-tetrazole-5-yl)-[1,1'-biphenyl]-4yl)-methyl)-pentanamido)-3-methyl butanoic acid-based ester derivatives as a new class of angiotensin-II receptor antagonists. For this purpose, a series of compounds were synthesized using a variety of phenols. Their chemical characterization was established by FTIR, 1HNMR, and 13CNMR techniques. The biological activities including antioxidant potentials using the DPPH assay, the antihypertensive assay, the urease enzyme inhibition assay, and the antibacterial assay using agar well diffusion methods were performed. All the new compounds showed significant free radical scavenging potentials more than the parent drug while retaining antihypertensive potentials along with urease inhibition properties. However, the AV2 test compound was found to be the most potent against hypertension. Most of the synthesized analogs showed urease inhibitory actions. Molecular docking studies were performed for all the active analogs to decode the binding detail of the ligands with receptors of the enzyme's active site.

Synthesis, DFT Studies, Molecular Docking and Biological Activity Evaluation of Thiazole-Sulfonamide Derivatives as Potent Alzheimer's Inhibitors.

Alzheimer's disease is a major public brain condition that has resulted in many deaths, as revealed by the World Health Organization (WHO). Conventional Alzheimer's treatments such as chemotherapy, surgery, and radiotherapy are not very effective and are usually associated with several adverse effects. Therefore, it is necessary to find a new therapeutic approach that completely treats Alzheimer's disease without many side effects. In this research project, we report the synthesis and biological activities of some new thiazole-bearing sulfonamide analogs (1-21) as potent anti-Alzheimer's agents. Suitable characterization techniques were employed, and the density functional theory (DFT) computational approach, as well as in-silico molecular modeling, has been employed to assess the electronic properties and anti-Alzheimer's potency of the analogs. All analogs exhibited a varied degree of inhibitory potential, but analog 1 was found to have excellent potency (IC50 = 0.10 ± 0.05 µM for AChE) and (IC50 = 0.20 ± 0.050 µM for BuChE) as compared to the reference drug donepezil (IC50 = 2.16 ± 0.12 µM and 4.5 ± 0.11 µM). The structure-activity relationship was established, and it mainly depends upon the nature, position, number, and electron-donating/-withdrawing effects of the substituent/s on the phenyl rings.

Genomic surveillance reveals the detection of SARS-CoV-2 delta, beta, and gamma VOCs during the third wave in Pakistan.

SARS-CoV-2 variants of concern (VOCs) have emerged worldwide and gained significant importance due to their high transmissibility and global spread, thus meriting close monitoring. In Pakistan, limited information is available on circulation of these variants as the alpha variant has been reported the main circulating lineage. The current study was designed to detect and explore the genomic diversity of SARS-CoV-2 lineages circulating during the third wave of the pandemic in the indigenous population. From May 01 to June 09, 2021, a total of 16 689 samples were tested using TaqPath™ COVID-19 kit for the presence of SARS-CoV-2. Overall, 2562 samples (15.4%) were COVID-19 positive. Out of these positive samples, 2124 (12.7%) did not show the spike gene amplification (spike gene target failure ([SGTF]), whereas 438 (2.6%) showed spike gene amplification (non-SGTF). A subset (n = 58/438) of non-SGTF samples were randomly selected for whole-genome sequencing. Among VOCs, 45% (n = 26/58) were delta, 46% (n = 27/58) were beta, and one was gamma variant. The delta variant cases were reported mainly from Islamabad (n = 15; 58%) followed by Rawalpindi and Azad Kashmir (n = 1; 4% each). Beta variant cases originated mainly from Karachi (n = 8; 30%) and Islamabad (n = 11; 41%) and the gamma variant case was reported in a traveler from Italy. The delta, beta, and gamma variants possessed lineage-specific spike mutations. Notably, two rare mutations (E484Q and L5F) were found in the delta variant. Furthermore, in the beta variant, two significant rare non-synonymous spike mutations (A879S and K444R) were also reported. High prevalence of beta and delta variants in local population may increase the number of cases in the near future and provides an early warning to national health authorities to take timely decisions and devise suitable interventions to contain a possible fourth wave.

Prospect of Anterior Gradient 2 homodimer inhibition via repurposing FDA-approved drugs using structure-based virtual screening.

Anterior Gradient 2 (AGR2) has recently been reported as a tumor biomarker in various cancers, i.e., breast, prostate and lung cancer. Predominantly, AGR2 exists as a homodimer via a dimerization domain (E60-K64); after it is self-dimerized, it helps FGF2 and VEGF to homo-dimerize and promotes the angiogenesis and the invasion of vascular endothelial cells and fibroblasts. Up till now, no small molecule has been discovered to inhibit the AGR2-AGR2 homodimer. Therefore, the present study was performed to prepare a validated 3D structure of AGR2 by homology modeling and discover a small molecule by screening the FDA-approved drugs library on AGR2 homodimer as a target protein. Thirteen different homology models of AGR2 were generated based on different templates which were narrowed down to 5 quality models sorted by their overall Z-scores. The top homology model based on PDB ID = 3PH9 was selected having the best Z-score and was further assessed by Verify-3D, ERRAT and RAMPAGE analysis. Structure-based virtual screening narrowed down the large library of FDA-approved drugs to ten potential AGR2-AGR2 homodimer inhibitors having FRED score lower than - 7.8 kcal/mol in which the top 5 drugs' binding stability was counter-validated by molecular dynamic simulation. To sum up, the present study prepared a validated 3D structure of AGR2 and, for the first time reported the discovery of 5 FDA-approved drugs to inhibit AGR2-AGR2 homodimer by using structure-based virtual screening. Moreover, the binding of the top 5 hits with AGR2 was also validated by molecular dynamic simulation. A validated 3D structure of Anterior Gradient 2 (AGR2) was prepared by homology modeling, which was used in virtual screening of FDA-approved drugs library for the discovery of prospective inhibitors of AGR2-AGR2 homodimer.

Genomic Characterization of SARS-CoV2 from Peshawar Pakistan Using Next-Generation Sequencing.

This study aimed to characterize the whole genome of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) isolated from an oropharyngeal swab specimen of a Pashtun Pakistani patient using next-generation sequencing. Upon comparing the SARS-CoV2 genome to the reference genome, a total of 10 genetic variants were identified. Among the 10 genetic variants, 1 missense mutation (c.1139A > G, p.Lys292Glu) in the Open Reading Frame 1ab (ORF1ab) positioned at 112 in the non-structural protein 2 (NSP2) was found to be unique. Phylogenetic analysis (n = 84) revealed that the current SARS-CoV2 genome was closely clustered with 8 Pakistani strains belonging to Punjab, Federal Capital, Azad Jammu and Kashmir (AJK), and Khyber Pakhtunkhwa (KP). In addition, the current SARS-CoV2 genome was very similar to the genome of SARS-CoV2 reported from Guam, Taiwan, India, the USA, and France. Overall, this study reports a slight mismatch in the SARS-CoV2 genome, indicating the presence of a single unique missense mutation. However, phylogenetic analysis revealed that the current SARS-CoV2 genome was closely clustered with 8 other Pakistani strains.

Flavonoids as Antidiabetic and Anti-Inflammatory Agents: A Review on Structural Activity Relationship-Based Studies and Meta-Analysis.

Flavonoids are a group of naturally occurring polyphenolic secondary metabolites which have been reported to demonstrate a wide range of pharmacological properties, most importantly, antidiabetic and anti-inflammatory effects. The relationship between hyperglycaemia and inflammation and vascular complications in diabetes is now well established. Flavonoids possessing antidiabetic properties may alleviate inflammation by reducing hyperglycaemia through different mechanisms of action. It has been suggested that the flavonoids' biochemical properties are structure-dependent; however, they are yet to be thoroughly grasped. Hence, the main aim of this review is to understand the antidiabetic and anti-inflammatory properties of various structurally diverse flavonoids and to identify key positions responsible for the effects, their correlation, and the effect of different substitutions on both antidiabetic and anti-inflammatory properties. The general requirement of flavonoids for exerting both anti-inflammatory and antidiabetic effects is found to be the presence of a C2-C3 double bond (C-ring) and hydroxyl groups at the C3', C4', C5, and C7 positions of both rings A and B of a flavonoid skeleton. Furthermore, it has been demonstrated that substitution at the C3 position of a C-ring decreases the anti-inflammatory action of flavonoids while enhancing their antidiabetic activity. Correlation is discussed at length to support flavonoids possessing essential pharmacophores to demonstrate equipotent effects. The consideration of these structural features may play an important role in synthesizing better flavonoid-based drugs possessing dual antidiabetic and anti-inflammatory effects. A meta-analysis further established the role of flavonoids as antidiabetic and anti-inflammatory agents.

Facile Synthesis of Functionalized Phenoxy Quinolines: Antibacterial Activities against ESBL Producing Escherichia coli and MRSA, Docking Studies, and Structural Features Determination through Computational Approach.

The synthesis of new 6-Bromoquinolin-4-ol derivatives (3a-3h) by Chan-Lam coupling utilizing different types of solvents (protic, aprotic, and mixed solvents) and bases was studied in the present manuscript. Furthermore, their potential against ESBL producing Escherichia coli (ESBL E. coli) and methicillin-resistant Staphylococcusaureus (MRSA) were investigated. Commercially available 6-bromoquinolin-4-ol (3a) was reacted with different types of aryl boronic acids along with Cu(OAc)2 via Chan-Lam coupling methodology utilizing the protic and aprotic and mixed solvents. The molecules (3a-3h) exhibited very good yields with methanol, moderate yields with DMF, and low yields with ethanol solvents, while the mixed solvent CH3OH/H2O (8:1) gave more excellent results as compared to the other solvents. The in vitro antiseptic values against ESBL E. coli and MRSA were calculated at five different deliberations (10, 20, 30, 40, 50 mg/well) by agar well diffusion method. The molecule 3e depicted highest antibacterial activity while compounds 3b and 3d showed low antibacterial activity. Additionally, MIC and MBC standards were calculated against the established bacteria by broth dilution method. Furthermore, a molecular docking investigation of the derivatives (3a-3h) were performed. Compound (3e) was highly active and depicted the least binding energy of -5.4. Moreover, to investigate the essential structural and physical properties, the density functional theory (DFT) findings of the synthesized molecules were accomplished by using the basic set PBE0-D3BJ/def2-TZVP/SMD water level of the theory. The synthesized compounds showed an energy gap from 4.93 to 5.07 eV.

Multitargeted Molecular Docking and Dynamic Simulation Studies of Bioactive Compounds from Rosmarinus officinalis against Alzheimer's Disease.

Alzheimer's disease (AD) has been associated with the hallmark features of cholinergic dysfunction, amyloid beta (Aß) aggregation and impaired synaptic transmission, which makes the associated proteins, such as ß-site amyloid precursor protein cleaving enzyme 1 (BACE I), acetylcholine esterase (AChE) and synapsin I, II and III, major targets for therapeutic intervention. The present study investigated the therapeutic potential of three major phytochemicals of Rosmarinus officinalis, ursolic acid (UA), rosmarinic acid (RA) and carnosic acid (CA), based on their binding affinity with AD-associated proteins. Detailed docking studies were conducted using AutoDock vina followed by molecular dynamic (MD) simulations using Amber 20. The docking analysis of the selected molecules showed the binding energies of their interaction with the target proteins, while MD simulations comprising root mean square deviation (RMSD), root mean square fluctuation (RMSF) and molecular mechanics/generalized born surface area (MM/GBSA) binding free energy calculations were carried out to check the stability of bound complexes. The drug likeness and the pharmacokinetic properties of the selected molecules were also checked through the Lipinski filter and ADMETSAR analysis. All these bioactive compounds demonstrated strong binding affinity with AChE, BACE1 and synapsin I, II and III. The results showed UA and RA to be potential inhibitors of AChE and BACE1, exhibiting binding energies comparable to those of donepezil, used as a positive control. The drug likeness and pharmacokinetic properties of these compounds also demonstrated drug-like characteristics, indicating the need for further in vitro and in vivo investigations to ascertain their therapeutic potential for AD.

In Vitro and In Silico Investigation of Diterpenoid Alkaloids Isolated from Delphinium chitralense.

This study reports the isolation of three new C20 diterpenoid alkaloids, Chitralinine A-C (1-3) from the aerial parts of Delphinium chitralense. Their structures were established on the basis of latest spectral techniques and single crystal X-rays crystallographic studies of chitralinine A described basic skeleton of these compounds. All the isolated Compounds (1-3) showed strong, competitive type inhibition against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in comparison to standard allanzanthane and galanthamine however, chitralinine-C remained the most potent with IC50 value of 11.64 ± 0.08 µM against AChE, and 24.31 ± 0.33 µM against BChE, respectively. The molecular docking reflected a binding free energy of -16.400 K Cal-mol-1 for chitralinine-C, having strong interactions with active site residues, TYR334, ASP72, SER122, and SER200. The overall findings suggest that these new diterpenoid alkaloids could serve as lead drugs against dementia-related diseases including Alzheimer's disease.

Antibacterial Effects of Flavonoids and Their Structure-Activity Relationship Study: A Comparative Interpretation.

According to the latest report released by the World Health Organization, bacterial resistance to well-known and widely available antibacterial drugs has become a significant and severe global health concern and a grim challenge to tackle in order to cure infections associated with multidrug-resistant pathogenic microorganisms efficiently. Consequently, various strategies have been orchestrated to cure the severe complications related to multidrug-resistant bacteria effectively. Some approaches involved the retardation of biofilm formation and multidrug-resistance pumps in bacteria as well as the discovery of new antimicrobial agents demonstrating different mechanisms of action. In this regard, natural products namely alkaloids, terpenoids, steroids, anthraquinone, flavonoids, saponins, tannins, etc., have been suggested to tackle the multidrug-resistant bacterial strains owing to their versatile pharmacological effects. Amongst these, flavonoids, also known as polyphenolic compounds, have been widely evaluated for their antibacterial property due to their tendency to retard the growth of a wide range of pathogenic microorganisms, including multidrug-resistant bacteria. The hydroxylation of C5, C7, C3', and C4'; and geranylation or prenylation at C6 have been extensively studied to increase bacterial inhibition of flavonoids. On the other hand, methoxylation at C3' and C5 has been reported to decrease flavonoids' antibacterial action. Hence, the latest information on the antibacterial activity of flavonoids is summarized in this review, with particular attention to the structure-activity relationship of this broad class of natural compounds to discover safe and potent antibacterial agents as natural products.

Synthesis of Functionalized Thiophene Based Pyrazole Amides via Various Catalytic Approaches: Structural Features through Computational Applications and Nonlinear Optical Properties.

In the present study, pyrazole-thiophene-based amide derivatives were synthesized by different methodologies. Here, 5-Bromothiophene carboxylic acid (2) was reacted with substituted, unsubstituted, and protected pyrazole to synthesize the amide. It was observed that unsubstituted amide (5-bromo-N-(5-methyl-1H-pyrazol-3-yl)thiophene-2-carboxamide (7) was obtained at a good yield of about 68 percent. The unsubstituted amide (7) was arylated through Pd (0)-catalyzed Suzuki-Miyaura cross-coupling, in the presence of tripotassium phosphate (K3PO4) as a base, and with 1,4-dioxane as a solvent. Moderate to good yields (66-81%) of newly synthesized derivatives were obtained. The geometry of the synthesized compounds (9a-9h) and other physical properties, like non-linear optical (NLO) properties, nuclear magnetic resonance (NMR), and other chemical reactivity descriptors, including the chemical hardness, electronic chemical potential, ionization potential, electron affinity, and electrophilicity index have also been calculated for the synthesized compounds. In this study, DFT calculations have been used to investigate the electronic structure of the synthesized compounds and to compute their NMR data. It was also observed that the computed NMR data manifested significant agreement with the experimental NMR results. Furthermore, compound (9f) exhibits a better non-linear optical response compared to all other compounds in the series. Based on frontier molecular orbital (FMO) analysis and the reactivity descriptors, compounds (9c) and (9h) were predicted to be the most chemically reactive, while (9d) was estimated to be the most stable among the examined series of compounds.