Current Drug Discovery Technologies - Volume 21, Issue 3, 2024

Background: Developing more potent antibacterial agents is one of the most important tasks of scientists in the health field due to the problem of antibiotic resistance. Among the antibiotic targets, we mention MurA (UDP-N-Acetylglucosamine Enolpyruvyl Transferase), which is a key enzyme of peptidoglycan biosynthesis of the bacterial cell wall. Objective: Our objective was to search for new inhibitors of the bacterial enzyme MurA by docking the analogues of its inhibitor T6361, a derivative of 5-sulfonoxy-anthranilic acid. Methods: 990 analogues of T6361 were docked in the first binding site of E.coli MurA (open form) using the FlexX program, and the ADME-Toxicity profile of the best ones was evaluated by SwissADME and PreADMET web servers. Results: Docking results revealed two T6361 analogues to provide better energy scores than T6361, and have similar interactions with the binding site of E.coli MurA namely,3-{[2-(piperidine-1-carbonyl) phenyl]sulfamoyl}benzoic acid and 3-{[2-(pyrrolidine-1 carbonyl)phenyl]sulfamoyl}benzoic acid. Moreover, the two molecules were found to possess good pharmacokinetics and low toxicity. Conclusion: We propose two analogues of T6361 as new potential inhibitors of MurA enzyme. Their good ADME-Toxicity profile qualifies them to reach in vitro and in vivo assays as future lead molecules.

Background: Cancer is a devastating disease. Many studies have shown that the primary causes of the aggressive and resistant types of cancer are the overexpression of receptors and growth factors, activation of oncogenes, and the inactivation of tumour suppressor genes. One such receptor is the epidermal growth factor receptor (EGFR), which is used as a drug target for the treatment of cancer. Objective:This study aimed to develop the new chemical entities of amide derivatives of chalcone as EGFR inhibitors using structure-activity relationship (SAR) studies, molecular docking, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) studies. Method: New chemical entities (NCE) were designed based on literature findings. The Schrodinger 13.4 software was used for the molecular docking study. While Quickprop and Pro Tox-II online tools were used for ADME and toxicity prediction, respectively. Result: In this work, all compounds were subjected to an in-silico ADMET analysis. After pharmacokinetic and toxicity profile predictions, the molecules were further analysed by molecular docking. As a result of molecular docking, molecules AC9 and AC19 showed comparable docking scores compared to standard Afatinib. Conclusion: Molecules AC9 and AC19 showed good docking scores and a promising ADMET profile. In the future, these derivatives can be further evaluated for wet lab studies and determination of their biological activity.

Background: Type 2 diabetes mellitus constitutes approximately 90% of all reported forms of diabetes mellitus. Insulin resistance characterizes this manifestation of diabetes. The prevalence of this condition is commonly observed in patients aged 45 and above; however, there is an emerging pattern of younger cohorts receiving diagnoses primarily attributed to lifestyle-related variables, including obesity, sedentary behavior, and poor dietary choices. The enzyme SGLT2 exerts a negative regulatory effect on insulin signaling pathways, resulting in the development of insulin resistance and subsequent elevation of blood glucose levels. The maintenance of glucose homeostasis relies on the proper functioning of insulin signaling pathways, while disruptions in insulin signaling can contribute to the development of type 2 diabetes. Objective: Our study aimed to identify novel SGLT2 inhibitors by high-throughput virtual Screening. Methods: We screened the May bridge Hit Discover database to identify potent hits followed by druglikeness, synthetic accessibility, PAINS alert, toxicity estimation, ADME assessment, and consensus molecular docking. Results: The screening process led to the identification of three molecules that demonstrated significant binding affinity, favorable drug-like properties, effective ADME, and minimal toxicity. Conclusion: The identified molecules could manage T2DM effectively by inhibiting SGLT2, providing a promising avenue for future therapeutic strategies.

Background: Diabetes mellitus (DM) is a metabolic disorder known to impair many physiological functions via reactive oxygen species (ROS). Aldose reductase, sorbitol dehydrogenase, dipeptidyl peptidase IV, α-amylase and α-glucosidase are pharmacotherapeutic protein targets in type-2 diabetes mellitus (T2DM). Inhibitors of these enzymes constitute a new class of drugs used in the management and treatment of T2DM. Some reports have claimed that medicinal plant extracts that serves as food (and as an antioxidant source) can reduce these alterations by eliminating ROS caused by DM. Ethnobotanical survey claims Jatropha gossypifolia commonly called “fignut” and “Lapa-lapa” in the Yoruba land of South-western Nigeria, to be used for the treatment and management of diabetes, in addition to its nutritive value. Objective: The nutritional composition and in-silico antidiabetic potential of the bioactive constituents of J. gossypifolia leaf extracts were investigated. Methods: Proximate, minerals and gas chromatography–mass spectroscopy (GC-MS) analysis were carried out using standard procedures. Phytocompounds present in J. gossypifolia methanol (JGM) and ethyl acetate (JGE) leaf extracts were tested as potential antagonists of selected protein targets via in-silico techniques. Drug-likeness, pharmacokinetic properties and toxicity of the promising docked ligands were also predicted. Results: The proximate and mineral analysis revealed good nutritional composition and mineral content. Additionally, cyclo-pentadecane and dibutyl phthalate from methanol extract, and benzene- 1,2,4,5-tetramethyl, benzene-1,2,3,5-tetramethyl, and benzene-1,3-dimethyl-5-(1-methylethyl) from ethyl acetate extract were present in J. gossypifolia leaf which exhibited a better binding affinity than the clinically prescribed standard, metformin. Conclusion: Benzene-1,2,4,5-tetramethyl from JGE extracts exhibited the most promising antidiabetic potential in-silico, suggesting its candidature as diabetes-target-protein inhibitor which may be developed for the treatment of type-2 diabetes mellitus.

Aim: This study aimed to formulate and characterize aceclofenac buccal film formulations made of different polymers and evaluate the effects of polymer type on buccal film properties. Materials and Methods: Five polymer types, namely hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (SCMC), polyvinyl alcohol (PVA), Eudragit S100, and Eudragit SR100, were used to prepare aceclofenac buccal film formulation either separately or combined by solvent-casting method. These formulations were evaluated in terms of physical appearance, folding test, film weight and thickness, drug content, percentage of elongation, moisture uptake, water vapor permeability, and in vitro drug release. Results: The addition of Eudragit polymer in most of the produced buccal films was unacceptable with low folding endurance. However, the dissolution profile of buccal films made from PVA and Eudragit SR100 provided a controlled drug release profile. Conclusion: Buccal films can be formulated using different polymers either individually or in combination to obtain the drug release profile required to achieve a desired treatment goal. Furthermore, the property of the buccal films depends on the type and concentration of the polymer used.

Background: Diabetic foot ulcer (DFU) is a prevalent complication of diabetes that can result in severe consequences. The cost of treating DFUs is high, and there is a lack of new therapies available in developing countries. This has created a demand for complementary and alternative treatments. The objective of this study was to assess the impact of aloe vera gel on the healing process of diabetic foot ulcers. Materials and Methods: The study was a double-blind, randomized, controlled clinical trial. The study samples were 66 patients with diabetic foot ulcers who were randomly assigned to two groups (intervention and control). All ulcers in both groups were washed with normal saline and dressed in sterile gauze. The ulcers in the intervention group were covered with a thin layer of Aloe Vera gel before the dressing. The Bates-Jensen Wound Assessment Tool (BWAT) was used on three occasions, including before the intervention period and at the end of each week. Data were analyzed using SPSS 16. Results: After three weeks, there was a notable contrast in the recovery pattern of the two groups. The patients who had aloe vera gel added to their dressing showed a more substantial decrease in the mean scores of their BWAT. Conclusion: These findings are promising and suggest that Aloe vera may be a safe and effective adjunctive treatment for diabetic foot ulcers. However, further research is needed to confirm these results and to investigate the underlying mechanisms of aloe vera's therapeutic effect on diabetic foot ulcers.

Background: According to the report, in 2022, the prevalence rate of depression in India was 4.50%, and the cases stood at 56,675,969. The development of antidepressant agents has reduced the number of depressant and suicidal cases. Many researchers have found that pyrimidine possesses antidepressant activity. With this background, we thought of synthesizing pyrimidine derivatives. Objective: The objective of this study is to carry out molecular docking, synthesis, characterization, and evaluation of 2-((4,6-diphenylpyrimidin-2-yl)oxy)-N-phenylacetamide derivatives (17-26) as in vivo antidepressant agent. Method: The designed compounds were checked for their activity using Molegro virtual docker (MVD) and were further synthesized. Benzaldehyde reacted with acetophenone to give compound (3), which gave compound (4) upon reaction with urea. In another reaction, substituted anilines (5) were reacted with chloroacetyl chloride (6) to yield compounds (7-16), which upon further reaction with compound (4) yielded the final derivatives (17-26). The synthesized compounds were characterized by spectral analysis and checked for their antidepressant activity. Result: The MolDock scores of the derivatives ranged from -147.097 to −182.095, whereas of active ligand IXX_801 was −115.566. All the synthesized pyrimidine derivatives showed better affinity towards the Cryo-EM structure of the wild-type human serotonin transporter complexed with vilazodone, imipramine, and 15B8 Fab protein (PDB ID: 7LWD) as compared to standard drug clomipramine (−101.064). All the synthesized derivatives were screened for antidepressant activity at a 100mg/kg dose level compared to the standard clomipramine HCl at a dose level of 20mg/kg. Among all the synthesized derivatives, compound 24 showed the most potent antidepressant activity, and Compound 20 showed moderate antidepressant activity, which reduced the duration of immobility times to 35.42% and 31.97% at 100mg/kg dose level when compared to the control, respectively. Conclusion: Compound 24 showed the highest MolDock score as well as found to be the most potent antidepressant agent.

Background: There are very few small-molecule drug candidates developed against SARS-CoV-2 that have been revealed since the epidemic began in November 2019. The typical medicinal chemistry discovery approach requires more than a decade of the year of painstaking research and development and a significant financial guarantee, which is not feasible in the challenge of the current epidemic. Objective: This current study proposes to find and identify the most effective and promising phytomolecules against SARS-CoV-2 in six essential proteins (3CL protease, Main protease, Papain- Like protease, N-protein RNA binding domain, RNA-dependent RNA polymerase, and Spike receptor binding domain target through in silico screening of 63 phytomolecules from six different Ayurveda medicinal plants. Methods: The phytomolecules and SARS-CoV-2 proteins were taken from public domain databases such as PubChem and RCSB Protein Data Bank. For in silico screening, the molecular interactions, binding energy, and ADMET properties were investigated. Results: The structure-based molecular docking reveals some molecules' greater affinity towards the target than the co-crystal ligand. Our results show that tannic acid, cyanidin-3-rutinoside, zeaxanthin, and carbolactone are phytomolecules capable of inhibiting SARS-CoV-2 target proteins in the least energy conformations. Tannic acid had the least binding energy of -8.8 kcal/mol, which is better than the binding energy of its corresponding co-crystal ligand (-7.5 kcal/mol) against 3 CL protease. Also, it has shown the least binding energy of -9.9 kcal/mol with a more significant number of conventional hydrogen bond interactions against the RdRp target. Cyanidin-3-rutinoside showed binding energy values of -8.8 and -7.6 kcal/mol against Main protease and Papain-like protease, respectively. Zeaxanthin was the top candidate in the N protein RBD with a binding score of - 8.4 kcal/mol, which is slightly better when compared to a co-crystal ligand (-8.2 kcal/mol). In the spike, carbolactone was the suitable candidate with the binding energy of -7.2 kcal/mol and formed a conventional hydrogen bond and two hydrophobic interactions. The best binding affinity-scored phytomolecules were selected for the MD simulations studies. Conclusion: The present in silico screening study suggested that active phytomolecules from medicinal plants could inhibit SARS-CoV-2 targets. The elite docked compounds with drug-like properties have a harmless ADMET profile, which may help to develop promising COVID-19 inhibitors.

Aim: This research work aimed to design and synthesize some new molecules of phenothiazine. The work’s emphasis was on forming new phenothiazines in two series, 1-(10H-phenothiazin- 10-yl)-2-((4-(1-(phenylimino)ethyl)phenyl)amino)ethan-1-one derivatives (4a-4j) and 1-(4-((2-oxo-2- (10H-phenothiazin-10-yl)ethyl)amino)phenyl)-3-phenylprop-2-en-1-one derivatives (P1-P5). Methods: Chloroacetylation of phenothiazine was done to afford 2-chloro-1-(10H-phenothiazin-10- yl)ethan-1-one, which was further reacted with 4-amino acetophenone to produce 2-((4- acetylphenyl)amino)-1-(10H-phenothiazin-10-yl)ethan-1-one. Then, it was treated with substituted anilines and substituted benzaldehydes to produce the final derivatives 4a-4j and P1-P5, respectively. Results: All 15 derivatives (4a-4j and P1-P5) were characterized by evaluating their Rf value, melting point, solubility, IR spectroscopy, and ¹HNMR spectroscopy. Molecular docking was performed by using AutoDock Vina v.1.2.0 (The Scripps Research Institute, La Jolla, CA, USA) docking software, and the anxiolytic activity of the derivatives was assessed by using the elevated plus maze model. Conclusion: The designed scheme was executed in the departmental laboratory. The chemical structure of the compounds was confirmed on the basis of TLC, IR, and ¹HNMR analyses. The docking study revealed a good docking score of the compounds. The Log P value of the compounds indicated their good penetration into CNS. The compounds were also screened for anxiolytic activity. Among them, compounds 4f, 4h, and P3 showed maximum activity as anti-anxiolytic agents.