Medicinal Chemistry - Volume 17, Issue 2, 2021

Background: Some species of Cordyceps sensu lato are famous Chinese herbs with significant biological activities, often used as edible food and traditional medicine in China. Cordyceps represents the largest entomopathogenic group of fungi, including 40 genera and 1339 species in three families and incertae sedis of Hypocreales. Objective: Most of the Cordyceps-derivatives have been approved clinically for the treatment of various diseases such as diabetes, cancers, inflammation, cardiovascular, renal and neurological disorders and are used worldwide as supplements and herbal drugs, but there is still need for highly efficient Cordyceps-derived drugs for fatal diseases with approval of the U.S. Food and Drug Administration. Methods: Computer-aided drug design concepts could improve the discovery of putative Cordyceps- derived medicine within less time and low budget. The integration of computer-aided drug design methods with experimental validation has contributed to the successful discovery of novel drugs. Results: This review focused on modern taxonomy, active metabolites, and modern drug design techniques that could accelerate conventional drug design and discovery of Cordyceps s. l. Successful application of computer-aided drug design methods in Cordyceps research has been discussed. Conclusion: It has been concluded that computer-aided drug design techniques could influence the multiple target-focused drug design, because each metabolite of Cordyceps has shown significant activities for the various diseases with very few or no side effects.

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 β-thalassemia. HbF inducers have the potential to reduce the clinical symptoms and blood transfusion dependence in the patients of β- 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 β- hemoglobinopathies.

Background: Triterpenoids exhibit a wide spectrum of antimicrobial activity. Objective: The objective of this study was to synthesize a series of nitrogen derivatives based on lupane, oleanane, and ursane triterpenoids with high antitubercular activity. Methods: Isonicotinoylhydrazones were prepared via the reaction of 3-oxotriterpenic acids or betulonic aldehyde with isoniazid (INH) in yields of 54-72%. N-Acylation of betulonic or azepanobetulinic acids led to lupane C28 hydrazides and dihydrazides. The derivatives were evaluated for their in vitro antimycobacterial activities against Mycobacterium tuberculosis (MTB) H37RV and single-drug resistance (SDR)-TB in the National Institute of Allergy and Infectious Diseases, USA. Molecular docking was performed to evaluate the possible binding modes of investigated compounds in the active site of Diterpene synthase (Rv3378c). Results: The obtained compounds are represented by C3 or C28 conjugates with hydrazine hydrate or INH. Some compounds demonstrated from high minimum inhibitory concentration (MIC ≤ 10 μg/mL) to excellent (MICs from 0.19 to 1.25 μg/mL) activity against MTB H37RV. Two lupane conjugates with INH were the leading compounds against MTB H37RV and some SDR-strains with MICs ranged from 0.19 to 1.70 μg/mL. Molecular docking of active compounds to diterpene synthase showed that these moieties accommodate the active site of the enzyme. Conclusion: It was revealed that the conjugation of lupanes with INH at C3 is more effective than at C28 and the lupane skeleton is preferable among oleanane and ursane types. The replacement of native hexacarbocyclic A ring to seven-member azepane ring is favorably for inhibition of both MTB H37RV and SDR-strains. These data could possibly mean that the antitubercular activity against INH-resistant strains (INH-R) came from both triterpenoid and isoniazid parts of the hybrid molecules. Azepanobetulin showed the highest activity against both INH-R strains in comparison with other triterpenoids and INH. Thus, the introduction of hydrazone, hydrazide (dihydrazide), or azepane moieties into the triterpenoid core is a promising way for the development of new anti-tubercular agents.

Background: Helicobacter pylori infection is accountable for most of the peptic ulcer and intestinal cancers. Due to the uprising resistance towards H. pylori infection through the present and common proton pump inhibitors regimens, the investigation of novel candidates is the inevitable issue. Medicinal plants have always been a source of lead compounds for drug discovery. The research of the related effective enzymes linked with this gram-negative bacterium is critical for the discovery of novel drug targets. Objective: The aim of the study is to identify the best candidate to evaluate the inhibitory effect of thymoquinone and thymol against H. pylori oncoproteins, Cag A and Vac A in comparison to the standard drug, metronidazole by using a computational approach. Materials and Methods: The targeted oncoproteins, Cag A and Vac A were retrieved from RCSB PDB. Lipinski’s rule and ADMET toxicity profiling were carried out on the phytoconstituents of the N. sativa. The two compounds of N. sativa were further analyzed by molecular docking and MD simulation studies. The reported phytoconstituents, thymoquinone and thymol present in N. sativa were docked with H. pylori Cag A and Vac A oncoproteins. Structures of ligands were prepared using ChemDraw Ultra 10 software and then changed into their 3D PDB structures using Molinspiration followed by energy minimization by using software Discovery Studio client 2.5. Results: The docking results revealed the promising inhibitory potential of thymoquinone against Cag A and Vac A with docking energy of -5.81 kcal/mole and -3.61kcal/mole, respectively. On the contrary, the inhibitory potential of thymol against Cag A and Vac A in terms of docking energy was -5.37 kcal/mole and -3.94kcal/mole as compared to the standard drug, metronidazole having docking energy of -4.87 kcal/mole and -3.20 kcal/mole, respectively. Further, molecular dynamic simulations were conducted for 5ns for optimization, flexibility prediction, and determination of folded Cag A and Vac A oncoproteins stability. The Cag A and Vac A oncoproteins-TQ complexes were found to be quite stable with the root mean square deviation value of 0.2nm. Conclusion: The computational approaches suggested that thymoquinone and thymol may play an effective pharmacological role to treat H. pylori infection. Hence, it could be summarized that the ligands thymoquinone and thymol bound and interacted well with the proteins Cag A and Vac A as compared to the ligand MTZ. Our study showed that all lead compounds had good interaction with Cag A and Vac A proteins and suggested them to be a useful target to inhibit H. pylori infection.

Background: Flavonoids are naturally occurring compounds with versatile healthpromoting effects against various diseases. Objective: This aim of this paper is to synthesize and evaluate the biological activity of novel flavone derivatives against cancer. Methods: A new series of 2-hydroxy-α,β-unsaturated ketones 2a-h, was synthesized via the reaction of N-substituted-indole-3-carboxaldehyde 1a-h with 2-hydroxy acetophenone in the presence of piperidine. The oxidative cyclization of 2a-h using hydrogen peroxide/KOH and/or dimethyl sulfoxide/I2 produced the corresponding 2-(N-substituted-1H-indol-3-yl)-3-hydroxy-4H-chromen- 4-ones 3a-h and 2-(N-substituted-1H-indol-3-yl)-4H-chromen-4-ones 4a-h, respectively. Antiproliferative activities for synthesized series were investigated against HCT-116 colon and MCF- 7 breast cancer cell lines. Molecular downstream effects were evaluated using RT-PCR. Moreover, molecular docking was carried out to pinpoint the binding mode of the most active compounds into the active site of Akt enzyme (PDB ID: 3QKK). Results: All compounds exhibited an anti-proliferative activity range of 52-97% and 67.2-99% against HCT-116 and MCF-7, respectively. Compounds 3b, 3h, 3g and 4h had a minimal inhibitory effect on normal BJ1 cells indicating their safety profile. Compounds 3b and 4h, in particular, exhibited the most potent antiproliferative activity against HCT116 and MCF7, meanwhile compounds 3g, 3h and 4g showed potent to moderate activity. Compound 3b had IC50 of 78.3 μM and 53.9 μM against HCT-116 and MCF-7 respectively with comparable IC50 for doxorubicin of 65.1 μM and 45.02 μM. Compound 3b exhibited significant down-regulation for Akt and significant up-regulation of CAS9 and CDKN1genes in all tested cell lines. Conclusion: The synthesized flavone derivatives and particularly compound 3b exhibited promising anticancer activity through Akt inhibition.

Background: Hypertension, one of the most common cardiovascular diseases that can cause coronary disease, stroke, myocardial infarction, and sudden death, it is the major contributor to cardiac failure as well as renal insufficiency. Objectives: As there are many cardio-active pyridazinone-base derivatives in clinical use, therefore, we aimed to synthesize a new series of pyridazin-3-ones and evaluate their vasorelaxant activity. Methods: A new series of synthesized compounds were carried out first by the synthesis of 6- flouroarylpyridazinones by cyclization of 3-(4-flourobenzoyl) propionic acid with hydrazine hydrate or arylhydrazines to provide the corresponding pyridazinone derivatives 2a-d. Mannich reaction was performed using morpholine or piperidine formaldehyde to obtain compounds 3a,b. On the other hand, reaction of 2a with various chloroacetamide intermediates, in dimethylformamide and potassium carbonate as a catalyst, afforded the target compounds 5a-c. The aromatic acid hydrazide intermediates 6a-g were prepared in 50-90% yield, by reacting to the prepared esters with hydrazine hydrate under reflux in ethanol. The two compounds 8a,b were prepared via condensation of 7a,b with ethyl chloroacetate in dry acetone. Finally, the target 2,4,6-trisubstituted pyridazinones 9a-c derivatives were obtained by the reaction of 7a with the appropriate aromatic aldehyde or substituted acetophenones. The new compounds were then evaluated for their vasorelaxant properties using isolated thoracic rat aortic rings. In addition, a homology model was built and molecular modeling simulation of these compounds into the active sites of the newly created α1a-adrenoceptor model was performed in order to predict and rationalize their affinities toward this receptor. Results: Among these compounds; 5a was the most potent, it exhibited approximately two-times the activity of prazosin (IC50 = 0.250, 0.487 mmol, respectively) also, fourteen compounds were more potent than prazosin.