Evaluation of Habenaria aitchisonii Reichb. for antioxidant, anti-inflammatory, and antinociceptive effects with in vivo and in silico approaches.

Habenaria aitchisonii Reichb was analyzed in this research, including its chemical composition and its in vitro antioxidant, anti-inflammatory, acute oral toxicity, and antinociceptive activity. The chloroform and ethyl acetate fractions were found to be the most powerful based on in vitro antioxidant, anti-inflammatory, and analgesic assays. The acute oral toxicity of the crude methanolic extract was determined before in vivo studies. The acetic acid and formalin tests were used to measure the antinociceptive effect, and the potential mechanisms involved in antinociception were explored. The carrageenan-induced paw edema test was used to examine the immediate anti-inflammatory effect, and many phlogistic agents were used to determine the specific mechanism. Furthermore, for ex vivo activities, the mice were sacrificed, the forebrain was isolated, and the antioxidant levels of glutathione (GSH), superoxide dismutase (SOD), thiobarbituric acid reactive substances (TBARS) and catalase (CAT) were estimated using a UV spectrophotometer. No toxicity was seen at oral dosages up to 3,000 mg/kg. The antinociceptive impact was much higher than the standard drug. Both the inflammatory and neurogenic phases of the formalin experiment revealed an analgesic effect in the chloroform and ethyl acetate fractions. In carrageenan anti-inflammatory assays, the chloroform fraction (Ha.Chf) was the most potent fraction. We further studied the GC-MS of crude plant extract and found a total of 18 compounds. In the anti-inflammatory mechanism, it was observed that the Ha.Chf inhibits the COX-2 as well as 5-LOX pathways. The results exhibited that this species is a good source of phytocomponents like germacrone, which can be employed as a sustainable and natural therapeutic agent, supporting its traditional use in folk medicine for inflammatory conditions and pain.

Phenolic phytochemistry, in vitro, in silico, in vivo, and mechanistic anti-inflammatory and antioxidant evaluations of Habenaria digitata.

Excessive and imbalance of free radicals within the body lead to inflammation. The objective of the current research work was to explore the anti-inflammatory and antioxidant potential of the isolated compounds from Habenaria digitata. In this study, the isolated phenolic compounds were investigated for in vitro and in vivo anti-inflammatory potential along with the antioxidant enzyme. The anti-inflammatory and antioxidant potential of the phenolic compounds was assayed via various enzymes like COX-1/2, 5-LOX and ABTS, DPPH, and H2O2 free radical enzyme inhibitory assay. These compounds were also explored for their in vivo antioxidant activity like examining SOD, CAT, GSH-Px, and MDA levels in the brain, heart, and liver. The anti-inflammatory potential was evaluated using the carrageenan-induced pleurisy model in mice. On the basis of initial screening of isolated compounds, the most potent compound was further evaluated for the anti-inflammatory mechanism. Furthermore, the molecular docking study was also performed for the potent compound. The phenolic compounds were isolated and identified by GC-MS/NMR analysis by comparing its spectra to the library spectra. The isolated phenolic compounds from H. digitata were 5-methylpyrimidine-24,4-diol (1), 3,5-dihydroxy-6-methyl-2,3-dihydropyran-4-one (2), 2-isopropyl-5-methylphenol (3), 3-methoxy-4-vinylphenol (4), and 2,6-dimethoxy-4-vinylphenol (5). In in vitro antioxidant assay, the most potent compound was compound 1 having IC50 values of 0.98, 0.90, and 5 µg/mL against ABTS, DPPH, and H2O2, respectively. Similarly, against COX1/2 and 5-LOX ,compound 1 was again the potent compound with IC50 values of 42.76, 10.70, and 7.40 µg/mL. Based on the in vitro results, compound 1 was further evaluated for in vivo antioxidant and anti-inflammatory potential. Findings of the study suggest that H. digitata contains active compounds with potential anti-inflammatory and antioxidant effects. These compounds could be screened as drug candidates for pharmaceutical research, targeting conditions associated with oxidative stress and inflammatory conditions in medicinal chemistry and support their ethnomedicinal use for inflammation and oxidative stress.

Drug repurposing of FDA-approved anti-viral drugs via computational screening against novel 6M03 SARS-COVID-19.

OBJECTIVE: The COVID-19 pandemic has been recognized as severe acute respiratory syndrome, one of the worst and disastrous infectious diseases in human history. Until now, there is no cure to this contagious infection although some multinational pharmaceutical companies have synthesized the vaccines and injecting them into humans, but a drug treatment regimen is yet to come. AIM: Among the multiple areas of SARS-CoV-2 that can be targeted, protease protein has significant values due to its essential role in viral replication and life. The repurposing of FDA-approved drugs for the treatment of COVID-19 has been a critical strategy during the pandemic due to the urgency of effective therapies. The novelty in this work refers to the innovative use of existing drugs with greater safety, speed, cost-effectiveness, broad availability, and diversity in the mechanism of action that have been approved and developed for other medical conditions. METHODS: In this research work, we have engaged drug reprofiling or drug repurposing to recognize possible inhibitors of protease protein 6M03 in an instantaneous approach through computational docking studies. RESULTS: We screened 16 FDA-approved anti-viral drugs that were known for different viral infections to be tested against this contagious novel strain. Through these reprofiling studies, we come up with 5 drugs, namely, Delavirdine, Fosamprenavir, Imiquimod, Stavudine, and Zanamivir, showing excellent results with the negative binding energies in Kcal/mol as - 8.5, - 7.0, - 6.8, - 6.8, and - 6.6, respectively, in the best binding posture. In silico studies allowed us to demonstrate the potential role of these drugs against COVID-19. CONCLUSION: In our study, we also observed the nucleotide sequence of protease protein consisting of 316 amino acid residues and the influence of these pronouncing drugs over these sequences. The outcome of this research work provides researchers with a track record for carrying out further investigational procedures by applying docking simulations and in vitro and in vivo experimentation with these reprofile drugs so that a better drug can be formulated against coronavirus.

Pharmacological evaluations of amide carboxylates as potential anti-Alzheimer agents: anti-radicals, enzyme inhibition, simulation and behavioral studies in animal models.

Alzheimer's disease (AD) is a neurological disorder that progresses gradually but irreversibly leading to dementia and is difficult to prevent and treat. There is a considerable time window in which the progression of the disease can be intervened. Scientific advances were required to help the researchers to identify the effective methods for the prevention and treatment of disease. This research was designed to investigate potential mediators for the remedy of AD, five new carboxylate amide zinc complexes (AAZ9-AAZ13) were synthesized and characterized by spectroscopic and physicochemical techniques. The biological evaluation was carried out based on the cholinesterase inhibitory mechanism. The preparation methodology provided the effective synthesis of targeted moieties. The in vitro pharmacological activities were evaluated involving AChE/BChE inhibition and antioxidant potential. All synthesized compounds displayed activity against both enzymes in higher or comparable to the standard drug Galantamine, a reversible inhibitor but the results displayed by compound AAZ10 indicated IC50 of 0.0013 µM (AChE) and 0.061 µM (BChE) as high values for dual AChE/BChE inhibition with potent anti-oxidant results. Structure activity relationship (SAR) indicated that the potent activity of compound AAZ10 appeared due to the presence of nitro clusters at the ortho position of an aromatic ring. The potent synthesized compound AAZ10 was also explored for the in-vivo Anti-Alzheimer activity and anti-oxidant activity. Binding approaches of all synthesized compounds were revealed through molecular docking studies concerning binding pockets of enzymes that analyzed the best posture interaction with amino acid (AA) residues providing an appreciable understanding of enzyme inhibitory mechanisms. Results indicate that synthesized zinc (II) amide carboxylates can behave as an effective remedy in the treatment of Alzheimer's disease.Communicated by Ramaswamy H. Sarma.

Phytochemical Analysis, Total Phenolic, Flavonoid Contents, and Anticancer Evaluations of Solvent Extracts and Saponins of H. digitata.

Cancer is one of the most challenging diseases in the modern era for the researchers and investigators. Extensive research worldwide is underway to find novel therapeutics for prevention and treatment of diseases. The extracted natural sources have shown to be one of the best and effective treatments for cell proliferation and angiogenesis. Different approaches including disc potato model, brine shrimp, and chorioallantoic membrane (CAM) assay were adopted to analyze the anticancer effects. Habenaria digitata was also evaluated for MTT activity against NIH/3T3 cell line. The dexamethasone, etoposide, and vincristine sulfate were used as a positive control in these assays. All of the extracts including crude extracts (Hd.Cr), saponin (Hd.Sp), n-hexane (Hd.Hx), chloroform (Hd.Chf), ethyl acetate (Hd.EA), and aqueous fraction (Hd.Aq) were shown excellent results by using various assays. For example, saponin and chloroform have displayed decent antitumor and angiogenic activity by using potato tumor assay. The saponin fraction and chloroform were shown to be the most efficient in potato tumor experiment, demonstrating 87.5 and 93.7% tumor suppression at concentration of 1000 µg/ml, respectively, with IC50 values of 25.5 and 18.3 µg/ml. Additionally, the two samples, chloroform and saponins, outperformed the rest of the test samples in terms of antiangiogenic activity, with IC50 28.63 µg/ml and 16.20 µg/ml, respectively. In characterizing all solvent fractions, the chloroform (Hd.Chf) and saponin (Hd.Sp) appeared to display good effectiveness against tumor and angiogenesis but very minimal activity against A. tumefaciens. The Hd.Chf and Hd.Sp have been prospective candidates in the isolation of natural products with antineoplastic properties.

Prospective Evaluation of an Amide-Based Zinc Scaffold as an Anti-Alzheimer Agent: In Vitro, In Vivo, and Computational Studies.

Alzheimer's disease is the most common progressive neurodegenerative mental disorder associated with loss of memory, decline in cognitive function, and dysfunction of language. The prominent pathogenic causes of this disease involve deposition of amyloid-ß plaques, acetylcholine neurotransmitter deficiency, and accumulation of neurofibrillary tangles. There are multiple pathways that have been targeted to treat this disease. The inhibition of the intracellular cyclic AMP regulator phosphodiesterase IV causes the increase in CAMP levels that play an important role in the memory formation process. Organometallic chemistry works in a different way in treating pharmacological disorders. In the field of medicinal chemistry and pharmaceuticals, zinc-based amide carboxylates have been shown to be a preferred pharmacophore. The purpose of this research work was to investigate the potential of zinc amide carboxylates in inhibition of phosphodiesterase IV for the Alzheimer's disease management. Swiss Albino mice under controlled conditions were divided into seven groups with 10 mice each. Group I was injected with carboxymethylcellulose (CMC) at 1 mL/100 g dose, group II was injected with Streptozotocin (STZ) at 3 mg/kg dose, group III was injected with Piracetam acting as a standard drug at 200 mg/kg dosage, while groups IV-VII were injected with a zinc scaffold at the dose regimen of 10, 20, 40, and 80 mg/kg through intraperitoneal injection. All groups except group I were injected with Streptozotocin on the first day and third day of treatment at the dose of 3 mg/kg through an intracerebroventricular route to induce Alzheimer's disease. Afterward, respective treatment was continued for all groups for 23 days. In between the treatment regimen, groups were analyzed for memory and learning improvement through various behavioral tests such as open field, elevated plus maze, Morris water maze, and passive avoidance tests. At the end of the study, different biochemical markers in the brain were estimated like neurotransmitters (dopamine, serotonin and adrenaline), oxidative stress markers (superoxide dismutase, glutathione, and catalase), acetylcholinesterase (AchE), tau proteins, and amyloid-ß levels. A PCR study was also performed. Results showed that the LD50 of the zinc scaffold is greater than 2000 mg/kg. Research indicated that the zinc scaffold has the potential to improve the memory impairment and learning behavior in Alzheimer's disease animal models in a dose-dependent manner. At the dose of 80 mg/kg, a maximum response was observed for the zinc scaffold. Maximum reduction in the acetylcholinesterase enzyme was observed at 80 mg/kg dose, which was further strengthened and verified by the PCR study. Oxidative stress was restored by the zinc scaffold due to the significant activation of the endogenous antioxidant enzymes. This research ended up with the conclusion that the zinc-based amide carboxylate scaffold has the potential to improve behavioral disturbances and vary the biochemical markers in the brain.

Succinimide Derivatives as Antioxidant Anticholinesterases, Anti-α-Amylase, and Anti-α-Glucosidase: In Vitro and In Silico Approaches.

Based on the diverse pharmacological potency and the structural features of succinimide, this research considered to synthesize succinimide derivatives. Moreover, these compounds were estimated for their biological potential in terms of anti-diabetic, anti-cholinesterase, and anti-oxidant capacities. The compounds were synthesized through Michael addition of various ketones to N-aryl maleimides. Similarly, the MOE software was used for the molecular docking study to explore the binding mode of the potent compounds against different enzymes. In the anti-cholinesterase activity, the compounds MSJ2 and MSJ10 exhibited outstanding activity against acetylcholinesterase (AChE), i.e., 91.90, 93.20%, and against butyrylcholinesterase (BChE), i.e., 97.30, 91.36% inhibitory potentials, respectively. The compounds MSJ9 and MSJ10 exhibited prominent α-glucosidase inhibitory potentials, i.e., 87.63 and 89.37 with IC50 value of 32 and 28.04 µM, respectively. Moreover, the compounds MSJ2 and MSJ10 revealed significant scavenging activity against DPPH free radicals with IC50 values of 2.59 and 2.52, while against ABTS displayed excellent scavenging potential with IC50 values 7.32 and 3.29 µM, respectively. The tentative results are added with molecular docking studies in the active sites of enzymes to predict the theoretical protein-ligand binding modes. Further detailed mechanism-based studies in animal models are essential for the in vivo evaluation of the potent compound.

Comparative in-vitro anti-inflammatory, anticholinesterase and antidiabetic evaluation: computational and kinetic assessment of succinimides cyano-acetate derivatives.

This research was planned to synthesize cyano-acetate derivatives of succinimide and evaluate its comparative biological efficacy as anti-inflammatory, anti-cholinesterase and anti-diabetic, which was further validated by molecular docking studies. The three cyano-acetate derivatives of succinimide including compound 23 Methyl 2-cyano-2-(2,5-dioxopyrrolidin-3-yl)acetate, compound 31 Methyl 2-cyano-2-(1-methyl-2,5-dioxopyrrolidin-3-yl)acetate and compound 44 Methyl 2-cyano-2-(1-ethyl-2,5-dioxopyrrolidin-3-yl) acetate were synthesized. The mentioned compounds were checked for in vitro anti-inflammatory, anti-cholinesterase and anti-diabetic (α-amylase inhibition) activity. To validate the in vitro results, computational studies were carried out using molecular operating environment to analyse the BE, i.e. binding energies of all synthesized compounds against the respective enzymes. The Compounds 23, 31, 44 exhibited anti-inflammatory via inhibiting COX-2 (IC50 value of 204.08, 68.60 and 50.93 µM, respectively), COX-1 (IC50 value of 287, 185, and 143 µM, respectively) and 5-LOX (IC50 value of 138, 50.76 and 20, 87 µM respectively). They exhibited choline-mimetic potential, such as compound 23, 31 and 44 inhibited AChE enzyme (IC50 value of 240, 174, and 134 µM, respectively) and BChE enzyme (IC50 value of 203, 134 and 97 µM, respectively). The Compounds 23, 31, 44 exhibited anti-diabetic effect via inhibiting α-amylase enzyme (IC50 values of 250, 106 and 60 µM, respectively). Molecular docking studies revealed that the synthesized compounds have good binding affinity in the binding pockets of AChE, BChE, COX-2, 5-LOX and α-amylase enzyme and showed high binding energies. The synthesized succinimide derivatives, i.e. compound 23, 31, 44 showed marked inhibitory activities against cyclooxygenase, lipoxygenase, α-amylase and cholinesterase enzymes. Among these three, compound 44 and 31 showed strong anti-inflammatory and anti-diabetic activity while they displayed moderate anti-cholinesterase activity supported by molecular docking results.Communicated by Ramaswamy H. Sarma.

Antioxidant Molecules Isolated from Edible Prostrate Knotweed: Rational Derivatization to Produce More Potent Molecules.

Prostrate knotweed also called Polygonum aviculare is an important edible plant. The polygonum is majorly known for the phenolics and antioxidants. The antioxidants combat the excessive free radicals within the body. The excessive free radicals are implicated in various other diseases like diabetes, Alzheimer's, and inflammation. This study was aimed at exploring the antioxidant bioactives and their derivatizations to produce new molecules with advanced pharmacological features. We have isolated six compounds (1-6) from Polygonum aviculare. Furthermore, rational-based chemical derivatives for compound 5 have been formed for the management of diabetes, Alzheimer's, and inflammation. In preliminary antioxidant studies, all the isolated compounds (1-6) showed potential results against DPPH and ABTS free radicals. Based on the IC50 and chemical nature of the compounds, compound 5 was subjected to derivatization. Keeping the phenolic part of compound 5 unaffected, hydroxy succinimide (5A) and thiazolidinedione (5B) were synthesized. The compound 5A was found to be a potent inhibitor of AChE, BChE, COX-1, COX-2, 5-LOX, and DPPH giving IC50 values of 10.60, 15.10, 13.91, 1.08, 0.71, and 1.05 µM, respectively. The COX-2 selectivity of compound 5A was found at 12.9. The compound 5B was found to be a potent multitarget antidiabetic agent giving IC50 values of 15.34, 21.83, 53.28, and 1.94 µM against α-glucosidase, α-amylase, protein tyrosine phosphatase 1B, and DPPH. Docking studies were performed to manipulate the binding interactions. The docking pose of all the tested compounds was found to have increased binding affinity against all tested targets that supported the in vitro results. Our results showed that Polygonum aviculare is a rich source of antioxidant compounds. The two new derivatives have enhanced pharmacological features to treat diabetes, inflammation, and Alzheimer's disease.

Exploring the Synergistic Anticancer Potential of Benzofuran-Oxadiazoles and Triazoles: Improved Ultrasound- and Microwave-Assisted Synthesis, Molecular Docking, Hemolytic, Thrombolytic and Anticancer Evaluation of Furan-Based Molecules.

Ultrasound- and microwave-assisted green synthetic strategies were applied to furnish benzofuran-oxadiazole 5a-g and benzofuran-triazole 7a-h derivatives in good to excellent yields (60-96%), in comparison with conventional methods (36-80% yield). These synthesized derivatives were screened for hemolysis, thrombolysis and anticancer therapeutic potential against an A549 lung cancer cell line using an MTT assay. Derivatives 7b (0.1%) and 5e (0.5%) showed the least toxicity against RBCs. Hybrid 7f showed excellent thrombolysis activity (61.4%) when compared against reference ABTS. The highest anticancer activity was displayed by the 5d structural hybridwith cell viability 27.49 ± 1.90 and IC50 6.3 ± 0.7 µM values, which were considerably lower than the reference drug crizotinib (IC50 8.54 ± 0.84 µM). Conformational analysis revealed the spatial arrangement of compound 5d, which demonstrated its significant potency in comparison with crizotinib; therefore, scaffold 5d would be a promising anticancer agent on the basis of cytotoxicity studies, as well as in silico modeling studies.

Organotin (IV) complexes with sulphonyl hydrazide moiety. Design, synthesis, characterization, docking studies, cytotoxic and anti-leishmanial activity.

Due to a lack of therapeutic options for the pathological condition of leishmaniasis, which is characterized by polymorphic lesions and skin surface infections, Leishmania genus parasites damaged dermis and mucosa. There was a need to synthesize and characterize some new complexes. This study evaluated the biological activities preferably anti-Leishmanial activity of organotin (IV) containing sulphonyl hydrazide derivatives. A series of six new organotin (IV) complexes 1-6 labeled as R2SnL2; R = Methyl (1), Butyl (2), Phenyl (3) and R3SnL; R = Methyl (4), Butyl (5), Phenyl (6) has been synthesized as reflux method derived from N'- (2,4-dinitrophenyl)-4-methylphenylsulfonylhydrazide (L). All compounds were characterized through FT-IR, 1HNMR, 13CNMR, and elemental analysis. Structural analysis confirms the formation of six complexes (1-6). All derivatives have been screened for their pharmacological activities. Interestingly, compound 1 showed promising activity against leishmania promastigotes with low cytotoxicity. All results were further elaborated through docking studies performed on leishmania donovoni synthetase PDB: ID 3QW3 that acts as an essential building block for the viability of Leishmania promastigotes. This research effectively synthesized sulphonyl hydrazide ligand and its six new organotin (IV) derivatives, which were tested for biological properties such as antibacterial, anti-fungal, anti-oxidant, and ideally anti-leishmanial activity and cytotoxicity. Studies have confirmed that these compounds have the potency to be a good candidate against leishmaniasis. Computational studies were carried out to recognize the binding affinities for leishmania donovoni synthetase.Communicated by Ramaswamy H. Sarma.

Prospective Application of Two New Pyridine-Based Zinc (II) Amide Carboxylate in Management of Alzheimer's Disease: Synthesis, Characterization, Computational and in vitro Approaches.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative illness described predominantly by dementia. Even though Alzheimer's disease has been known for over a century, its origin remains a mystery, and researchers are exploring many therapy options, including the cholinesterase technique. A decreased acetylcholine ACh neurotransmitter level is believed to be among the important factors in the progression of Alzheimer's disease. METHODS: In continuation of synthesizing potential anti-Alzheimer agents and known appreciative pharmacological potential of amide-containing compounds, this study presents the synthesis of two novel amide-based transition metal zinc (II) complexes, AAZ7 and AAZ8, attached with a heterocyclic pyridine ring, which was synthesized and characterized by Fourier transform infrared spectroscopy (FT-IR), elemental analysis, 1H_NMR, and 13C_NMR. FT-IR spectroscopic records showed the development of bidentate ligand as Δν value was decreased in both complexes when compared with the free ligand. Both of the synthesized complexes were analyzed for acetylcholinesterase and butyrylcholinesterase inhibitory potential along with the antioxidizing activity. RESULTS: Importantly, the complex of AAZ8 exhibited more potent activity giving IC50 values of 14 µg/mL and 18µg/mL as AChE and BChE cholinesterase inhibitors, respectively, when compared with standard positive control galantamine. Interestingly, AAZ8 also displayed promising antioxidant potential by showing IC50 values of 35 µg/mL for DPPH and 29 µg/mL for ABTS in comparison with positive control ascorbic acid. CONCLUSION: Herein, we report two new amide carboxylate zinc (II) complexes which were potentially analyzed for various biological applications like acetylcholinesterase (AChE), butyrylcholinesterase (BChE) inhibitory potentials, and antioxidant assays. Computational docking studies also simulated results to understand the interactions. Additionally, thermodynamic parameters utilizing molecular dynamic simulation were performed to determine the ligand protein stability and flexibility that supported the results. Studies have shown that these compounds have the potential to be good anti-Alzheimer candidates for future studies due to inhibition of cholinesterase enzymes and display of free radical scavenging potential against DPPH as well as ABTS free radicals.

Zinc metal carboxylates as potential anti-Alzheimer's candidate: in vitro anticholinesterase, antioxidant and molecular docking studies.

In search of suitable therapy for the management of Alzheimer's disease, this study was designed to evaluate metal complexes against its biochemical targets. Zinc metal carboxylates (AAZ1-AAZ6) were evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The antioxidant in combination with anticholinesterase activity can be considered as an important target in the management of Alzheimer's disease. Therefore, these compounds were also screened for ABTS and DPPH free radical scavenging activity. In AChE inhibition assay, we noticed encouraging IC50 values of 33.07 and 59.52 µM for compounds AAZ5 and AAZ3, respectively. However, when we tested BChE activity, we observed an outstanding IC50 of 0.056 µM for compound AAZ6. Amazingly all of our compounds (AAZ1-AAZ6) were proved to be strong antioxidants which actively supplement the anti-Alzheimer's activity. The majority of our compounds exhibited lower IC50 values than the standard ascorbic acid in both DPPH and ABTS assays. We also correlated our results with molecular docking studies. Results elaborated that AAZ1 and AAZ5 exhibit strong interactions with amino acids HIS 362, HIS 398, GLU 306 ARG 289 and SER 237 inside binding pocket of targeted protein. In remarks, we can claim that our synthesized zinc metal carboxylates have strong potency to manage Alzheimer's disease on both anticholinesterase and antioxidant targets. Communicated by Ramaswamy H. Sarma.