Blocking the major inflammatory pathways by newly synthesized thiadiazine derivatives via in-vivo, in-vitro and in-silico mechanism.

A series of new thiadiazine derivatives including 2-(5-alkyl/aryl-6-thioxo-1,3,5-thiadiazinan-3-yl) propanoic acids (a) and 4-methyl-2-(5-alkyl/aryl-6-thioxo-1,3,5-thiadiazinan-3-yl) pentanoic acids (b) were synthesized by reacting primary alkyl/aryl amines with CS2, followed by reaction with formaldehyde and amino acids. The chemical structures of synthesized compounds were confirmed by 13C- NMR and 1H- NMR techniques. The inhibitory potential of major inflammatory enzymes, COX-2 and 5-LOX was examined. Moreover, anti-nociceptive and anti-inflammatory activities were evaluated in the in vivo thermally induced nociceptive, and carrageenan induced paw edema models in mice. The in-vitro results reflect that these compounds exhibited concentration dependent inhibition of COX-2 and 5-LOX. The tested compounds at 50 mg/kg showed significant effect on thermally induced pain, and reduced latency time (seconds) as compared to the vehicle treated animals. Moreover, tested compounds exhibited percent inhibition of paw edema in the carrageenan induced paw edema model in mice. Furthermore, the binding modes of the most active COX-2 and 5-LOX inhibitors were determined through computational methods. The computational study reflects that the docked compounds have high binding affinities for COX-2 and 5-LOX enzymes, which leads to inhibition of these enzymes.

Synthesis of new phenoxymethylcoumarin clubbed 4-arylthiazolylhydrazines as α-glucosidase inhibitors and their kinetics and molecular docking studies.

The current studies mainly demonstrate the coumarin based azomethine-clubbed thiazoles synthesis and their in-vitro evaluation for the first time against α-glucosidase. Due to the catalytic role of α-glucosidase, it has become a precise target for the treatment of type diabetes mellitus (T2DM). The high rate of prevalence of diabetes and its associated health related problems led us to scrutinize the anti-diabetic capability of the synthesized thiazole derivatives (6a-6k). The anticipated structures of prepared compounds were confirmed through FT-IR and NMR spectroscopic methods. All the compounds showed several times potent activity than the standard drug, acarbose (IC50 = 873.34 ± 1.67 µM) against α-glucosidase with IC50 values in range of 0.87 ± 0.02-322.61 ± 1.14 µM. The compound 6k displayed the highest anti-diabetic activity (IC50 = 1.88 ± 0.03 µM). Kinetic study revealed that these are competitive inhibitors for α-glucosidase. The mode of binding of the synthesized molecules were further evaluated by molecular docking, which reflects the importance of azomethine group in protein-ligand interaction. The docking scores are complementary with the IC50 values of compounds while the interaction pattern of the compounds clearly demonstrates their structure-activity relationship. Current study reported medicinal importance of thiazole derivative as future drug candidates for the management of Type 2 Diabetes Mellitus (T2DM).

One pot domino synthesis of new 3,5-disubstituted-tetrahydro-2H-1,3,5-thiadiazine-2-thiones (THTTs) as anti-inflammatory and antinociceptive candidates: A proof from in-vivo to in-vitro and in-silico mechanistic studies.

A series of alkyl/aryl/aralkylamines or amino acids appended tetrahydro-2H-1,3,5-thiadiazine-2-thiones (4a-i, 5a-g, 6 and 7) were synthesized via one pot domino synthesis. The synthesis involved reacting alkyl/aryl/aralkylamines or amino acids with carbon disulfide employing basic aqueous medium and further cyclization with formaldehyde and alkyl/aryl/aralkylamines or amino acids. In addition, the carboxy-functionalized 1,3,5-thiadiazine-2-thione 6 was further subjected to esterification. All the structures were confirmed through spectral techniques i.e IR, 1H NMR, 13C NMR, and MS analysis. Furthermore, the newly synthesized compounds were biologically assessed via in vitro COX-2 and 5-LOX assays, in vivo anti-nociceptive and anti-inflammatory activities. Among the screened compounds, 6, 5f, and 7 exhibited highest inhibitory potency against COX-2 with IC50 values of 11.96, 13.54, and 13.93 µM, respectively. Moreover, compounds 6 and 7 exhibited excellent inhibitory potential against 5-LOX with IC50 values of 14.01 and 14.13 µM. The in-vivo anti-inflammatory bioassay studies showed that compounds 6, 7 and 5f dramatically reduced the paw edema size at 1 h and 3 h time intervals. In the anti-nociceptive activity, compound 6 showed pain protection comparative to Tramadol in all tested time intervals. In addition, studies of molecular docking revealed the compounds binding modes in the allosteric site of COX-2 and active site of 5-LOX, where these compounds exhibited higher binding scores and good binding interactions.

Incensole derivatives from frankincense: Isolation, enhancement, synthetic modification, and a plausible mechanism of their anti-depression activity.

Encouraged by the potent anti-depression activities of incensole (1) and incensole acetate (2) isolated from the resin of Boswellia papyrifera in our previous work, different derivatives of 1 and 2 were synthesized in the present study. The reaction of 1 with m-CPBA afforded the mono-epoxide derivative 3a, while the same reaction with 2 led to three different epoxide derivatives 3a, 3b, and 3c. Oxidation of 1 with PCC to get compound 3b, however along with the target 3b, the reaction gave three interesting side products (3c-3e). Oxime (3b-1) resulted from the reaction of 3b with hydroxylamine hydrochloride in pyridine, while epoxidation of 2 generate three epoxide products (4a-4c). The structures of all products were unambiguously confirmed using NMR and Mass spectrometry. Compounds 3a-e and 4a-c (0.1-3 mg/kg, i.p.) demonstrated promising anti-depression activities in classical mouse models of depression of FST and TST. The results showed that compounds 3a-e and 4a-c (0.1-3 mg/kg, i.p.) caused dose dependent reduction in immobility time compared to the vehicle control, with 3c-3e and 4b-4c demonstrating higher potency and efficacy. The findings of the open field test excluded the motor effects of these compounds, thus further confirming their anti-depression activity. Preliminary investigation into their mechanism of action using GABA antagonist, PTZ and molecular docking has predicted that compounds 3e and 4c bind at the GABA binding site of GABAA receptor to produce GABAergic effects. Furthermore, the promising anti-depression potency of compounds 1 and 2 and their derivatives make them lead compounds for drug discovery.

Bio-Potency and Molecular Docking Studies of Isolated Compounds from Grewia optiva J.R. Drumm. ex Burret.

In the study, two novel compounds along with two new compounds were isolated from Grewia optiva. The novel compounds have never been reported in any plant source, whereas the new compounds are reported for the first time from the studied plant. The four compounds were characterized as: 5,5,7,7,11,13-hexamethyl-2-(5-methylhexyl)icosahydro-1H-cyclopenta[a]chrysen-9-ol (IX), docosanoic acid (X), methanetriol mano formate (XI) and 2,2'-(1,4-phenylene)bis(3-methylbutanoic acid (XII). The anticholinesterase, antidiabetic, and antioxidant potentials of these compounds were determined using standard protocols. All the isolated compounds exhibited a moderate-to-good degree of activity against acetylcholinesterases (AChE) and butyrylcholinesterase (BChE). However, compound XII was particularly effective with IC50 of 55 µg/mL (against AChE) and 60 µg/mL (against BChE), and this inhibitory activity is supported by in silico docking studies. The same compound was also effective against DPPH (2,2-diphenyl-1-picrylhydrazyl) and ABTS (2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid) radicals with IC50 values of 60 and 62 µg/mL, respectively. The compound also significantly inhibited the activities of α-amylase and α-glucosidase in vitro. The IC50 values for inhibition of the two enzymes were recorded as 90 and 92 µg/mL, respectively. The in vitro potentials of compound XII to treat Alzheimer's disease (in terms of AchE and BChE inhibition), diabetes (in terms of α-amylase and α-glucosidase inhibition), and oxidative stress (in terms of free radical scavenging) suggest further in vivo investigations of the compound for assessing its efficacy, safety profile, and other parameters to proclaim the compound as a potential drug candidate.

α-Glucosidase Inhibition and Molecular Docking Studies of Natural Brominated Metabolites from Marine Macro Brown Alga Dictyopteris hoytii.

Bioassay guided isolation of the methanolic extract of marine macro brown alga Dictyopteris hoytii afforded one new metabolite (ethyl methyl 2-bromobenzene 1,4-dioate, 1), one new natural metabolite (diethyl-2-bromobenzene 1,4-dioate, 2) along with six known metabolites (3-8) reported for the first time from this source. The structure elucidation of all these compounds was achieved by extensive spectroscopic techniques including 1D (1H and 13C) and 2D (NOESY, COSY, HMBC and HSQC) NMR and mass spectrometry and comparison of the spectral data of known compounds with those reported in literature. The in vitro α-glucosidase inhibition studies confirmed compound 7 to be the most active against α-glucosidase enzyme with IC50 value of 30.5 ± 0.41 µM. Compounds 2 and 3 demonstrated good inhibition with IC50 values of 234.2 ± 4.18 and 289.4 ± 4.91 µM, respectively, while compounds 1, 5, and 6 showed moderate to low inhibition. Furthermore, the molecular docking studies of the active compounds were performed to examine their mode of inhibition in the binding site of the α-glucosidase enzyme.

Unraveling the role of cloud computing in health care system and biomedical sciences.

Cloud computing has emerged as a transformative force in healthcare and biomedical sciences, offering scalable, on-demand resources for managing vast amounts of data. This review explores the integration of cloud computing within these fields, highlighting its pivotal role in enhancing data management, security, and accessibility. We examine the application of cloud computing in various healthcare domains, including electronic medical records, telemedicine, and personalized patient care, as well as its impact on bioinformatics research, particularly in genomics, proteomics, and metabolomics. The review also addresses the challenges and ethical considerations associated with cloud-based healthcare solutions, such as data privacy and cybersecurity. By providing a comprehensive overview, we aim to assist readers in understanding the significance of cloud computing in modern medical applications and its potential to revolutionize both patient care and biomedical research.

Discovery of Novel Natural Inhibitors Against SARS-CoV-2 Main Protease: A Rational Approach to Antiviral Therapeutics.

BACKGROUND/AIM: The global pandemic caused by the novel SARS-CoV-2 virus underscores the urgent need for therapeutic interventions. Targeting the virus's main protease (Mpro), crucial for viral replication, is a promising strategy. OBJECTIVE: The current study aims to discover novel inhibitors of Mpro. METHODS: The current study identified five natural compounds (myrrhanol B (C1), myrrhanone B (C2), catechin (C3), quercetin (C4), and feralolide (C5) with strong inhibitory potential against Mpro through virtual screening and computational methods, predicting their binding efficiencies and validated it using the in-vitro inhibition activity. The selected compound's toxicity was examined using the MTT assay on a human BJ cell line. RESULTS: Compound C1 exhibited the highest binding affinity, with a docking score of -9.82 kcal/mol and strong hydrogen bond interactions within Mpro's active site. A microscale molecular dynamics simulation confirmed the stability and tight fit of the compounds in the protein's active pocket, showing superior binding interactions. in vitro assays validated their inhibitory effects, with C1 having the most significant potency (IC50 = 2.85 µM). The non-toxic nature of these compounds in human BJ cell lines was also confirmed, advocating their safety profile. CONCLUSION: These findings highlight the effectiveness of combining computational and experimental approaches to identify potential lead compounds for SARS-CoV-2, with C1-C5 emerging as promising candidates for further drug development against this virus.

The 7-Hydroxyflavone attenuates chemotherapy-induced neuropathic pain by targeting inflammatory pathway.

Vincristine and paclitaxel are widely used chemotherapeutic drugs for the treatment of brain tumors, breast cancer, leukemia, lymphomas, and malignant solid tumors. Though, these drugs are associated with some severe adverse effects including peripheral neuropathic pain. The anti-nociceptive and anti-inflammatory properties of the 7-Hydroxyflavone (7HF) were evaluated in the mice using thermally- and chemically-induced nociception, naloxone antagonistic test, and carrageenan-induced paw edema models. Initially, the in-vitro cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitory assays were carried out. Peripheral neuropathic pain was induced in the Sprague Dawley (SD) rats by administration of paclitaxel (4 mg/kg) and vincristine (200 µg/kg) on days 1, 3, 5, 7, and 9, respectively. The protective effect of 7HF was assessed against the chemotherapy-induced peripheral neuropathy in the rats. Moreover, the expression of the inflammatory mediators in the spinal cord was investigated through RT-PCR. In addition, a computational study was performed to find the potential therapeutic targets and the binding mechanism of 7HF. The 7HF caused concentration-dependent inhibition of COX-2 and 5-LOX, it attenuated the nociceptive pain, carrageenan-induced paw edema, and the development of mechanical and cold allodynia, and hyperalgesia dose-dependently without causing motor coordination deficit. Likewise, the 7HF decreased the vincristine-induced increased expression of different inflammatory mediators including COX-2, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and nuclear factor-kappa B (NF-κB). The computational study showed the effective interactions of 7HF with the binding sites of NF-κB, COX-2, and 5-LOX, exert its inhibitory activities. These findings reveal that the 7HF has anti-nociceptive, anti-inflammatory, and anti-neuropathic potentials.

Attenuation of spatial memory in 5xFAD mice by targeting cholinesterases, oxidative stress and inflammatory signaling using 2-(hydroxyl-(2-nitrophenyl)methyl)cyclopentanone.

Alzheimer's disease (AD) is classified pathologically as a progressive neurological disorder associated with memory decline. The study was designed to assess the underlying molecular signaling involved in the neuroprotective effect of the 2-(hydroxyl-(2-nitrophenyl)methyl)cyclopentanone (2NCP) as a novel therapeutic agent for AD. In this connection, in vitro cholinesterases inhibitory and antioxidant activities were investigated. In vivo studies were carried out on a well-known 5xFAD mice model in different behavioural models such as light/dark box,balance beam, rotarod, elevated plus maze (EPM),novel object recognition (NOR), paddling Y-maze, and Morris water maze (MWM) tests. Hippocampus (HC) and frontal cortex (FC) homogenates were examined for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities, 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals, glutathione S-transferase (GST), glutathione (GSH), and catalase. Further, we examined the expression of inflammatory cytokines and Nrf2 in the HC and FC through RT-PCR. Computational studies were conducted to predict the binding mode of the 2NCP with target sites of nuclear factor-κB (NF-κB) and cholinesterases. The findings of in vitro assays revealed that the IC50 values of the 2NCP against AChE and BChE were 17 and 23 µg/ml respectively. DPPH antioxidant assay displayed an IC50 value for the 2NCP was 62 µg/ml. Whereas, theex vivo study depicted that the activities of AChE and BChEwere significantly reduced. Moreover, free radicals load, GSH level, catalase and GST activities were significantly declined. Furthermore, in vivostudies showed that the 2NCP treated animals exhibited gradual memory improvement and improved motor functions. RT-PCR study revealed that mRNA levels of the inflammatory mediators (IL-1ß, IL-6, TNF-α) were significantly reduced, while the expression of antioxidant Nrf2 was significantly increased.The molecular docking studies further confirmed that the 2NCP showed excellent binding affinities for NF-κB and cholinesterases. Taken together, the 2NCP improves spatial memory and learning, short- and long-term memory,markedly inhibits cholinesterases, reduced neuroinflammation, and mitigated oxidative stress in the 5xFAD mice; hence the 2NCP may be a potential candidate for the management of AD.

Genome Subtraction and Comparison for the Identification of Novel Drug Targets against Mycobacterium avium subsp. hominissuis.

Mycobacterium avium complex (MAC) is a major cause of non-tuberculous pulmonary and disseminated diseases worldwide, inducing bronchiectasis, and affects HIV and immunocompromised patients. In MAC, Mycobacterium avium subsp. hominissuis is a pathogen that infects humans and mammals, and that is why it is a focus of this study. It is crucial to find essential drug targets to eradicate the infections caused by these virulent microorganisms. The application of bioinformatics and proteomics has made a significant impact on discovering unique drug targets against the deadly pathogens. One successful bioinformatics methodology is the use of in silico subtractive genomics. In this study, the aim was to identify the unique, non-host and essential protein-based drug targets of Mycobacterium avium subsp. hominissuis via in silico a subtractive genomics approach. Therefore, an in silico subtractive genomics approach was applied in which complete proteome is subtracted systematically to shortlist potential drug targets. For this, the complete dataset of proteins of Mycobacterium avium subsp. hominissuis was retrieved. The applied subtractive genomics method, which involves the homology search between the host and the pathogen to subtract the non-druggable proteins, resulted in the identification of a few prioritized potential drug targets against the three strains of M. avium subsp. Hominissuis, i.e., MAH-TH135, OCU466 and A5. In conclusion, the current study resulted in the prioritization of vital drug targets, which opens future avenues to perform structural as well as biochemical studies on predicted drug targets against M. avium subsp. hominissuis.

Exploring biological efficacy of coumarin clubbed thiazolo[3,2-b][1,2,4]triazoles as efficient inhibitors of urease: A biochemical and in silico approach.

Combating several pathological conditions associated with ureolytic enzyme (urease) remains a formidable challenge because of the lack of effective and safe drug therapies. In this regard, the development of potent inhibitors of urease could be considered as a promising remedy. Herein, we report a new library of structurally diverse hybrid heteroaromatics featuring coumarin and thiazolotriazole motifs in one combined unit. These new chemical scaffolds accessed through the integration approach were shown to inhibit the enzyme urease from jack bean at variable efficacies. An initial structure-activity relationship analysis guided through the variation of several functional groups at the aryl ring connected to the thiazole core revealed compound 6o (IC50 = 4.35 ±â€¯0.18 µM) as the most potent inhibitor. The inhibitory strength of 6o was 5-fold compared to thiourea (standard; IC50 = 20.8 ±â€¯0.59 µM). In the molecular docking analysis, 6o was stabilized in the active pocket through various binding interactions. The presence of an amino moiety at the meta position of the phenyl ring facilitates hydrogen bonding with the sulfhydryl group of Cys322 (2.11 Å) in addition to an interaction observed between the thiazole sulfur and nickel atoms present in the active site. Moreover, this amino group also interacts with the carbonyl oxygen of Ala366 at a distance of 2.75 Å. The chromenone moiety of compound 6o is stabilized by the side chains of various amino acid residues including Ala279, Thr301, Pro303, Thr304, His315 and Met367.