Exploring the structural activity relationship of the Osimertinib: A covalent inhibitor of double mutant EGFRL858R/T790M tyrosine kinase for the treatment of Non-Small Cell Lung Cancer (NSCLC).

The USFDA granted regular approval to Osimertinib (AZD9291) on March 2017, for treating individuals with metastatic Non-Small Cell Lung Cancer having EGFR T790M mutation. Clinically, Osimertinib stands at the forefront for the treatment of patients with Non-Small Cell Lung Cancer. Osimertinib forms a covalent bond with the Cys797 residue and predominantly spares binding to WT-EGFR, thereby reducing toxicity and enabling the administration of doses that effectively inhibit T790M. However, a high percentage of patients treated with Osimertinib (AZD9291) developed a tertiary cysteine797 to serine797 (C797S) mutation in the EGFR kinase domain, rendering resistance to it. This comprehensive review sheds light on the chemistry, computational aspects, structural features, and expansive spectrum of biological activities of Osimertinib and its analogues. The in-depth exploration of these facets serves as a valuable resource for medicinal chemists, empowering them to design better Osimertinib analogues. This exhaustive study not only provides insights into improving potency but also emphasizes considerations for mutant selectivity and optimizing pharmacokinetic properties. This review acts as a guiding beacon for the strategic design and development of next-generation Osimertinib analogues.

Synthesis, biological evaluation, and In silico molecular docking of N-(4-(4-substitutedphenyl)-6-(substituted aryl) pyrimidin-2-yl)-2-(2-isonicotinoyl hydrazinyl) acetamide.

Isonicotinohydrazide is the first-line medication in the prevention and treatment of tuberculosis. Antitubercular, antibacterial, antifungal, antiviral, anti-inflammatory, antimalarial activity, anticancer, antineoplastic activity, and anti-HIV activity are all demonstrated by drugs with a pyrimidine ring. The current study focuses on the synthesis of N-(4-(substituted-phenyl)-6-(substituted-aryl) pyrimidin-2-yl)-2-(2-isonicotinoylhydrazinyl) acetamide from isonicotinohydrazide. Newly synthesized compounds were characterized by spectral studies (IR, 1 H-NMR, 13 C-NMR, and mass spectroscopy). They were screened for their antituberculosis, antimalarial, and antiprotozoal activities and compared with standard drugs. Molecular docking of isonicotinohydrazide-bearing pyrimidine motifs was also done for some of the active compounds.

Benzimidazole and piperidine containing novel 1,2,3-triazole hybrids as anti-infective agents: Design, synthesis, in silico and in vitro antimicrobial efficacy.

Cu alkyne-azide cycloaddition was used to easily synthesize a library of novel heterocycles containing benzimidazole and piperidine based 1,2,3-triazole(7a-7l) derivatives. The synthesized analogs were characterized by various spectroscopic techniques like FTIR, 1 H nuclear magnetic resonance (NMR), 13 C NMR, and mass spectrometry. All these novel bioactive compounds (7a-7l) were evaluated for in vitro antibacterial and antifungal efficacy. Compound 7k exhibited appreciable potent activity against Escherichia coli strain. Compounds 7a, 7b, 7f, and 7i showed excellent potent activity against all bacterial strains. Compound 7b, 7c, 7d, and 7g derivatives showed excellent effects when tested in vitro for antifungal activity against various fungal strains. Additionally, a molecular docking investigation revealed that compound 7k has the ability to bind to the active site of the E. coli DNA gyrase subunit protein and form hydrogen bonds with significant amino acid residues Asp73 and Asp49 in the active sites. In a 100 ns molecular dynamics simulation, the E. coli DNA gyrase protein's steady capacity to bind compound 7k was shown by the low measured root mean square deviation, which was an indication of the complex's conformational stability.

Anti-malarial and Multi-bioactive Co (II), Cu (II) and Ni (II) Salen Complexes: Synthesis, Characterization and Computational Studies.

Herein, we report anti-malarial, anti-bacterial and anti-inflammatory activities of theN2O2 donor tetradentate salen ligand and its CoL, NiL, and CuL metal complexes. All the compoundswere synthesized and characterized by various spectroscopic analytical methods.Thein-vitro antimalarial investigations revealed that the complex CuL exhibited equipotency with quinine drug having IC50 value 0.25 µg/mL.The compound L shows significant inhibition of bacterial spp.viz.E. Coli, P. Aeruginosa, and S. Aureus (MIC=12.5-50µg/mL), while the compound CoL (MIC=12.5µg/mL) exhibited potency against gram-positive bacteria. In the in-vitro anti-inflammatory study, the compound CuL has moderate activity than other tested compounds. The compound CuL showedthe highest anti-malarial docking score with enzyme pLDH at -8.12 Kcal/mol. The DFT study also gives authentication of higher antimalarial activity of CuL due to high dipole moment. None of the potent compound was found cytotoxic towards verocell lines.

Design, synthesis, biological evaluation, and in silico studies of quinoxaline derivatives as potent p38α MAPK inhibitors.

A new series of quinoxaline derivatives possessing the hydrazone moiety were designed, synthesized, and screened for in-vitro anti-inflammatory activity by the bovine serum albumin (BSA) denaturation technique, and for antioxidant activity, by the (2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. The synthesized compounds were also tested for p38α mitogen-activated protein (MAP) kinase inhibition. The in-vivo anti-inflammatory activity was assessed by the carrageenan-induced rat paw edema inhibition method. All the compounds (4a-n) exhibited moderate to high in-vitro anti-inflammatory activity. Compound 4a displayed the highest inhibitory activity in the BSA assay (83.42%) in comparison to the standard drug diclofenac sodium (82.90%), while 4d exhibited comparable activity (81.87%). The DPPH assay revealed that compounds 4a and 4d have free radical scavenging potential (74.70% and 74.34%, respectively) comparable to the standard butylated hydroxyanisole (74.09%). Furthermore, the p38α MAP kinase inhibition assay demonstrated that compound 4a is highly selective against p38α MAP kinase (IC50 = 0.042) in comparison to the standard SB203580 (IC50 = 0.044). The five most active compounds (4a-4d and 4f) with good in-vitro profiles were selected for in-vivo anti-inflammatory studies. Compounds 4a and 4d were found to display the highest activity (83.61% and 82.92% inhibition, respectively) in comparison to the standard drug diclofenac sodium (82.65% inhibition). These compounds (4a and 4d) also exhibited better ulcerogenic and lipid peroxidation profiles than diclofenac sodium. The molecular docking and molecular dynamics simulation studies were also performed and found to be in agreement with the p38α MAP kinase inhibitory activity.

Design and synthesis of some novel hybrid molecules based on 4-thiazolidinone bearing pyridine-pyrazole scaffolds: molecular docking and molecular dynamics simulations of its major constituent onto DNA gyrase inhibition.

Due to multidrug resistance, microbial infections have become significant on a global level. As infections caused by several resistant bacteria and fungi severely harm mankind, scientists have developed new antibiotics to combat these infections. In order to develop novel antimicrobial agents, a series of 4-thiazolidinone-based 5-arylidene hybrids (5a-o) have been designed and synthesized to evaluate their antibacterial and antifungal activities. For the determination of the structure of a novel synthesized hybrid, various spectral techniques, e.g., IR, 1H NMR, 13C NMR, and Mass spectroscopy, were used. Two bacterial gram-negative (Escherichia coli and Pseudomonas aeruginosa), two gram-positive strains (Staphylococcus aureus and Streptococcus pyogenes), and one fungal strain (Candida albicans) were used to evaluate antimicrobial activity. Compounds 5c, 5g, and 5i were effective due to their MIC values of 62.5 µg/mL against tested bacterial strains (S. pyogenes (5c), P. aeruginosa (5g), and E. coli (5i), respectively.) and 250 µg/mL against C. albicans fungal strains, respectively. Additionally, molecular docking and 100 ns molecular dynamic simulations were carried out to investigate the stability of molecular contacts and to establish how the newly synthesized inhibitors fit together in the most stable conformations.

Microwave produced 8-methyl-1,2,4,8-tetraazaspiro[4.5]dec-2-en-3-amine derivatives: their in vitro and in silico analysis.

Compound 1 is formed by a microwave-assisted multicomponent reaction of 1-methylpiperidin-4-one, 2-amino-4-methoxy-6-methyl-1,3,5-triazine, and thiosemicarbazide, followed by the synthesis of Schiff base 2a-l with a variety of aldehydes. A comparison was made between the conventional and microwave methods, and the microwave approach was shown to be considerably superior to the classical method since it takes less time and produces higher yields. Several spectral investigations, including 1H NMR, 13C NMR, Mass, and IR spectroscopy, are used to characterize the complete series. In vitro antibacterial testing suggests that compounds 2c, 2f, and 2g are promising antibacterial agents, although compounds 2d, 2e, and 2l are effective antimycobacterial agents when compared to the conventional medicine Rifampicin. The docking score from docking studies is considerable, which validates the results of the biological examination. Molecular docking was performed on Escherichia coli DNA gyrase. According to the in silico ADME analysis, each drug molecule is ideal for use in terms of drug solubility, hydrogen bonding, and cell permeability.

Chrysin based pyrimidine-piperazine hybrids: design, synthesis, in vitro antimicrobial and in silico E. coli topoisomerase II DNA gyrase efficacy.

Ten chrysin-based pyrimidine-piperazine hybrids have been evaluated in vitro for antimicrobial activity against eleven bacterial and two fungal strains. All compounds 5a-j exhibited moderate to good inhibition, with MIC values ranging from 6.25 to 250 µg/ml. At 6.25 µg/ml and 12.5 µg/ml MIC values, respectively, compounds 5b and 5h demonstrated the most promising potency against E. coli, outperforming ampicillin, chloramphenicol, and ciprofloxacin. None of the substances had the same level of action as norfloxacin. 5a, 5d, 5g, 5h, and 5i have exhibited superior antifungal efficacy than Griseofulvin against C. albicans with 250 µg/ml MIC. All the compounds were also individually docked into the E. coli DNA gyrase ATP binding site (PDB ID: 1KZN) and CYP51 inhibitor (PDB ID: 5V5Z). The most active compound, 5h and 5g displayed a Glide docking score of - 5.97 kcal/mol and - 10.99 kcal/mol against DNA gyrase and 14α-demethylase enzyme CYP51 respectively. Potent compounds 5b, 5h, and 5g may be used to design new, innovative antimicrobial agents, according to in vitro, ADMET, and in silico biological efficacy analyses.

Design and synthesis of pyrrolo[2,3-d]pyrimidine linked hybrids as α-amylase inhibitors: molecular docking, MD simulation, ADMET and antidiabetic screening.

Novel pyrrolo[2,3-d]pyrimidine-based analogues were designed, synthesized, and evaluated for their ability to inhibit the α-amylase enzyme in order to treat diabetes. In vitro antidiabetic analysis demonstrated excellent antidiabetic action for compounds 5b, 6c, 7a, and 7b, with IC50 values in the 0.252-0.281 mM range. At a 200 µg/mL concentration, the exceptional percent inhibition values for compounds 5a, 5b, 5d, and 6a varied from 97.79 ± 2.86% to 85.56 ± 4.13% overperforming the standard (acarbose). Molecular docking of all compounds performed with Bacillus paralicheniformis α-amylase enzyme. The most active compounds via in vitro and non-toxic via in silico ADMET and molecular docking analysis, hybrids 6c, 7a, and 7b displayed binding affinity from - 8.2 and - 8.5 kcal/mol. Molecular dynamic simulations of most active compound 5b and 7a investigated into the active sites of the Bacillus paralicheniformis α-amylase enzyme for a 100-ns indicating the stability of hybrid-protein complex. Consistent RGyr values for the two complexes under study further suggest that the system's proteins are closely packed in the dynamic state. Synthesized analogs' in vitro biological assessments, ADMET, molecular docking, and MD modelling reveal that 5b, 6c, 7a, and 7b hybrid analogs may be employed in the development of future antidiabetic drugs.

Mycobacterial FtsZ and inhibitors: a promising target for the anti-tubercular drug development.

The emergence of multidrug-resistant tuberculosis (MDR-TB) strains has rendered many anti-TB drugs ineffective. Consequently, there is an urgent need to identify new drug targets against Mycobacterium tuberculosis (Mtb). Filament Forming Temperature Sensitive Gene Z (FtsZ), a member of the cytoskeletal protein family, plays a vital role in cell division by forming a cytokinetic ring at the cell's center and coordinating the division machinery. When FtsZ is depleted, cells are unable to divide and instead elongate into filamentous structures that eventually undergo lysis. Since the inactivation of FtsZ or alterations in its assembly impede the formation of the Z-ring and septum, FtsZ shows promise as a target for the development of anti-mycobacterial drugs. This review not only discusses the potential role of FtsZ as a promising pharmacological target for anti-tuberculosis therapies but also explores the structural and functional aspects of the mycobacterial protein FtsZ in cell division. Additionally, it reviews various inhibitors of Mtb FtsZ. By understanding the importance of FtsZ in cell division, researchers can explore strategies to disrupt its function, impeding the growth and proliferation of Mtb. Furthermore, the investigation of different inhibitors that target Mtb FtsZ expands the potential for developing effective treatments against tuberculosis.

Synthesis, Biological Evaluation, and Molecular Modeling Studies of New 1,3,4-Thiadiazole Derivatives as Potent Antimicrobial Agents.

In this work, the synthesis, characterization, and biological activities of a new series of 1,3,4-thiadiazole derivatives were investigated. The structures of final compounds were identified using 1 H-NMR, 13 C-NMR, elemental analysis, and HRMS. All the new synthesized compounds were then screened for their antimicrobial activity against four types of pathogenic bacteria and one fungal strain, by application of the MIC assays, using Ampicilin, Gentamycin, Vancomycin, and Fluconazole as standards. Among the compounds, the MIC values of 4 and 8 µg/mL of the compounds 3f and 3g, respectively, are remarkable and indicate that these compounds are good candidates for antifungal activity. The docking experiments were used to identify the binding forms of produced ligands with sterol 14-demethylase to acquire insight into relevant proteins. The MD performed about 100 ns simulations to validate selected compounds' theoretical studies. Finally, using density functional theory (DFT) to predict reactivity, the chemical characteristics and quantum factors of synthesized compounds were computed. These results were then correlated with the experimental data. Furthermore, computational estimation was performed to predict the ADME properties of the most active compound 3f.

Illicium verum L. (Star Anise) Essential Oil: GC/MS Profile, Molecular Docking Study, In Silico ADME Profiling, Quorum Sensing, and Biofilm-Inhibiting Effect on Foodborne Bacteria.

Illicium verum, or star anise, has many uses ranging from culinary to religious. It has been used in the food industry since ancient times. The main purpose of this study was to determine the chemical composition, antibacterial, antibiofilm, and anti-quorum sensing activities of the essential oil (EO) obtained via hydro-distillation of the aerial parts of Illicium verum. Twenty-four components were identified representing 92.55% of the analyzed essential oil. (E)-anethole (83.68%), limonene (3.19%), and α-pinene (0.71%) were the main constituents of I. verum EO. The results show that the obtained EO was effective against eight bacterial strains to different degrees. Concerning the antibiofilm activity, trans-anethole was more effective against biofilm formation than the essential oil when tested using sub-inhibitory concentrations. The results of anti-swarming activity tested against P. aeruginosa PAO1 revealed that I. verum EO possesses more potent inhibitory effects on the swarming behavior of PAO1 when compared to trans-anethole, with the percentage reaching 38% at a concentration of 100 µg/mL. The ADME profiling of the identified phytocompounds confirmed their important pharmacokinetic and drug-likeness properties. The in silico study using a molecular docking approach revealed a high binding score between the identified compounds with known target enzymes involved in antibacterial and anti-quorum sensing (QS) activities. Overall, the obtained results suggest I. verum EO to be a potentially good antimicrobial agent to prevent food contamination with foodborne pathogenic bacteria.

Design, synthesis, molecular docking and molecular dynamics studies of novel triazolothiadiazine derivatives containing furan or thiophene rings as anticancer agents.

Breast cancer is the most common cancer type amoung post-menopausal women. Aromatase inhibitors were used in the treatment of patients. However, drug resistance may develop in long-term drug use, especially in 3rd and 4th stage (advanced) cancer cases. Therefore, there is a constant need for new agents. In this study, new triazolothiadiazine derivatives were synthesized and their anticancer activities were investigated. Compounds 2k, 2s, and 2w showed inhibitor activity against MCF-7 cell line with IC50 = 4.63 ± 0.10; 2.23 ± 0.16; 3.13 ± 0.08 µM value, respectively. As a result of in vitro aromatase enzyme inhibition test, compound 2s was the most active derivative with IC50 = 0.058 ± 0.023 µM. In addition, DNA synthesis inhibition percentages of the compounds were measured by the BrdU method. The intermolecular interactions of the promising compounds with aromatase enzyme were investigated through the SP docking approach, which revealed significant binding interaction energies associated with these compounds. Following that, the interaction's stability was assessed using a typical atomistic 100 ns dynamic simulation study. A number of parameters derived from MD simulation trajectories were computed and validated for the protein-ligand complex's stability under the dynamic conditions.

Multifunctional Derivatives of Spiropyrrolidine Tethered Indeno-Quinoxaline Heterocyclic Hybrids as Potent Antimicrobial, Antioxidant and Antidiabetic Agents: Design, Synthesis, In Vitro and In Silico Approaches.

To combat emerging antimicrobial-resistant microbes, there is an urgent need to develop new antimicrobials with better therapeutic profiles. For this, a series of 13 new spiropyrrolidine derivatives were designed, synthesized, characterized and evaluated for their in vitro antimicrobial, antioxidant and antidiabetic potential. Antimicrobial results revealed that the designed compounds displayed good activity against clinical isolated strains, with 5d being the most potent (MIC 3.95 mM against Staphylococcus aureus ATCC 25923) compared to tetracycline (MIC 576.01 mM). The antioxidant activity was assessed by trapping DPPH, ABTS and FRAP assays. The results suggest remarkable antioxidant potential of all synthesized compounds, particularly 5c, exhibiting the strongest activity with IC50 of 3.26 ± 0.32 mM (DPPH), 7.03 ± 0.07 mM (ABTS) and 3.69 ± 0.72 mM (FRAP). Tested for their α-amylase inhibitory effect, the examined analogues display a variable degree of α-amylase activity with IC50 ranging between 0.55 ± 0.38 mM and 2.19 ± 0.23 mM compared to acarbose (IC50 1.19 ± 0.02 mM), with the most active compounds being 5d, followed by 5c and 5j, affording IC50 of 0.55 ± 0.38 mM, 0.92 ± 0.10 mM, and 0.95 ± 0.14 mM, respectively. Preliminary structure-activity relationships revealed the importance of such substituents in enhancing the activity. Furthermore, the ADME screening test was applied to optimize the physicochemical properties and determine their drug-like characteristics. Binding interactions and stability between ligands and active residues of the investigated enzymes were confirmed through molecular docking and dynamic simulation study. These findings provided guidance for further developing leading new spiropyrrolidine scaffolds with improved dual antimicrobial and antidiabetic activities.

Design, Synthesis and Biological Evaluation of Syn and Anti-like Double Warhead Quinolinones Bearing Dihydroxy Naphthalene Moiety as Epidermal Growth Factor Receptor Inhibitors with Potential Apoptotic Antiproliferative Action.

Our investigation includes the synthesis of new naphthalene-bis-triazole-bis-quinolin-2(1H)-ones 4a−e and 7a−e via Cu-catalyzed [3 + 2] cycloadditions of 4-azidoquinolin-2(1H)-ones 3a−e with 1,5-/or 1,8-bis(prop-2-yn-1-yloxy)naphthalene (2) or (6). All structures of the obtained products have been confirmed with different spectroscopic analyses. Additionally, a mild and versatile method based on copper-catalyzed [3 + 2] cycloaddition (Meldal−Sharpless reaction) was developed to tether quinolinones to O-atoms of 1,5- or 1,8-dinaphthols. The triazolo linkers could be considered as anti and syn products, which are interesting precursors for functionalized epidermal growth factor receptor (EGFR) inhibitors with potential apoptotic antiproliferative action. The antiproliferative activities of the 4a−e and 7a−e were evaluated. Compounds 4a−e and 7a−e demonstrated strong antiproliferative activity against the four tested cancer cell lines, with mean GI50 ranging from 34 nM to 134 nM compared to the reference erlotinib, which had a GI50 of 33 nM. The most potent derivatives as antiproliferative agents, compounds 4a, 4b, and 7d, were investigated for their efficacy as EGFR inhibitors, with IC50 values ranging from 64 nM to 97 nM. Compounds 4a, 4b, and 7d demonstrated potent apoptotic effects via their effects on caspases 3, 8, 9, Cytochrome C, Bax, and Bcl2. Finally, docking studies show the relevance of the free amino group of the quinoline moiety for antiproliferative action via hydrogen bond formation with essential amino acids.

Synthesis, molecular docking, DFT study, and in vitro antimicrobial activity of some 4-(biphenyl-4-yl)-1,4-dihydropyridine and 4-(biphenyl-4-yl)pyridine derivatives.

The evolution of microbial resistance necessitates the development of new antimicrobial drugs that are more effective than those currently on the market. To address this problem, we have prepared a series of novel 4-(biphenyl-4-yl)-1,4-dihydropyridine and 4-(biphenyl-4-yl)pyridine derivatives via Hantzsch reaction using nine different compounds containing active methylene group. IR, NMR, and mass spectra were used to determine the structures. Using ampicillin and griseofulvin as standards, the titled compounds were investigated for their antibacterial activity against different bacteria and fungi. Compounds 1f, 1g, 2f, and 2g have the best antibacterial activity against Gram-negative bacteria (minimum inhibitory concentration = 50 µg/ml), while 1f, 1h, 2g, and 2h have high antifungal activity against Candida albicans (minimum inhibitory concentration = 100 µg/ml). To gain a better understanding of the binding process and affinity for the bacterial Staphylococcus epidermidis protein, researchers used molecular docking and molecular mechanics, as well as the generalized Born model and solvent accessibility-based binding free energy. The active compounds 1g, 1h, and 2f have good docking scores of -5.575, -5.949, and -5.234, respectively, whereas compound 2c has the greatest docking score (-6.23). The HOMO-LUMO energy gap and molecular electrostatic potential were used to evaluate the reactivity of promising compounds, which were then associated with antibacterial efficacy.

Novel, selective acrylamide linked quinazolines for the treatment of double mutant EGFR-L858R/T790M Non-Small-Cell lung cancer (NSCLC).

T790M mutation is the most common mechanism of acquired resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). To overcome this resistance, 4-anilinoquinazoline-based irreversible inhibitors afatinib, dacomitinib has been developed. However, the clinical application of these irreversible inhibitors is limited due to its narrow selectivity against L858R/T790M mutant EGFR. In an attempt to develop potent and selective EGFR T790M inhibitors, we have designed and synthesized two series of novel acrylamide linked quinazolines. Among them, compounds 2i (IC50 0.171 µM) and 11h (IC50 0.159 µM) were identified as potent compounds, which displayed selective and potent anti-proliferative activity on gefitinib-resistant cell line NCI-H1975 as compared to the gefitinib and WZ4002 in cellular assay. Furthermore, a molecular dynamic simulation of 11h was carried out to assess the stability to form a complex with the L858R/T790M EGFR Kinase domain, which demonstrated that complex was stable for the 100 ns and form strong crucial covalent binding contacts with the thiol group of Cys797 residue. Finally, satisfactory in silico pharmacokinetics properties of 2i, 11h and 11i compounds were predicted. The synthesized compounds were also evaluated for in vitro cytotoxic activity/hepatotoxicity against HepG2 cell line through MTT assay. The results revealed that compounds exhibited lower cytotoxicity to HepG2 cells.

Novel thiomorpholine tethered isatin hydrazones as potential inhibitors of resistant Mycobacterium tuberculosis.

Novel chemotherapeutic agents against multidrug resistant-tuberculosis (MDR-TB) are urgently needed at this juncture to save the life of TB-infected patients. In this work, we have synthesized and characterized novel isatin hydrazones 4(a-o) and their thiomorpholine tethered analogues 5(a-o). All the synthesized compounds were initially screened for their anti-mycobacterial activity against the H37Rv strain of Mycobacterium tuberculosis (MTB) under level-I testing. Remarkably, five compounds 4f, 4h, 4n, 5f and 5m (IC50 = 1.9 µM to 9.8 µM) were found to be most active, with 4f (IC50 = 1.9 µM) indicating highest inhibition of H37Rv. These compounds were further evaluated at level-II testing against the five drug-resistant strains such as isoniazid-resistant strains (INH-R1 and INH-R2), rifampicin-resistant strains (RIF-R1 and RIF-R2) and fluoroquinolone-resistant strain (FQ-R1) of MTB. Interestingly, 4f and 5f emerged as the most potent compounds with IC50 of 3.6 µM and 1.9 µM against RIF-R1 MTB strain, followed by INH-R1 MTB strain with IC50 of 3.5 µM and 3.4 µM, respectively. Against FQ-R1 MTB strain, the lead compounds 4f and 5f displayed excellent inhibition at IC50 5.9 µM and 4.9 µM, respectively indicating broad-spectrum of activity. Further, molecular docking, ADME pharmacokinetic and molecular dynamics simulations of the compounds were performed against the DNA gyrase B and obtained encouraging results.

Tomatidine and Patchouli Alcohol as Inhibitors of SARS-CoV-2 Enzymes (3CLpro, PLpro and NSP15) by Molecular Docking and Molecular Dynamics Simulations.

Considering the current dramatic and fatal situation due to the high spreading of SARS-CoV-2 infection, there is an urgent unmet medical need to identify novel and effective approaches for prevention and treatment of Coronavirus disease (COVID 19) by re-evaluating and repurposing of known drugs. For this, tomatidine and patchouli alcohol have been selected as potential drugs for combating the virus. The hit compounds were subsequently docked into the active site and molecular docking analyses revealed that both drugs can bind the active site of SARS-CoV-2 3CLpro, PLpro, NSP15, COX-2 and PLA2 targets with a number of important binding interactions. To further validate the interactions of promising compound tomatidine, Molecular dynamics study of 100 ns was carried out towards 3CLpro, NSP15 and COX-2. This indicated that the protein-ligand complex was stable throughout the simulation period, and minimal backbone fluctuations have ensued in the system. Post dynamic MM-GBSA analysis of molecular dynamics data showed promising mean binding free energy 47.4633 ± 9.28, 51.8064 ± 8.91 and 54.8918 ± 7.55 kcal/mol, respectively. Likewise, in silico ADMET studies of the selected ligands showed excellent pharmacokinetic properties with good absorption, bioavailability and devoid of toxicity. Therefore, patchouli alcohol and especially, tomatidine may provide prospect treatment options against SARS-CoV-2 infection by potentially inhibiting virus duplication though more research is guaranteed and secured.

Is there seasonal variation in gallstone related admissions in England?

BACKGROUND: Gallstone related pathology (GRP) accounts for a significant proportion of general surgery admissions. The aim of this study is to investigate if seasonal variation for GRP admissions exist in England allowing improved resource allocation and planning. METHODS: This multicentre retrospective cohort study included only emergency adult (≥18 years old) admissions to acute secondary care with ICD-10 codes associated with gallstones between 01/01/2010 to 31/12/2019 in England using Hospital Episode Statistics data. Seasons were defined according to United Kingdom Met Office. RESULTS: A total of 396 879 GRP related admissions were recorded during the specified period, accounting for 1.44% of all emergency admissions. Our study suggests a significant seasonal peak in Summer (n = 102 620) based cumulative admissions per season and a linear regression model (p < 0.001), followed by Autumn (n = 102 267), then Spring (n = 97 807) and finally Winter (n = 94 185). Spectral analysis confirmed there is seasonality in the emergency GRP admissions every 12 months. A forecasting model was shown to be reliable; all observed admissions for 2019 were within the 95% prediction intervals for each month for the proportion of emergency GRP admissions. CONCLUSION: Resource allocation towards the Summer months to target seasonal peaks in GRP should be considered.