Letters in Drug Design & Discovery - Volume 19, Issue 9, 2022

Background: Narcolepsy, also known as Gélineau syndrome, is a chronic and neurological disease that affects 0.05% of the European population, though that percentage could be higher due to the diagnostic difficulties. The main symptom is excessive daytime sleepiness, although it may be accompanied by cataplexy, sleep paralysis and hypnagogic hallucinations. Objective: Nowadays, there is no cure for narcolepsy, and the treatment is symptomatic; psychostimulants for sleepiness by means of amphetamines, methylphenidate, or modafinil, and antidepressants and sodium oxybate for treating cataplexy. Methods: This is a short review regarding pharmacotherapy for narcolepsy. Results: Hypocretins were discovered in 1998. They are neuropeptides whose deficiency is responsible for this symptomatology, which has opened up a new field of investigation. Conclusion: Agonists of hypocretins could be a promising therapy against this disease.

Background: Tyrosinase is the enzyme responsible for the conversion of tyrosine to dopaquinone, which is related to melanoma, neurodegenerative disorders, freckles, pigmented acne and age spots. Controlling the tyrosinase activity could be an important way for treating overproduction of melanin. Objective: The development of safe and specific tyrosinase inhibitors could be used to treat hypermelanosis. Methods: 5-nitro-1H-benzo[d]imidazole-2(3H)-thione was synthesized from 4-nitro-o-phenylenediamine and carbon disulfide. The nitro group of 5-nitro-1H- S-1 ESI-HRMS benzo[d]imidazole-2(3H)-thione was reduced with iron powder. The 5-amino-1H-benzo[d]imidazole- 2(3H)-thione Schiff base derivatives were obtained by the reaction of 5-amino-1H-benzo[d]imidazole-2(3H)-thione with substituted benzaldehyde. The tyrosinase inhibitory activities were investigated. The studies of kinetic analysis, metalchelating properties, docking and cytotoxicity were also performed. Results: All of the compounds showed strong tyrosinase inhibitory activities with 5-((4-nitrobenzylidene) amino)-1H-benzo [d]imidazole-2(3H)-thione (S-4) as the best tyrosinase inhibitor with an IC50 value of 4.8 ± 1.4 nM. Compound S-4 exhibited mixed type inhibition of mushroom tyrosinase, with Ki 15 nM and Kis 42 nM. Copper binding to S-4 was detected spectrophotometrically and 1-100 μ S-4 displayed negligible cytotoxicity to murine B16 melanoma cells. Conclusion: Our results demonstrated that these benzimidazolethione Schiff base derivatives might be promising candidates as tyrosinase inhibitors.

Background: Condensed triazoles are a well-known class of heterocyclic compounds due to a wide range of biological activities. The study is dedicated to the evaluation of the antimicrobial potential of new functional derivatives of thiazolo[2,3-c][1,2,4]triazoles. Methods: Effective, easy-to-implement and low-cost routes for production of title compounds via electrophilic intramolecular heterocyclization are reported. Bactericidal and fungicidal activities against Gram-positive and Gram-negative bacteria and fungus were studied. The influence of functional groups on the biological activity of tested thiazolo[2,3-c][1,2,4]triazoles is discussed. Results: Microbiological evaluation shows that 6-[(trichlorotellanyl)methyl]-[1,3]thiazolo[2,3- c][1,2,4]triazol-3-amine hydrogen chloride 2a and 3-(2-hydroxyphenyl)-6-[(trichloro-λ⁴-tellanyl)methyl]- 5,6-dihydro-[1,3]thiazolo[2,3-c][1,2,4]triazole 2g have a high bactericidal activity and Cu (I) salts of 3-(2- hydroxyphenyl)-6-iodomethyl/6-methylidene-5,6-dihydro-[1,3]thiazolo-[2,3-c][1,2,4]triazoles 5a,c have a high fungicidal activity. Conclusion: It is concluded that these products or their derivatives may be of practical benefit as bactericidal and fungicidal agents.

Background: Drug repositioning is an important subject in drug-disease research. In the past, most studies simply used drug descriptors as the feature vector to classify drugs or targets or used qualitative data about drug-target or drug-disease to predict drug-target interactions. These data provide limited information for drug repositioning. Objective: Considering both drugs and targets and constructing quantitative drug-target interaction descriptors as a method of drug characteristics are of great significance to the study of drug repositioning. Methods: Taking anticancer and anti-inflammatory drugs as research objects, the interaction sites between drugs and targets were determined by molecular docking. Sixty-seven drug-target interaction descriptors were calculated to describe the drug-target interactions, and 22 important descriptors were screened for drug classification by SVM, LightGBM, and MLP. Results: The accuracy of SVM, LightGBM, and MLP reached 93.29%, 92.68%, and 94.51%, their Matthews correlation coefficients reached 0.852, 0.840, and 0.882, and their areas under the ROC curve reached 0.977, 0.969, and 0.968, respectively. Conclusion: Using drug-target interaction descriptors to build machine learning models can obtain better results for drug classification. Number of atom pairs, force field, hydrophobic interactions, and bSASA are the key features for classifying anticancer and anti-inflammatory drugs.

Background: Aminopeptidase N (APN) is a type II transmembrane zinc ion-dependent metalloprotease. It is closely related to many processes of tumor occurrence and development, such as the formation of new blood vessels and tumor metastasis. Recent studies have shown that APN is a member of the family of surface markers of liver cancer stem cells. Therefore, APN small molecule inhibitors may have multiple compound functions, exerting multiple anti-tumor effects at multiple stages of cancer occurrence and development. Methods: Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) approaches were employed in the study. Results: Both internal and external cross-validations were conducted to obtain high predictive and satisfactory CoMFA model (q² = 0.627, r² = 0.995, SEE = 0.043) and CoMSIA model (q² = 0.575, r² = 0.998, SEE = 0.031) values. The statistical results obtained from CoMFA and CoMSIA models were found to be credible and having remarkable predictive power. Conclusion: The results of 3D-QSAR are reliable and significant with high predictive (q²) ability, and a lower value of the standard error of estimation indicates a good correlation between predicted and observed activity. All these results have revealed many useful structural insights to improve the activity of the newly designed APN small molecule inhibitors.

Background: Malaria was one of the deadliest infectious diseases in 2021. Indeed, this infection, mostly caused by a protozoan called Plasmodium falciparum, is responsible for more than 200 million cases and around 400 000 related deaths annually, mainly in Africa. Despite the availability of effective drugs, the number of patients has increased since 2015, which could be due to parasite resistance as well as resistance in the pathogen's vectors, Anopheles mosquitoes. Consequently, it is necessary to search for new alternative treatments. Methods: Polyphenols, more precisely small phenolic acids, could represent a good starting point for new antimalarials. Indeed, these molecules, including caffeic acid (1), possess several pharmacological activities and an interesting pharmacokinetic profile. Therefore, we have developed several small derivatives of this scaffold to define the potential pharmacophore responsible for the antiplasmodial properties. Results: A good to low activity on Plasmodium falciparum (IC50 = 16-241 μM) was observed, especially for the small ester derivatives (2-6). These molecules were good antiplasmodials compared to their mother compound (IC50 = 80 μM) and showed selectivity against human cells. These structures have also highlighted the need for catechol and carboxyl moieties in the anti-Plasmodium effect. Conclusion: None of the synthetic caffeate derivatives reported here seemed sufficiently effective to become a potential antimalarial (IC50 < 1 μM). However, the significant increase of their efficacy on the malarial agent and the selectivity to human cells highlighted their potential as new leads for future developments.

Background: The polyol pathway, an alternative way of carbohydrate metabolism, is activated by hyperglycemia. Aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, is responsible for the reduction of glucose to sorbitol. Inhibiting the aldose reductase enzyme and reducing the polyol pathway is considered an effective method to prevent and postpone the onset of diabetic complications. Objective: Therefore, in this work, we investigate the inhibition effects of certain resorcinol derivatives and the positive control compound quercetin on the AR enzyme in vitro and in silico. These phenolic compounds, whose inhibitory effects on the AR enzyme were investigated, were also compared with known drugs in terms of their drug-like characteristics. Methods: Three methods were used to determine the inhibitory effects of resorcinol derivatives on recombinant human AR enzyme. After the in vitro inhibition effects were determined spectrophotometrically, the binding energy and binding modes were determined by molecular docking method. Finally, the MM-GBSA method was used to determine the free binding energies of the inhibitors for the AR enzyme. Results: 5-pentylresorcinol compound showed the strongest inhibition effect on recombinant human AR enzyme with an IC50 value of 9.90 μM. The IC50 values of resorcinol, 5-methylresorcinol, 4- ethylresorcinol, 4-hexylresorcinol, 2-methylresorcinol, and 2,5-dimethylresorcinol compounds were determined as 49.50 μM, 43.31 μM, 19.25 μM, 17.32 μM, 28.87 μM, 57.75 μM, respectively. Conclusion: The results of this research showed that resorcinol compounds are effective AR inhibitors. These findings are supported by molecular docking, molecular mechanics, and ADME investigations undertaken to corroborate the experimental in vitro results.

Background: Among the many types of chemical scaffolds, isatin derivatives, including their Schiff bases, have been extensively studied to find novel therapeutic agents against cancer. Amide or urea groups containing derivatives were also discovered to be tyrosine kinase inhibitors. Objective: This study aims to find potent compounds by designing 16 novel urea and sulfonamide derivatives of isatin Schiff bases. Methods: Compounds were tested against PC-3, HepG2, SH-SY5Y, A549 cancerous, and NIH/3T3 noncancerous cell lines using cell culture assay. Results: Among the tested compounds 7a, 7b, 7c, 7d, 7h, 8a, and 8f presented potential inhibitions against cellular proliferation activities of HepG2 cells with average IC50 values of 31.97, 42.13, 31.50, 47.98, 32.59, 43.44, and 37.81 μM, respectively. They showed better inhibition potencies than the reference compound doxorubicin, and its value was measured as 51.15 μM in the same culture assay. The cytotoxic activities of the compounds in other cell lines were found to be less potent compared to doxorubicin. Conclusion: In vitro experiments demonstrated that designed compounds have the first evidence that they might be active against hepatocellular carcinoma. According to ADME prediction results, all compounds presented drug-like and good metabolic properties.

Background: Galactofuranoyltransferase-2 (GlfT2) enzyme involved in the galactan polymerization of the arabinogalactan (AG) region of the mycolylarabinogalactan-peptidoglycan (mAGP) complex, an important component of the mycobacterial cell wall. Objective: With the existing challenge, the study focused on identifying certain commercially available flavonoids through molecular docking studies against the Galactofuranoyltransferase-2 enzyme. Methods: The initial pharmacokinetic screening was carried out using Lipinski’s rule of 5 with the help of Molinspiration software. In this perspective, Apigenin, Kaempferol, Rutin, Silibinin and Vitexicarpin were selected for the current study. Except for rutin all other selected flavonoids did not show any violations and were thereby selected for the docking studies using AutoDock 4.2. Results: The docking results showed that the selected flavonoids have excellent binding energy values between −8.98 to −6.58 kcal/mol against the GlfT2 enzyme. The theoretical inhibition constant was found to be in the range of 260.90 nM to 15.13 μM which coincides with the binding energies of the selected compounds. Conclusion: From the selected flavonoids, Silibinin showed excellent binding scores and has the potential to inhibit the GlfT2 enzyme. Silibinin could act as a novel GlfT2 inhibitor with promising therapeutic activity with low toxicity profile against tuberculosis.