Identification of potent compounds against SARs-CoV-2: An in-silico based drug searching against Mpro.

The worldwide pandemic of coronavirus disease 2019 (COVID-19) along with the various newly discovered major SARS-CoV-2 variants, including B.1.1.7, B.1.351, and B.1.1.28, constitute the Variant of Concerns (VOC). It's difficult to keep these variants from spreading over the planet. As a result of these VOCs, the fifth wave has already begun in several countries. The rapid spread of VOCs is posing a serious threat to human civilization. There is currently no specific medicine available for the treatment of COVID-19. Here, we present the findings of methods that used a combination of structure-assisted drug design, virtual screening, and high-throughput screening to swiftly generate lead compounds against Mpro protein of SARs-CoV-2. Therapeutics, in addition to vaccinations, are an essential element of the healthcare response to COVID-19's persistent threat. In the current study, we designed the efficient compounds that may combat all emerging variants of SARs-CoV-2 by targeting the common Mpro protein. The present study was aimed to discover new compounds that may be proposed as new therapeutic agents to treat COVID-19 infection without any adverse effects. For this purpose, a computational-based virtual screening of 352 in-house synthesized compounds library was performed through molecular docking and Molecular Dynamics (MD) simulation approach. As a result, four novel potent compounds were successfully shortlisted by implementing certain pharmacological, physiological, and ADMET criteria i.e., compounds 3, 4, 21, and 22. Furthermore, MD simulations were performed to evaluate the stability and dynamic behavior of these compounds with Mpro complex for about 30 ns. Eventually, compound 22 was found to be highly potent against Mpro protein and was further evaluated by applying 100 ns simulations. Our findings showed that these shortlisted compounds may have potency to treat the COVID-19 infection for which further experimental validation is proposed as part of a follow-up investigation.

Synthesis and Erythroid Induction Activity of New Thiourea Derivatives.

BACKGROUND: The use of medicinal agents to augment the fetal hemoglobin (HbF) accretion is an important approach for the treatment of sickle-cell anemia and ß-thalassemia. HbF inducers have the potential to reduce the clinical symptoms and blood transfusion dependence in the patients of ß- hemoglobinopathies. OBJECTIVE: The current study was aimed to examine the erythroid induction potential of newly synthesized thiourea derivatives. METHODS: Thiourea derivatives 1-27 were synthesized by using environmentally friendly methods. Compounds 3, 10 and 22 were found to be new. The structures of synthesized derivatives were deduced by using various spectroscopic techniques. These derivatives were then evaluated for their erythroid induction using the human erythroleukemic K562 cell line, as a model. The benzidine-H2O2 assay was used to evaluate erythroid induction, while HbF expression was studied through immunocytochemistry using the Anti-HbF antibody. Cytotoxicity of compounds 1-27 was also evaluated on mouse fibroblast 3T3 cell line and cancer Hela cell line using MTT assay. RESULT: All the compounds (1-27) have not been reported for their erythroid induction activity previously. Compounds 1, 2, and 3 were found to be the potent erythroid inducing agents with % induction of 45± 6.9, 44± 5.9, and 41± 6.1, at 1.56, 0.78, and 0.78 µM concentrations, respectively, as compared to untreated control (12 ± 1 % induction). Furthermore, compound 1, 2, and 3 significantly induced fetal hemoglobin the expression up to 4.2-fold, 4.06-fold, and 3.52-fold, respectively, as compared to untreated control. Moreover, the compounds 1-4, 6-9, 11, 12, 15, 17, 19, 22, 23, and 25 were found to be non-cytotoxic against the 3T3 cell line. CONCLUSION: This study signifies that the compounds reported here may serve as the starting point for the designing and development of new fetal hemoglobin inducers for the treatment of ß- hemoglobinopathies.

Thiourea derivatives induce fetal hemoglobin production in-vitro: A new class of potential therapeutic agents for ß-thalassemia.

Fetal hemoglobin (HbF) induction is a cost-effective therapeutic approach for the treatment of ß-hemoglobinopathies like ß-thalassemia and sickle cell anemia. The present study discusses the potential of thiourea derivatives as new class of compounds that induce the fetal hemoglobin production. HbF inducing effect of thiourea derivatives was studied using experimental cell system, the human erythroleukemic K562 cell line. Erythroid induction of K562 cells was studied by the benzidine/H2O2 reaction, total hemoglobin production was estimated by plasma hemoglobin assay kit, and γ-globin gene expression by RT-qPCR, whereas fetal hemoglobin production was estimated by flow cytometry and immunofluorescence microscopy. The results indicated that newly synthesized thiourea derivative are potent inducers of erythroid differentiation of K562 cells with an increased γ-globin gene expression and fetal hemoglobin production. Moreover, these compounds showed no cytotoxic effect and inhibition on K562 cells at HbF inducing concentrations. It is important to note that hydroxyurea is a cytotoxic chemotherapeutic agent and have deleterious side effects, reflecting the need to identify new safe and effective HbF induces. These results signify thiourea derivatives as promising HbF inducers, with the potential to be studied against hematological disorders, including ß-thalassemia and sickle cell anemia.

Inhibition of Adipogenesis by Thiourea Derivatives.

BACKGROUND: Obesity is one of the major health problems with inherent risk of type 2 diabetes, hypertension, CVDs, etc. Adipogenesis is a major contributor in the process of obesity. Inhibition of adipocytes differentiation is one of the key approaches to treat obesity. OBJECTIVE: To discover the new inhibitors of adipogenesis as the treatment for obesity. METHOD: We describe here, the synthesis, and anti-adipogenic activity of thiourea derivatives 1-14. These derivatives were synthesized by the reactions of phenyl and pentafluorophenyl isothiocyanate with different aromatic amines. Pure compounds 1-14 were evaluated for their in vitro antiadipogenesis activity employing 3T3-L1 cells lines. RESULTS: Compounds 1-3, 5-9, and 11-14 significantly inhibited the pre-adipocyte differentiation into adipocytes, which was measured by staining the cells, and through morphological examination. Compound 10 (1-(4"-Chlorophenyl)-3-(pentafluorophenyl)-thiourea) showed a potent inhibition of adipocyte differentiation with IC50 = 740.00 ± 2.36 nM, which was more potent than the standards, epigallocatechin gallate (IC50 = 16.73 ± 1.34 µM), and curcumin (IC50 = 18.62 ± 0.74 µM). All other compounds showed a moderate to weak anti-adipogenesis activity. Compounds 1- 14 were also evaluated for their cytotoxicity. Compounds 3, 10, and 14 showed some toxicity to the cancer cell lines, while compounds 2, 3, 10, 12, and 14 showed a moderate to weak cytotoxicity against the normal cell lines. CONCLUSION: All the compounds reported in this paper are known, except compound 11. They have been identified as new inhibitors of Adipogenesis. Adipogenesis is the process of adipocytes differentiation from pre-adipocytes. This extensively studied model of cell diff differentiation. Further synthetic modifications, and optimization of anti-adipogenic activity may lead to the development of anti-obesity agents.