Current Drug Discovery Technologies - Volume 18, Issue 5, 2021

Background: Hydatidosis is one of the most dangerous zoonosis diseases in the world caused by the larval stage of the broad-worm or Echinococcus granulosus parasite. Today, cysts’ rupture or content leakage during surgery and involvement of organs adjacent to the organ involved, and consequently secondary cysts, are the major concern for hydatid cyst surgeons. Therefore, using scolicidal substances such as hypertonic saline 20%, silver nitrate and formalin has been considered to reduce the risk of protoscoleces spread and recurrence of disease in recent years. The current work was designed to assess the antiparasitic effects of Capparis spinose L. extract against hydatid cyst protoscoleces. Methods: Collected protoscoleces from liver fertile hydatid cysts of infected sheep were exposed to the different concentrations of the essential oil (150, 300, 600 mg/mL) for 5-60 min in vitro and ex vivo. Then by using the eosin exclusion assay, the viability of protoscoleces was studied. The primary phytochemical analysis of the C. spinosa extract was done to assess the presence of tannins, alkaloids, saponins, flavonoids, terpenoids and glycosides. Results: C. spinosa extract exhibited a powerful protoscolicidal activity in vitro so at the dose of 300 and 600 mg/ml, it entirely eliminated the parasite after 10 and 5 minutes; whereas at lower doses, it demonstrated weak protoscolicidal activity. In ex vivo assay, no similar effect to in vitro assay was observed, so more time was required to show a potent protoscolicidal activity. C. spinosa extract, at the concentrations of 300 and 600 mg/mL after an exposure time of 20 and 12 min, killed 100% of protoscoleces within the hydatid cyst, respectively. The findings of primary phytochemical screening of the C. spinosa extract demonstrated the existence of flavonoids, tannins, terpenoids, glycosides and alkaloids in this plant. Conclusion: The obtained results in vitro and ex vivo exhibited potent protoscolicidal effects of C. spinosa extract particularly at the concentrations of 600 and 300 mg/ml, which entirely eliminated the parasite after 5-20 min exposure. However, more supplementary works are required to verify these findings through assessing in animal models and clinical subjects.

Background: Adenosine receptors (AR) have emerged as competent and innovative nondopaminergic targets for the development of potential drug candidates and thus constitute an effective and safer treatment approach for Parkinson’s disease (PD). Xanthine derivatives are considered as potential candidates for the treatment Parkinson’s disease due to their potent A2A AR antagonistic properties. Objective: The objectives of the work are to study the impact of substituting N7-position of 8-m/pchloropropoxyphenylxanthine structure on in vitro binding affinity of compounds with various AR subtypes, in vivo antiparkinsonian activity and binding modes of newly synthesized xanthines with A2A AR in molecular docking studies. Methods: Several new 7-substituted 8-m/p-chloropropoxyphenylxanthine analogues have been prepared. Adenosine receptor binding assays were performed to study the binding interactions with various subtypes and perphenazine induced rat catatonia model was used for antiparkinsonian activity. Molecular docking studies were performed using Schrödinger molecular modeling interface. Results: 8-para-substituted xanthine 9b bearing an N7-propyl substituent displayed the highest affinity towards A2A AR (Ki = 0.75 μM) with moderate selectivity versus other AR subtypes. 7-Propargyl analogue 9d produced significantly long-lasting antiparkinsonian effects and also produced potent and selective binding affinity towards A2A AR. In silico docking studies further highlighted the crucial structural components required to develop xanthine derived potential A2A AR ligands as antiparkinsonian agents. Conclusion: A new series of 7-substituted 8-m/p-chloropropoxyphenylxanthines having good affinity for A2A AR and potent antiparkinsonian activity has been developed.

Introduction: Nowadays, researchers have been attempting to use herbal products as medicines which have proven to cause lesser side effects. The fruit part of Trachyspermum ammi (L.) - Ajwain has been an integral part of the Indian medicine system with much importance in Ayurveda and Unani medicine system and is prescribed by Vaidya gurus and Hakim in raw form or as a major constituent in the powdered formulations. Objective: This research aimed to evaluate acute and sub-acute toxicity of standardized T. ammi fruit and its anti-inflammatory property using experimental models. Methods: The extract of herbs was spectroscopically analyzed for the estimation of the number of bioactive compounds. Then acute and sub-acute toxicity analysis of the herbal extract was performed to ensure the toxic effects, if any. Biochemical parameters like ALT, AST, ALP, etc. and histopathological analysis were determined to study the toxicity of the extract. Then, the anti-inflammatory activity of the T. ammi fruit extract employing Carrageenan and formalin-induced edema model in rats was studied. Results: Ajwain seeds have a pungent smell and a characteristic odor. The powder microscopy clearly showed endosperm, unicellular warty trichomes, striated cuticle in surface view, vittae, endodermis, and vascular strand. Phytochemical tests reported the presence of carbohydrates, alkaloids, tannins, etc. and characteristic peaks in UV, Mass, NMR, FTIR and HPLC were observed for the extract. Acute and sub-acute toxicity studies did not report any toxicity, and significant anti-inflammatory action was recorded. Conclusion: The spectroscopic and pharmacognostic analysis has shown the strong presence of flavonoids, mineral matter, protein, phenols, saponins, carbohydrates, volatile oils, fiber, glycosides and fat. Spectroscopic study interpretations have shown the presence of compounds like thymol, para-cymene, γ-terpinene, α- and β-pinene, carvone, limonene, saponins,, β-phellandrene, βfenchyl alcohol, α-thujene, β-phellendrene, α-thujene, etc. No signs of toxicity were recorded in acute and sub-acute toxicity studies assessing the relative weight and histopathological analysis. Significant anti-inflammatory potential of T. ammi fruit extract was found and LD50 was found to be beyond 3000 mg/kg. The results of this study could be useful; in setting the quality parameters for further identification of the crude herb and preparation of the monograph.

Background: The recent outbreak of Coronavirus SARS-CoV-2 (Covid-19), which has rapidly spread around the world in about three months with tens of thousands of deaths recorded so far is a global concern. An urgent need for potential therapeutic intervention is of necessity. M^pro is an attractive druggable target for the development of anti-COVID-19 drug development. Methods: Compounds previously characterized by Melissa officinalis were queried against the main protease of coronavirus SARS-CoV-2 using a computational approach. Results: Melitric acid A and salvanolic acid A had higher affinity than lopinavir and ivermectin using both AutodockVina and XP docking algorithms. The computational approach was employed in the generation of the QSAR model using automated QSAR, and in the docking of ligands from Melissa officinalis with SARS-CoV-2 Mpro inhibitors. The best model obtained was KPLS_Radial_ 28 (R² = 0.8548 and Q²=0.6474, which was used in predicting the bioactivity of the lead compounds. Molecular mechanics based MM-GBSA confirmed salvanolic acid A as the compound with the highest free energy and predicted bioactivity of 4.777; it interacted with His-41 of the catalytic dyad (Cys145-His41) of SARS-CoV-2 main protease (M^pro), as this may hinder the cutting of inactive viral protein into active ones capable of replication. Conclusion: Salvanolic acid A can be further evaluated as a potential M^pro inhibitor.

Background: Multiple sclerosis is an autoimmune chronic inflammatory disease of the central nervous system that can lead to some serious disabilities. Despite using various immunomodulatory and anti-inflammatory drugs that have therapeutic effects, they cannot reduce its progression completely and have some unwanted side effects too. The immunomodulatory and anti-inflammatory effects of the β-D-Mannuronic acid (M2000) have been proven in several surveys, and the present research was designed to determine its toxicity and therapeutic effects in MS patients. Methods: This study was performed on 15 MS patients who took 25 mg/kg/day the oral form of the β-D-Mannuronic acid for six months, and 15 healthy people as a control group. Serum levels of Urea, Creatinine, GGT, Vitamin D3, Uric acid, and Anti-Phospholipids were compared to evaluate the therapeutic and possible toxic effects of this drug after this period. Results: Non- toxic effects through the study of urea, creatinine, GGT, and non-significant changes in uric acid and anti-Phospholipids levels, besides a significant rise in vitamin, D3 levels in the M2000 treated cases were found. Conclusions: Our results suggested that β-D-Mannuronic acid is a safe drug and has no toxicity when administered orally and also has some therapeutic effects in MS patients.

Background and Objective: Tremendous advances have been made in the development of new pharmacotherapuetic agents and less invasive techniques to help men with lower urinary tract symptoms. The use of 5α-reductase inhibitor (5-ARI) is restricted to the patients with large prostate volumes, whose symptoms are refractory to antiandrogens or α–adrenergic blockers. Out of the various synthesized 5-reductase inhibitors with different substituents on the steroidal nucleus, esters have been found to exhibit high anti-androgenic activity. Methods: In our attempt to find new, safer and potent 5-ARI and our continued interest in azasteorids, esters of 17a-Aza-D-homo-5-androsten-3β-ol with synergistic effect were synthesized and characterized using different analytical techniques. The compounds were evaluated for their 5α-reductase inhibitory activity in-vivo by their effect on serum androgen level by ELISA assay procedure. The interaction with receptors was studied using an advanced docking programme to predict the correlation of the synthesized compounds with actual biological activity. Results: The target compounds (6-12) showed increased anti-androgenic activity as compared to finasteride and control, which imply that the target compounds are effective in inhibiting 5α-reductase. Particularly, compound 6 showed the highest inhibitory activity and greater affinity for the 5- AR receptor with the highest dock score. The results of these studies when compared with Finasteride showed increased solubility and dissolution of target compound 6. Conclusion: Compound 6 showed immense potential with improved efficacy and better bioavailability, thus makes it a suitable candidate for further studies and optimal formulation.

Background: 8-Phenyltheophylline derivatives exhibit prophylactic effects at a specific dose but do not produce the cardiovascular or emetic side effects associated with xanthines, thereby exhibiting unique characteristics of potential therapeutic importance. Methods: Novel series of 8-(proline/pyrazole)-substituted xanthine analogs have been synthesized. The affinity and selectivity of compounds to adenosine receptors have been assessed by radioligand binding studies. The synthesized compounds also showed good bronchospasmolytic properties (increased onset of bronchospasm; decreased duration of jerks) with 100% survival of animals in comparison to the standard drug. Besides, compound 8f & 9f showed good binding affinity in comparison to other synthesized compounds in the micromolar range. Results: The maximum binding affinity of these compounds was observed for A2B receptors, which was ~ 7 or 10 times higher as compared to A1, A2A and A3 receptors. The newly synthesized derivatives 8f, 9a-f, 17g-m, and 18g-m displayed significant protection against histamine aerosol induced bronchospasm in guinea pigs. Conclusion: Newly synthesized proline/pyrazole based xanthines compounds showed a satisfactory binding affinity for adenosine receptor subtypes. Replacement or variation of substituted proline ring with substituted pyrazole scaffold at the 8th-position of xanthine moiety resulted in the reduction of adenosine binding affinity and bronchospasmolytic effects.

Background: Free radicals can lead to liver dysfunction. Quality control of traditional formulations ensures their safe, pure, and pharmaceutical efficacy. “Qurs-e-Vard”, containing petals of Rosa damascena Mill., fruits of Rhus coriaria L. and roots of Glycyrrhiza glabra L. has been suggested as a hepatoprotective preparation in Traditional Persian Medicine (TPM). Objective: This study was directed at the evaluation of the phytochemical characterization, standardization, and in vitro antioxidant activity determination of a solid formulation and its components. Methods: Some qualitative and quantitative controls were performed like ash value, heavy metals investigation, and microbial contamination. The phytochemical assays were used for obtaining total phenolic and flavonoid contents with spectrophotometric methods. 2, 2-Diphenyl-1-c (DPPH) and Nitric Oxide (NO) assays were run for determining Radical scavenging activities of the formulation and its components. Ferric reducing antioxidant power assay (FRAP) was determined as well. Results: Total phenolic contents of hydroalcoholic and aqueous extracts of the polyherbal formulation measured respectively, (376±0.93) and (297.6±0.96) mg of gallic acid/g of dry matter. Total flavonoid contents of the formulation were also measured (36.27±0.98) for hydroalcoholic extract and (17.79±0.86) mg of quercetin/g of dry matter for aqueous extract. The IC50 of hydroalcoholic and aqueous extract was obtained (88.14±1.15) and (140.78±2.98) μg/ml, respectively. NO scavenging percentages (200μg/ml) of hydroalcoholic and aqueous extracts were measured (59.11±2.15) and (65.08±2.35). FRAP values of hydroalcoholic and aqueous extracts were achieved (255.24±3.45) and (134.57±3.45) μg/ml as well. Conclusion: Our findings indicated that this polyherbal formulation and its components have justifiable antioxidant effects.

Background: For decades, Praziquantel has been the undisputed drug of choice for all schistosome infections, but rising concerns due to the unelucidated mechanism of action of the drug and unavoidable reports of emerging drug resistant strains has necessitated the need for alternative treatment drug. Moreover, current apprehension has been reinforced by total dependence on the drug for treatment hence, the search for novel and effective anti-schistosomal drugs. Methods: This study made use of bioinformatic tools to determine the structural binding of the Universal G4LZI3 Stress Protein (USP) in complex with ten polyphenol compounds, thereby highlighting the effectiveness of these recently identified ‘lead’ molecules in the design of novel therapeutics targeted against schistosomiasis. Upregulation of the G4LZI3 USP throughout the schistosome multifaceted developmental cycle sparks interest in its potential role as a druggable target. The integration of in silico tools provides an atomistic perspective into the binding of potential inhibitors to target proteins. This study therefore, implemented the use of Molecular Dynamic (MD) simulations to provide functional and structural insight into key conformational changes upon binding of G4- ZLI3 to these key phenolic compounds. Results: Post-MD analyses revealed unique structural and conformational changes in the G4LZI3 protein in complex with curcumin and catechin respectively. These systems exhibited the highest binding energies, while the major interacting residues conserved in all the complexes provides a route map for structure-based drug design of novel compounds with enhanced inhibitory potency against the G4LZI3 protein. Conclusion: This study suggests an alternative approach for the development of anti-schistosomal drugs using natural compounds.

Background: Shrimp waste, as an important source of natural carotenoids, is produced in large quantities in the seafood processing industry. One of the important characteristics of carotenoids is their ability to act as antioxidants, thus protecting cells and tissues from the damaging effects of free radicals and singlet oxygen. Aims: The aim of this study was to find an effective method for carotenoid extraction (Enzymatic and alkaline treatment) from shrimp waste and compare their antioxidant potential with synthetic antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) using sunflower oil. Methods: The sunflower oil was exposed to three concentrations of extracted carotenoid (470, 235, and 118 mg/kg) and synthetic antioxidants. The inhibition of lipid peroxidation was evaluated for Malondialdehyde and peroxide value. Results and Discussion: The mean values of carotenoid extract were 243 and 170 mg/kg for enzymatic and alkaline treatment, respectively. Therefore, the highest efficacy of carotenoid extraction was obtained from enzymatic extraction. The oil samples containing 470 ppm carotenoid, which were extracted by alcalase as the default treatment, exhibited a less peroxide value and higher antioxidant potential than the oil samples containing synthetic antioxidants. Conclusion: According to the results, the synthetic antioxidants can be replaced by extracted carotenoids from shrimp waste as a natural antioxidant to inhibit oxidation.