Naphtho[2,1-b]furan derived triazole-pyrimidines as highly potential InhA and Cytochrome c peroxidase inhibitors: Synthesis, DFT calculations, drug-likeness profile, molecular docking and dynamic studies

Napthofuran and its fused heterocyclic derivatives evaluated with varied biological activity functional groups comprise an important class of compounds for new chemical entities. We here in reporting synthesis of new 3-(4-substituted phenyl)naphtho[1′,2′:4,5]furo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidines 6(a-f). Structures of the newly synthesized compounds were confirmed by making use of spectroscopic techniques like IR, NMR and Mass. The DFT calculations were taken for the selected molecules using B3LYP hybrid functional with a 6–31+G (d, p) all-electron basis set using the Gaussian 09 package. The bioactivity predictions were evaluated for the synthesized compounds. The In vitro biological activities were reported for the all compounds 6(a-f). The compound 6a showed high activity of anti-TB and antioxidant activity with at MIC 1.6 μg/ml and at percentage of inhibition (72.54±0.21) at 10μg/ml respectively. The compound 6f (73.21±0.11) showed antioxidant activity better than standard drug BHA (71.32±0.13) at 10 μg/ml. Furthermore, the docking studies for the newly synthesized molecules were carried out by Auto dock software with proteins InhA (4TZK),Cytochrome c peroxidase (2 × 08) and protease (Mpro) of SARS-CoV-2 Omicron (PDB ID: 7TOB). All the compounds showed a strong binding affinity for the docked proteins. The outcome of docking results showed that compound 6ahad excellent binding energies -10.8, -9.4, and -9.0 kcal/mol with 4TZK, 2 × 08, and 7TOB respectively. Lastly, the protein stability, fluctuations of APO-Protein, protein-ligand complexes were investigated through Molecular Dynamics (MD) simulations studies using Desmond Maestro 11.3 and potential lead molecules were identified. © 2023

Herbal and Ayurvedic Plants as Remedial Approach for Viral Diseases with Focus on COVID-19: A Narrative Review

Background: Infectious diseases have posed a major threat to human survival for centu-ries and can devastate entire populations. Recently, the global outbreak of COVID-19 has increased exponentially, affecting more than 200 countries and millions of lives since the fall of 2019, largely due to the ineffectiveness of existing antiviral therapies. WHO announced it a public health emer-gency of international concern. A significant waiting period in antiviral therapy hindered by the rapid evolution of severe acute respiratory syndrome-coronavirus-2 aggravated the situation ensuing imposition of strict laws (e.g., communal dissociation, international travel restrictions, and mainte-nance of hygiene) that would help in inhibiting further outspread of COVID-19. Ayurveda system of medicine offers a holistic approach to the COVID-19 pandemic. Objective(s): This review aims to highlight the potential of medicinal herbs and Ayurvedic drugs as the remedial approach for viral diseases, such as COVID-19. Method(s): We reviewed the literature from journal publication websites and electronic databases, such as Bentham, Science Direct, Pub Med, Scopus, USFDA, etc. Result(s): The drugs used in the traditional system of medicine have the potential to prevent and cure the infected patient. Ayurvedic therapies are known for regulating immunity and rejuvenation properties that behold much promise in the management of COVID-19 disease. Government of India, Ministry of AYUSH recommends some precautionary fitness measures and an increase in immunity with special reference to respiratory health. Conclusion(s): While there is no medication for COVID-19 as of now, taking preventive measures and boosting body immunity is highly recommended. A number of medicinal plants that play an im-portant role in revitalizing the immune system are easily accessible in home remedies.Copyright © 2023 Bentham Science Publishers.

New Halogenated Compounds from Halimeda macroloba Seaweed with Potential Inhibitory Activity against Malaria.

Malaria is one of the most important infectious diseases worldwide. The causative of the most severe forms of malaria, Plasmodium falciparum, has developed resistances against all the available antimalarial drugs. In the present study, the phytochemical investigation of the green seaweed Halimeda macroloba has afforded two new compounds 1-2, along with 4 known ones 3-6. The structures of the compounds had been confirmed using 1& 2D-NMR and HRESIMS analyses. Extensive machine-learning-supported virtual-screening suggested cytochrome-C enzyme as a potential target for compound 2. Docking, absolute-binding-free-energy (ΔGbinding) and molecular-dynamics-simulation (MDS) of compound 2 revealed the strong binding interaction of this compound with cytochrome-C. In vitro testing for crude extract and isolated compounds revealed the potential in vitro inhibitory activity of both extract and compound 2 against P. falciparum. The crude extract was able to inhibit the parasite growth with an IC50 value of 1.8 ± 0.35 µg/mL. Compound 2 also showed good inhibitory activity with an IC50 value of 3.2 ± 0.23 µg/mL. Meanwhile, compound 6 showed moderate inhibitory activity with an IC50 value of 19.3 ± 0.51 µg/mL. Accordingly, the scaffold of compound 2 can be considered as a good lead compound for the future development of new antimalarial agents.

Does melatonin protect fetal brain during maternal hypothyroidism? An experimental study

Objectives: To study the effects of melatonin in preventing neonatal neuronal apoptosis induced by maternal hypothyroidism. Methods: Twelve healthy female Wistar rats, 12-16 weeks, were divided equally into three groups. Group-A was labelled as control. Group-B was made hypothyroid by giving 15mg/kg of propylthiouracyl (PTU) daily whereas Group-C was given PTU along with melatonin (10mg of melatonin/kg/day) in drinking water. After one week of treatment, the female rats were allowed to mate and conceive. The treatment of all groups continued throughout the period of pregnancy and lactation. After delivery, a total of 30 pups, 10 from each group, were labelled and sacrificed on 22nd day of life. The serum levels of TSH, T3 and T4 of the pups were measured. The brains were extracted from the skull and homogenized for isolation of mitochondria to determine the levels of cytochrome c oxidase and for isolation of RNAs to measure the levels of gene expressions of caspases 3, 9 and 8. Results: Group-B pups showed a significant increase in serum levels of TSH (21 ± 3.7 mg/dl), and gene expression levels of caspase 3 (0.85±0.02) and 9 (0.69±0.02) where as in Group-C, there was visible reduction in concentration of TSH (15 ± 2.4 mg/dl), caspase 3 (0.50±0.02) and 9 (0.25±0.01) expressions. Increase in cytochrome c oxidase enzyme concentration (3.416 ± 0.001) in Group-B was the result of mitochondrial outer membrane rupture, causing decrease in the number of neurons by accelerating apoptosis. A decrease in its level in Group-C (2.100 ± 0.001) indicated inhibition of apoptosis. Conclusion: Intake of melatonin during pregnancy and lactation protected the brains of offspring from extensive apoptosis during maternal hypothyroidism.

Transcranial Photobiomodulation Therapy for Sexual Dysfunction Associated with Depression or Induced by Antidepressant Medications

Sexual dysfunction (SD) is frequently encountered in patients suffering from depression. There is a bidirectional relationship between various types of SD and depression, so the presence or treatment of one condition may exacerbate or improve the other condition. The most frequent sexual problem in untreated depressed patients is declining sexual desire, while in treated depressed patients it is difficulties with erection/ejaculation and with orgasm. Numerous classes of neuropsychiatric medications, commonly used in depressed patients—such as antidepressant, antipsychotic, alpha sympathetic, and opioid drugs—may cause SD. Photobiomodulation (PBM) therapy, also called low-level light/laser therapy, is a novel neuromodulation technique for neuropsychiatric conditions, such as depression. Transcranial PBM (tPBM) targets the cellular metabolism—through the mitochondrial respiratory enzyme, cytochrome c oxidase—and has numerous cellular and physiological beneficial effects on the central nervous system. This paper represents a comprehensive review of the application of tPBM to SD, coexisting with depression or induced by antidepressant medications.

Effects of levamisole on sexual behavior, reproductive hormones and testicular histopathology in male rats

AIM: Levamisole, an antiparasitic drug, was reported to have positive effects in various clinical trials in the treatment of COVID-19. However, the number of studies on the effects of levamisole on the reproductive system and sexual behavior in male rats is limited. The present study aimed to investigate the possible effects of levamisole on sexual behavior, testicular histopathology, serum gonadotropin, and testosterone levels in male rats. METHODS: Twenty male Sprague-Dawley rats were divided into two groups as control and levamisole were used. Rats were given levamisole (2 mg/kg) dissolved in distilled water for 30 days, while only distilled water was administered to the control group by oral gavage. Finally, sexual behavior tests (SBT) were performed for 30 min. Then, the animals were decapitated, blood samples and testis tissues were taken. The Bax, Hsp70 and cytochrome c immunohistochemistry staining were performed in testis tissues, and gene expression levels were measured by real-time PCR. The luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels were measured by ELISA in serum samples. RESULTS: In SBT parameters, mount latency (ML, p<0.001), intromission latency (IL, p<0.01), and the postejaculatory interval (PEI, p<0.01) were significantly prolonged. Also, the copulatory rate (CR, p<0.05) was significantly reduced. Serum LH, FSH, and testosterone levels did not change. In the histopathological stainings, irregularities in the seminiferous tubule germinal epithelium, congestion, edema in the interstitial area, and metaphase arrest in some spermatocytes were detected in the levamisole group (p<0.001). Levamisole treatment also significantly increased cytochrome c, Bax, and Hsp 70 immunoreactivities and Bax (p=0.05) and Hsp 70 (p<0.01) gene expression levels in testicular tissue. CONCLUSION: Levamisole may decrease sexual motivation and copulation efficiency. Also, it may adversely affect testicular histopathology in male rats.

Cytochrome c: Using Biological Insight toward Engineering an Optimized Anticancer Biodrug.

The heme protein cytochrome c (Cyt c) plays pivotal roles in cellular life and death processes. In the respiratory chain of mitochondria, it serves as an electron transfer protein, contributing to the proliferation of healthy cells. In the cell cytoplasm, it activates intrinsic apoptosis to terminate damaged cells. Insight into these mechanisms and the associated physicochemical properties and biomolecular interactions of Cyt c informs on the anticancer therapeutic potential of the protein, especially in its ability to subvert the current limitations of small molecule-based chemotherapy. In this review, we explore the development of Cyt c as an anticancer drug by identifying cancer types that would be receptive to the cytotoxicity of the protein and factors that can be finetuned to enhance its apoptotic potency. To this end, some information is obtained by characterizing known drugs that operate, in part, by triggering Cyt c induced apoptosis. The application of different smart drug delivery systems is surveyed to highlight important features for maintaining Cyt c stability and activity and improving its specificity for cancer cells and high drug payload release while recognizing the continuing limitations. This work serves to elucidate on the optimization of the strategies to translate Cyt c to the clinical market.

SARS-Cov-2 spike protein fragment 674-685 protects mitochondria from releasing cytochrome c in response to apoptogenic influence.

In spite of numerous studies, many details of SARS-Cov-2 interaction with human cells are still poorly understood. The 674-685 fragment of SARS-Cov-2 spike protein is homologous to the fragment of α-cobratoxin underlying its interaction with α7 nicotinic acetylcholine receptors (nAChRs). The interaction of 674-685 peptide with α7 nAChR has been predicted in silico. In the present paper we confirm this prediction experimentally and investigate the effect of SARS-Cov-2 spike protein peptide on mitochondria, which express α7 nAChRs to regulate apoptosis-related events. We demonstrate that SARS-Cov-2 spike protein peptide 674-685 competes with the antibody against 179-190 fragment of α7 nAChR subunit for the binding to α7-expressing cells and mitochondria and prevents the release of cytochrome c from isolated mitochondria in response to 0.5 mM H2O2 but does not protect intact U373 cells against apoptogenic effect of H2O2. Our data suggest that the α7 nAChR-binding portion of SARS-Cov-2 spike protein prevents mitochondria-driven apoptosis when the virus is uncoated inside the cell and, therefore, supports the infected cell viability before the virus replication cycle is complete.