Drug repurposing against SARS-CoV-2 using computational approaches.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has generated a critical need for treatments to reduce morbidity and mortality associated with this disease. However, traditional drug development takes many years, which is not practical solution given the current pandemic. Therefore, a viable option is to repurpose existing drugs. The structural data of several proteins vital for the virus became available shortly after the start of the pandemic. In this review, we discuss the importance of these targets and their available potential inhibitors predicted by the computational approaches. Among the hits identified by computational approaches, 35 candidates were suggested for further evaluation, among which ten drugs are in clinical trials (Phase III and IV) for treating Coronavirus 2019 (COVID-19).

Conformational polymorphs of 3-cyclopropyl-5-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1,2,4-oxadiazole.

The dipharmacophore compound 3-cyclopropyl-5-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1,2,4-oxadiazole, C12H11N5O, was studied on the assumption of its potential biological activity. Two polymorphic forms differ in both their molecular and crystal structures. The monoclinic polymorphic form was crystallized from more volatile solvents and contains a conformer with a higher relative energy. The basic molecule forms an abundance of interactions with relatively close energies. The orthorhombic polymorph was crystallized very slowly from isoamyl alcohol and contains a conformer with a much lower energy. The basic molecule forms two strong interactions and a large number of weak interactions. Stacking interactions of the `head-to-head' type in the monoclinic structure and of the `head-to-tail' type in the orthorhombic structure proved to be the strongest and form stacked columns in the two polymorphs. The main structural motif of the monoclinic structure is a double column where two stacked columns interact through weak C-H...N hydrogen bonds and dispersive interactions. In the orthorhombic structure, a single stacked column is the main structural motif. Periodic calculations confirmed that the orthorhombic structure obtained by slow evaporation has a lower lattice energy (0.97 kcal mol-1) compared to the monoclinic structure.

A Novel Series of [1,2,4]Triazolo[4,3-a]Pyridine Sulfonamides as Potential Antimalarial Agents: In Silico Studies, Synthesis and In Vitro Evaluation.

For the development of new and potent antimalarial drugs, we designed the virtual library with three points of randomization of novel [1,2,4]triazolo[4,3-a]pyridines bearing a sulfonamide fragment. The library of 1561 compounds has been investigated by both virtual screening and molecular docking methods using falcipain-2 as a target enzyme. 25 chosen hits were synthesized and evaluated for their antimalarial activity in vitro against Plasmodium falciparum. 3-Ethyl-N-(3-fluorobenzyl)-N-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonamide and 2-(3-chlorobenzyl)-8-(piperidin-1-ylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one showed in vitro good antimalarial activity with inhibitory concentration IC50 = 2.24 and 4.98 µM, respectively. This new series of compounds may serve as a starting point for future antimalarial drug discovery programs.

Concomitant polymorphic forms of 3-cyclopropyl-5-(2-hydrazinylpyridin-3-yl)-1,2,4-oxadiazole.

The dipharmacophore compound 3-cyclopropyl-5-(2-hydrazinylpyridin-3-yl)-1,2,4-oxadiazole, C10H11N5O, was studied on the assumption of its potential biological activity. Two concomitant polymorphs were obtained on crystallization from isopropanol solution and these were thoroughly studied. Identical conformations of the molecules are found in both structures despite the low difference in energy between the four possible conformers. The two polymorphs differ crucially with respect to their crystal structures. A centrosymmetric dimer formed due to both stacking interactions of the `head-to-tail' type and N-H...N(π) hydrogen bonds is the building unit in the triclinic structure. The dimeric building units form an isotropic packing. In the orthorhombic polymorphic structure, the molecules form stacking interactions of the `head-to-head' type, which results in their organization in a column as the primary basic structural motif. The formation of N-H...N(lone pair) hydrogen bonds between two neighbouring columns allows the formation of a double column as the main structural motif. The correct packing motifs in the two polymorphs could not be identified without calculations of the pairwise interaction energies. The triclinic structure has a higher density and a lower (by 0.60 kcal mol-1) lattice energy according to periodic calculations compared to the orthorhombic structure. This allows us to presume that the triclinic form of 3-cyclopropyl-5-(2-hydrazinylpyridin-3-yl)-1,2,4-oxadiazole is the more stable.

The role of hydrogen sulfide in the progression of chronic obstructive pulmonary disease in patients with non-alcoholic steatohepatitis

Introduction: The steady increase in the incidence of comorbidity of chronic obstructive pulmonary disease and non-alcoholic steatohepatitis against the background of obesity in people of working age in Ukraine and in the world stipulates the need of investigation of the mechanisms of interconnection and the search for new factors of the pathogenesis of progression of this comorbid pathology. Attention to the role of hydrogen sulfide in the development of fibrosis has only been recently paid. The aim: To establish the role of hydrogen sulfide in the mechanisms of progression of chronic obstructive pulmonary disease and non-alcoholic steatohepatitis against the background of obesity. Material and methods: Materials and methods: 100 patients with chronic obstructive pulmonary disease have been examined, including 49 with non-alcoholic steatohepatitis and obesity of the 1st stage: group 1 ­ 28 patients with chronic obstructive pulmonary disease (2B GOLD); group 2 ­ 23 patients with chronic obstructive pulmonary disease (3C, D); group 3 ­ 25 patients with chronic obstructive pulmonary disease (2B) with non-alcoholic steatohepatitis; group 4 ­ 24 patients with chronic obstructive pulmonary disease (3C, D) and non-alcoholic steatohepatitis. The average age of patients was (47.3±3.1) years. There were 20 apparently healthy persons of the corresponding age and sex in the control group. Results: The received data confirm that patients with chronic obstructive pulmonary disease secondary to non-alcoholic steatohepatitis, which developed against the background of obesity, suffer from a significant increase in the synthesis of collagen and glycoproteins, accompanied by an ineffective resorption of newly formed collagen due to insufficient activation of collagenolysis and proteolysis, a significant imbalance in the connective tissue metabolism system, which leads to progressive fibrosis of the lungs and liver and disturbances of their functions. This was caused by the disorder of H2S homeostasis, confirmed by the data of correlation analysis. Conclusions: Patients with chronic obstructive pulmonary disease and non-alcoholic steatohepatitis, which developed against the background of obesity, are characterized by a significant increase in the synthesis of collagen and glycoproteins, which was accompanied by an ineffective resorption of newly formed collagen against the background of substantial activation of proteinase inhibitors (α2-MG), accompanied by the hyperproduction of nitrogen monoxide, endothelin-1, hyperlipidemia, deficiency of hydrogen sulfide liberation.

Clinical and pathogenetic features of nonalcoholic steatohepatitis for comorbidity with bronchial asthma on the background of obesity.

OBJECTIVE: Introduction: The comorbid flow of non-alcoholic steatohepatitis (NASH) and bronchial asthma (BA) on the background of obesity is often recently drawn to the attention of both practitioners and researchers . The aim of our study was to study the changes in the functional state of the liver and the dependence of the external respiration function in patients with non-alcoholic steatohepatitis in combination with bronchial asthma and obesity. PATIENTS AND METHODS: Materials and methods: The study was attended by 50 people aged from 30 to 50 years (average age 42 years), of which 40% were men and 60% women. Of these, 30 patients with obesity I degree (BMI greater than 30 kg / m2) non-alcoholic steatohepatitis was detected, and in 20 of patients, non-alcoholic steatohepatitis was combined with obesity of the I degree and persistent bronchial asthma of moderate severity. Duration of the disease was from 2 to 6 years. The control group consisted of 20 practically healthy persons (PHPs) of the corresponding age and sex. RESULTS: Results: In patients with NASH with comorbid BA and obesity I degree there are more noticed syndromes of cytolysis and cholestasis, mesenchymal inflammation, more significant changes in the liver, as evidenced by the low AST/ALT ratio in this group. Patients with non-alcoholic steatohepatitis on the background of obesity of the I degree with the addition of bronchial asthma of moderate severity and the persistent flow at the exacerbation phase, the content in the blood of markers of the activity of cytolysis of hepatocytes increases (increased activity of aminotransferases serum, p <0,05), cholestasis (increased contentof direct bilirubin in the blood, p <0,05, cholesterol activity, p<0,05, gamma-glutamyltransferase activity, p <0,05 and alkaline phosphatase, p <0,05) and mesenchymal inflammation (increase in the thyme test, p <0,05), which testifies to the aggravating factor and the impact of BA on the course of NASH. CONCLUSION: Conclusion: The presence of visceral obesity and nonalcoholic steatohepatitis in patients with bronchial asthma leads to the accumulation of its clinical course, the deepening of changes in the function of external respiration by obstructive type (a possible decrease in FEV1 and PEF, p<0.05). The presence of obesity and NASH contributed to the development of restrictive type of respiratory insufficiency in the form of a possible decrease in Vital capacity (VC, p<0,05) in patients without BA, and in patients with NASH and obesity with BA, which significantly aggravated its course.