Breaking the stress with a non-rigid connector.

Lone standing abutments or pier abutments have usually been restored with a conventional fixed partial denture (FPD) using a rigid connector between the pontics and the retainers. However, such fixed and rigid restorations have been associated with a higher rate of debonding, microleakage, caries, etc., The aim of the modern day prosthodontics is the preservation of what remains as given by M.M Devan. As a result, a non rigid connector (NRC) may be the connector of choice in situations of pier abutment. A NRC acts as a stress breaker so that the anterior and posterior segments can move independent of each other. This case report presents a simple method of rehabilitating a patient with a pier abutment in the upper right posterior region of the mouth. Rehabilitation was done by FPD with an inverted key-keyway type NRC. Follow up was done up to 11 months.

Development in the Synthesis of Bioactive Thiazole-Based Heterocyclic Hybrids Utilizing Phenacyl Bromide.

Heterocyclic hybrid frameworks represent a burgeoning domain within the realms of drug discovery and medicinal chemistry, attracting considerable attention in recent years. Thiazole pharmacophore fragments, inherent in natural products such as peptide alkaloids, metabolites, and cyclopeptides, have demonstrated a broad spectrum of pharmacological potentials. Given their profound biological significance, a plethora of thiazole-based hybrids have been synthesized through the conjugation of thiazole moieties with bioactive pyrazole and pyrazoline fragments. This review systematically presents a compendium of robust methodologies for the synthesis of thiazole-linked hybrids, employing the (3 + 2) heterocyclization reaction, specifically the Hantzsch-thiazole synthesis, utilizing phenacyl bromide as the substrate. The strategic approach of molecular hybridization has markedly enhanced drug efficacy, mitigated resistance to multiple drugs, and minimized toxicity concerns. The resultant thiazole-linked hybrids exhibit a myriad of medicinal properties viz. anticancer, antibacterial, anticonvulsant, antifungal, antiviral, and antioxidant activities. This compilation of methodologies and insights serves as a valuable resource for medicinal chemists and researchers engaged in the design of novel thiazole-linked hybrids endowed with therapeutic attribute.

Pearls & Oy-sters: Bibrachial Amyotrophy From a Dural Tear.

Bibrachial amyotrophy signifies a clinical phenotype characterized by weakness in both upper extremities with preserved strength in the face, neck, and lower extremities. The underlying causes of bibrachial amyotrophy are broad. We report a patient exhibiting bibrachial amyotrophy who initially received a diagnosis of amyotrophic lateral sclerosis (ALS); however, his clinical course and NCS/EMG were atypical for ALS. Further evaluation demonstrated dural tears with CSF leak, resulting in a compressive extradural fluid collection, ventral myelopathy, and intracranial hypotension. Dural tear and ALS have overlapping features, including the manifestation of the bibrachial amyotrophy phenotype and the presence of T2 hyperintensities in the anterior horn cells, recognized by an "owl's eye" appearance on spine MRI. Clinical and radiologic vigilance is required to identify rare cases of dural tear causing ventral myelopathy that manifest as bibrachial amyotrophy.

Physicochemical parameters for design and development of lead herbicide molecules: Is 'Lipinski's rule of 5' appropriate for herbicide discovery?

BACKGROUND: Herbicide use has been a great add-on in agriculture, aiding weed management in crop fields, thereby escalating crop production. However, the development of resistance in weeds against the existing herbicides is a setback. The development of herbicide resistance has compelled the agrochemical industries to replace existing herbicides with novel agrochemicals. Developing new herbicide molecules through traditional methods is time-consuming and cost-prohibitive. The use of high-throughput virtual screening (HTVS) through physicochemical properties, de novo design and combinatorial design of molecules with cutting-edge computational methods is an alternative to the traditional techniques in lead molecule discovery. The lack of optimal physicochemical criteria for screening herbicide-like molecules has become a hindrance in the process. RESULTS: In this study, physicochemical parameters [molecular weight, aromatic atoms, rotatable bonds, hydrogen-bonding capacity, topological polar surface area (TPSA), polarity and solubility] of known herbicide molecules have been studied and evaluated, and optimal criteria have been proposed for target-specific herbicides. Properties including molecular weight and hydrogen (H)-bond acceptor atoms tend to have higher values, but the range of H-bond donor atoms is relatively lower. These are distinguishable characteristics in herbicides when compared with oral drugs. Significant variations in optimal physicochemical parameters between herbicides of different groups (targeting weeds with different modes of action) have been observed. CONCLUSION: The proposed parameters for respective target sites could be used as filters for in silico screening, designing and developing of target-specific lead herbicide molecules. © 2023 Society of Chemical Industry.

Flap sub-domain dynamics of serine-threonine phosphatase (Stp1) of Staphylococcus aureus: an accelerated molecular dynamics simulation study.

Vancomycin and daptomycin are commonly used glycopeptide antibiotics to cure Gram-positive staphylococcal infections. The clinical isolates of mutant Staphylococcus aureus strains, Methicillin-Resistant (MRSA) and Vancomycin-Resistant (VRSA), have developed resistance against these antibiotics. A recently discovered Serine/threonine phosphatase (Stp1) is an Mn+2 containing protein at the active site with a flap sub-domain that participates in the phospho-signaling system of bacterial cell wall formation. The flap sub-domain probably regulates substrates recruitment and release with an extra Mn+2, possibly highly flexible as in the other homologous family of proteins. In this study, the flap sub-domain has been sampled with conventional and accelerated molecular dynamics (cMD and aMD) simulations to get other sub-optimal conformational states of the protein that are nearly impossible to observe through experimental methods. Trajectory analysis has shown that protein remained static in cMD while dynamic in aMD with RMSD of ∼2Å and ∼3Å, respectively. Accelerated MD has shown greater flexibility of ∼4 Å in the flap sub-domain, while cMD only captured a deviation of ∼ 2 Å. Later, the dynamic cross-correlation map (DCCM) confirmed that the flap sub-domain is significantly more flexible than the other part of the structure, indicating its role in substrate regulation. Secondary structure transition in the flap sub-domain, i.e. 3-10 helix and turn (PRO159 - ILE163) region of the flap sub-domain shifted into α-helix, which is a more stable structure. Further, the trajectory has been clustered, and conformational states extracted, which may be exploited in structure-based antibiotics discovery.Communicated by Ramaswamy H. Sarma.

Comparison of single and multiple file rotary endodontic instruments for debris and irrigant extrusion: An in vitro study.

Aim: The aim of this study was to assess and compare the quantity of apically debris which was extruded apically by TruNatomy (TN), ProTaper Next (PTN), HyFlex electric discharge machining (EDM), and HyFlex controlled memory (CM), following root canal preparation. Materials and Methods: Sixty extracted single-canal mandibular premolars were used. The root canal preparation was done with TN, HyFlex EDM, PTN, or HyFlex CM files. The preweight debris, which was extruded apically, was collected in the Eppendorf tube and later on incubated at 670°C for 3 days and weighed again to record the extruded debris. Results: The result showed that there was a significant reduction in debris extrusion by TN system, followed by PTN system, HyFlex EDM, and maximum extrusion in HyFlex CM (P < 0.05). Between the PTN and TN groups as well as between the HyFlex EDM and HyFlex CM groups, statistically significant difference was not observed (P > 0.05). Conclusion: Apical debris extrusion is the inherent nature of the all file systems. Nevertheless, the TN file system produced substantially minimum debris extrusion among other systems compared in the study.

Unravelling the synthetic and therapeutic aspects of five, six and fused heterocycles using Vilsmeier-Haack reagent.

The aim of this review is to encapsulate the synthetic protocols and medicinal aspects of a wide range of heterocyclic compounds using the Vilsmeier-Haack (V. H.) reagent. These derivatives act as excellent precursors having different aryl ring functionalities and could be used for the synthesis of a variety of heterocyclic scaffolds. The V. H. reagent, a versatile reagent in organic chemistry, is used to formylate various heterocyclic compounds of medicinal interest. Due to the different chemical interactions, efficacy, and potency of V. H. reagents, plenty of heterocyclic compounds can be synthesized which serve as a constituent in various novel medications and acts as a bridge between biology and chemistry. These carboxylate moieties can effectively cooperate as precursors for several multi-component reactions (MCR) including Strecker synthesis, Bucherer-Berg reaction and post-MCR cyclization, modified variants with various pharmaceutical applications such as anti-tumor, anti-convulsant, anti-chitosomal and so on.

Comparative evaluation of fracture resistance among conventional versus herbal irrigants in root canal treated teeth: In vitro study.

To evaluate the efficacy of conventional irrigants and herbal extracts materials which helps to resist fracture of endodontically treated teeth. 75 maxillary human permanent incisor teeth instrumented using ProTaper rotary files till apical size(F4). Instrumented samples divided into 5 groups with n = 15 based on various irrigants used. Group I: normal saline, Group II: 5% sodium hypochlorite (NaOCl), Group III: 2% chlorohexidine, Group IV: 10% Azadirachta indica (neem extract) and Group V: 10% Ocimum sanctum (tulsi extract).After that, root canals were proceeded to be filled by using single gutta-percha cone and Sealapex sealer. Specimens were then prepared and loaded until root fracture occurred. Maximum mean flexural strength of dentin (fracture resistance) was obtained from group treated with 2% chlorohexidine and 10% neem extract. Least fracture resistance was observed with 5% NaOCl. Herbal irrigants can be used as an alternative to NaOCl as they exhibit high fracture resistance.

Advances in Aß imaging probes: a comprehensive study of radiolabelled 1,3-diaryl-2-propen-1-ones for Alzheimer's disease: a review.

Alzheimer's disease (AD) is a formidable neurodegenerative disorder characterized by cognitive decline, memory impairment and inability to perform everyday tasks. In the pursuit of innovative diagnostic and therapeutic strategies, the synthesis and application of radiolabelled compounds have garnered significant attention. This review delves into the synthesis and biological significance of radiolabelled 1,3-diaryl-2-propen-1-ones, commonly known as chalcones, as Aß imaging probes for AD. These versatile chalcone derivatives have demonstrated noteworthy potential as radiotracers for visualizing Aß imaging probes, which are hallmark pathologies of AD. This review encompasses an exploration of chalcone synthesis via diverse methodologies and their biological implications, both as standalone entities and as precursors for intricate natural products. In addition, the pivotal role of advanced imaging techniques, such as single-photon emission computed tomography (SPECT) and positron emission tomography (PET), using various radioisotopes is highlighted. The use of radiopharmaceutical agents, including [18F]FDG, [18F]FMAPO, [11C]6-Me-BTA-1, [124/125I]IBETA, and [64Cu]YW-7 as potent tools for early diagnosis and therapeutic advancement is explored. This review underscores the critical nexus between radiolabelled chalcones and their pivotal role in advancing diagnostic and therapeutic paradigms in AD research. Furthermore, this study encapsulated the role of radiolabelled chalcone emphasizing their prospective implications for drug development and therapeutic interventions. A focal point of paramount significance is the elucidation of Aß imaging probes and its important role in the combat against AD, with a particular emphasis on their role in facilitating early diagnosis and fostering advancements in therapeutic strategies.

6-Ethoxy-4- N-(2-morpholin-4-ylethyl) -2-N-propan-2-yl-1,3, 5-triazine-2, 4-diamine endows herbicidal activity against Phalaris minor a weed of wheat crop field: An in -silico and experimental approaches of herbicide discovery.

Phalaris minor is a major weed of wheat crop which has evolved resistance against herbicides. Isoproturon is the most accepted herbicide developed resistance in 1992. Later, introduced herbicides also developed resistance and cross-resistance to their respective binding sites. Isoproturon binds at the QB binding site of the D1 protein of photosystem-II (PS-II), which blocks the electron transfer in photosynthesis. In this work, we have carried out a series of computational studies to prioritize the promising herbicides against D1 protein of P. minor. Through the computational studies, twenty-four lead molecules are prioritized which have shown a higher binding affinity and inhibition constant than the reference ligand molecule. The binding and conformational stability of docked complexes was evaluated by molecular dynamics simulations and binding free energy calculations i.e., MM/PBSA. A list of amino acids such as Ala225, Ser226, Phe227, and Asn229 present in the binding site of protein is obtained to be playing an important role in the stability of the protein-lead complex via hydrogen bond and π-π interactions. Binding free energy calculation revealed that the selected lead molecule binding is energetically favorable and driven by electrostatic interactions. Among 24 leads, computational results have uncovered eight promising compounds as potential herbicides which have shown comparable physiochemical profile, better docking scores, system stability, H-bond occupancy, and binding free energy than terbutryn, a reference molecule. These prioritized molecules were custom synthesized and evaluated for their herbicidal activity and specificity through whole plant assay under laboratory-controlled conditions. The lead molecule ELC5 (6-ethoxy-4-N-(2-morpholin-4-ylethyl)-2-N-propan-2-yl-1,3,5-triazine-2,4-diamine) has shown comparable activity to the reference herbicide(isoproturon) against P. minor.

Sequence and structural similarities of ACCase protein of Phalaris minor and wheat: An insight to explain herbicide selectivity.

Uncontrolled growth of Phalaris minor in the wheat (Triticum aestivum) crop has remained a problem, leading to a massive reduction in wheat grain production. Herbicides have been used to control the weed, which leads to the development of frequent resistance in P. minor and mutant biotypes were also reported (Trp2027Cys and Ile2041Asn). Development of resistance enforced agro researchers to analyses the action of herbicide on P. minor. In this study, the sequence and structure of P. minor and T. aestivum Acetyl CoA Carboxylase (ACCase) have been analysed to locate the differences in their sequence and structure and to formulate a plausible explanation of the selectivity of herbicides which may help in the rationale discovery of noble herbicides. The sequence and 3D structure analysis of weed and wheat ACCase indicate minute differences in the distantly located amino acid residues. However, proteins are conserved at the binding site of herbicides with no mutation at the catalytic site. Analysis indicates that herbicides selectively target P. minor ACCase might be due to unknown other reasons, but not due to differences in their protein sequence and structure.

New generation VMAT2 inhibitors induced parkinsonism.

•Drug induced parkinsonism caused by valbenazine and deutetrabenazine.•Possible side effects of VMAT-2 inhibitors.•Valbenazine and deutetrabenazine can unmask underlying Parkinson's Disease.

Structural elucidation of transmembrane domain zero (TMD0) of EcdL: A multidrug resistance-associated protein (MRP) family of ATP-binding cassette transporter protein revealed by atomistic simulation.

ATP-Binding cassette (ABC) transporters play an extensive role in the translocation of diverse sets of biologically important molecules across membrane. EchnocandinB (antifungal) and EcdL protein of Aspergillus rugulosus are encoded by the same cluster of genes. Co-expression of EcdL and echinocandinB reflects tightly linked biological functions. EcdL belongs to Multidrug Resistance associated Protein (MRP) subfamily of ABC transporters with an extra transmembrane domain zero (TMD0). Complete structure of MRP subfamily comprising of TMD0 domain, at atomic resolution is not known. We hypothesized that the transportation of echonocandinB is mediated via EcdL protein. Henceforth, it is pertinent to know the topological arrangement of TMD0, with other domains of protein and its possible role in transportation of echinocandinB. Absence of effective template for TMD0 domain lead us to model by I-TASSER, further structure has been refined by multiple template modelling using homologous templates of remaining domains (TMD1, NBD1, TMD2, NBD2). The modelled structure has been validated for packing, folding and stereochemical properties. MD simulation for 0.1 µs has been carried out in the biphasic environment for refinement of modelled protein. Non-redundant structures have been excavated by clustering of MD trajectory. The structural alignment of modelled structure has shown Z-score -37.9; 31.6, 31.5 with RMSD; 2.4, 4.2, 4.8 with ABC transporters; PDB ID 4F4C, 4M1 M, 4M2T, respectively, reflecting the correctness of structure. EchinocandinB has been docked to the modelled as well as to the clustered structures, which reveals interaction of echinocandinB with TMD0 and other TM helices in the translocation path build of TMDs.

Leuckart Synthesis and Pharmacological Assessment of Novel Acetamide Derivatives.

A new concatenation of N-(1-(4-bromophenyl)ethyl)-2-phenoxyacetamide and N-(1-(4-methoxyphenyl) ethyl)-2-phenoxyacetamide derivatives having 2-phenoxy-N-(1-phenylethyl)acetamide nucleus as common in both the types was synthesized for the sake of achieve titled compounds as potential cytotoxic, anti-inflammatory, analgesic and antipyretic agents. All the novel derivatives have been synthesized through multi-step reaction sequence starting from Leuckart reaction. The structural assignments of the new compounds have been determined by virtue of their IR, 1H NMR, 13C NMR, elemental analysis and mass spectrum analysis. All the synthesized compounds were assessed for cytotoxicity and anti-inflammatory, analgesic and antipyretic effects. Among the series, compounds 3a, 3c, 3g and 3h possess cytotoxic, anti-inflammatory, analgesic and antipyretic activities comparable with standard drugs. The synthesized compounds were found to be active because of the presence of bromo, tert- butyl and nitro groups at position 4 of phenoxy nucleus.

Acetamides: chemotherapeutic agents for inflammation-associated cancers.

Now clear evidences are available to support the hypothesis that inflammation accelerates the conditions including events and molecules that reach to various types of cancers. Inflammation is a normal response to infection containing the innate and adaptive immune systems. However, when allowed to continue, unresolved, perturbation of cellular microenvironment takes place; therefore, it leads to adaptations in genes that are linked to cancer. In addition, a lot of data are accessible confirming the concept that tumour microenvironment is orchestrated by various inflammatory cells and goes to neoplastic process and finally invasion, migration and metastasis. However, infiltrations of leucocytes lead to angiogenesis, propagation and invasion. An inflammatory microenvironment that perhaps fostering impact of angiogenesis include cytokines, chemokines, enzymes and growth factors that play key role for expansion and invasion of cancer cells. This insight highlights the pathogenesis of inflammation-associated cancers and also touches and fosters the role of acetamides for the treatment and chemoprevention of carcinomas that are allied with inflammation.

Anticancer, anti-inflammatory, and analgesic activities of synthesized 2-(substituted phenoxy) acetamide derivatives.

The aphorism was to develop new chemical entities as potential anticancer, anti-inflammatory, and analgesic agents. The Leuckart synthetic pathway was utilized in development of novel series of 2-(substituted phenoxy)-N-(1-phenylethyl)acetamide derivatives. The compounds containing 1-phenylethylamine as basic moiety attached to substituted phenols were assessed for their anticancer activity against MCF-7 (breast cancer), SK-N-SH (neuroblastoma), anti-inflammatory activity, and analgesic activity. These investigations revealed that synthesized products 3a-j with halogens on the aromatic ring favors as the anticancer and anti-inflammatory activity. Among all, compound 3c N-(1-(4-chlorophenyl)ethyl)-2-(4-nitrophenoxy)acetamide exhibited anticancer, anti-inflammatory, and analgesic activities. In conclusion, 3c may have potential to be developed into a therapeutic agent.