Letters in Drug Design & Discovery - Volume 17, Issue 1, 2020

Background: Cinnamic acid is a key intermediate in shikimate and phenylpropanoid pathways. It is found both in free form, and especially in the form of esters in various essential oils, resins and balsams which are very important intermediates in the biosynthetic pathway of several natural products. The cinnamic derivatives play a vital role in the formation of commercially important intermediate molecules which are necessary for the production of different bioactive compounds and drugs. Different substitutions on basic moiety lead to various biological activities. Furthermore, combination of appropriate pharmacophore groups with cinnamic acid derivatives were developed to give hybrids in order to find out promising drug candidates as inhibitors of multiple biological targets associated with inflammation. We found interesting to continue our efforts to design and synthesise three series of novel cinnamic acid-based hybrids: a) nitrooxy esters of cinnamic acid, b) ethers and c) amides of cinnamic acids with arginine, as pleiotropic candidates against multiple targets of inflammation. Methods: The synthesis of cinnamic was established by a Knoevenagel-Doebner condensation of the suitable aldehyde either with malonic acid in the presence of pyridine and piperidine, or with phenylacetic acid in the precence of triethylamine in acetic anhydride. The synthesis of the corresponding esters was conducted in two steps. The ethers were synthesized in low yields, with 1,2 – dibromoethane in dry acetone, in the presence of K2CO3, to give oily products. The corresponding cinnamic amides were synthesised in a single step. The synthesised hybrids were tested as lipoxygenase (LOX) and cyclooxygenase (COX) inhibitors in vitro. In silico docking was applied to all the novel derivatives. Several molecular properties of the hybrids were calculated in order to evaluate their drug likeness. Results: A number of esters, ethers and amides of selected cinnamic acids, either phenyl substituted or not, has been synthesised and subjected to modelling studies. The compounds were studied in vitro/in vivo for their inhibitory activities on cox and lox, and as antioxidants. Log P values of all the title compounds except of 3a (5.38) were found to be less than 5 and are in agreement to Lipinski’s rule of five, suggesting satisfactory permeability across cell membrane. The molecular modelling study seems to be in accordance with the experimental results for LOX and COX-2. The result of antioxidant activity for amide 3b supports the anti-lox activity. Compound 5d presents the higher in vivo anti-inflammatory. Conclusion: According to the experimental findings compounds 3b and 5d can be used as lead compounds for the design of new molecules to target inflammation.

Background: Oximes and nitrofuranyl derivatives are particularly important compounds in medicinal chemistry. Thus, many researchers have been reported to possess antibacterial, antiparasitic, insecticidal and fungicidal activities. Methods: In this work, we report the synthesis and the biological activity against Mycobacterium tuberculosis H37RV of a series of fifty aryl oximes, ArCH=N-OH, I, and eight nitrofuranyl compounds, 2-nitrofuranyl-X, II. Results: Among the oximes, I: Ar = 2-OH-4-OH, 42, and I: Ar = 5-nitrofuranyl, 46, possessed the best activity at 3.74 and 32.0 μM, respectively. Also, 46, the nitrofuran compounds, II; X = MeO, 55, and II: X = NHCH2Ph, 58, (14.6 and 12.6 μM, respectively), exhibited excellent biological activities and were non-cytotoxic. Conclusion: The compound 55 showed a selectivity index of 9.85. Further antibacterial tests were performed with compound 55 which was inactive against Enterococcus faecalis, Klebisiella pneumonae, Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella typhymurium and Shigella flexneri. This study adds important information to the rational design of new lead anti-TB drugs. Structure-activity Relationship (SAR) is reported.

Background: Radiotherapy is a treatment method for cancer mostly utilized for about 60% of cancer patients. Peripheral neuropathy is one of the severe complications of radiotherapy. Two stages of neuropathy will occur following irradiation; electrophysiological and biochemical variations as the first stage, while the second stage involves fibrosis of soft tissues surrounding the exposed nerve. This novel study aimed to investigate the radioprotective effects of melatonin against ionizing radiation-induced sciatic nerve damage. Methods: 60 rats were randomly assigned to four groups; C (Control), M (Melatonin), R (Radiation), MR (Radiation + Melatonin). Their right legs were exposed to 30 Gy single dose gamma rays. Melatonin (100 mg/kg) was administered 30 min before irradiation and once daily (5 mg/kg) till the day of rats’ sacrifice. Their exposed nerve tissues were evaluated for biochemical changes in addition to Electromyography (EMG) and Nerve Conduction Study (NCS). Results: 4, 12 and 20 weeks post-irradiation, EMG and NCS examinations in R group showed reduced Compound Muscle Action Potential (CMAP) representing axonal degeneration when compared with C and M groups. Prolonged latency and a decrease in Conduction Velocity (CV) gave an indication of demyelinating neuropathy at 12 and 20 weeks. EMG and NCS results of R group showed partial nerve lesion. Biochemical assessments showed that irradiation of sciatic nerve led to increased MDA level, as well as decreased CAT and SOD activities. However, in all cases, treatment with melatonin can reverse these effects. Conclusion: We conclude that melatonin can improve electrophysiological, oxidative stress and antioxidant defense features of irradiated rats’ sciatic nerves. We would also recommend the use of melatonin in an optimal and safe dose. It should be administered over a long period of time for effective protection of the peripheral nerve tissues, as well as improving the therapeutic ratio of radiotherapy.

Background: Enoyl acyl carrier protein reductase (InhA) is a validated target for Mycobacterium. It is an enzyme which is associated with the biosynthesis of mycolic acids in type II fatty acid synthase system. Mycobacterial cell wall majorly comprises mycolic acids, which are responsible for virulence of the microorganism. Several diphenyl ether derivatives have been known to be direct inhibitors of InhA. Objective: In the present work, a Quantitative Structure Activity Relationship (QSAR) study was performed to identify the structural features of diphenyl ether analogues which contribute to InhA inhibitory activity in a favourable way. Methods: Both 2D and 3D QSAR models were built and compared. Several fingerprint based 2D QSAR models were generated and their relationship with the structural features was studied. Models which corroborated the inhibitory activity of the molecules with their structural features were selected and studied in detail. Results: A 2D-QSAR model, with dendritic fingerprints having regression coefficient, for test set molecules Q2 =0.8132 and for the training set molecules, R2 =0.9607 was obtained. Additionally, an atom-based 3D-QSAR model with Q2 =0.7697 and R2 =0.9159 was also constructed. Conclusion: The data reported by various models provides guidance for the designing of structurally new diphenyl ether inhibitors with potential activity against InhA of M. tuberculosis.

Background: The advantageous health effects of extracts from different types of plants have been known for centuries and the search for new natural extracts is very important at present. Methods: In this study, the antioxidant and the antimicrobial activities of Aesculus hippocastanum mother tincture (TM) against a range of foodborne bacteria were investigated to determine the major components and the action spectrum and the antimicrobial efficacy of the extract. Results: Results demonstrated a high antioxidant ability; total polyphenolic content was 506.8 ± 15.2mg GAE/100ml and the highest content was found for flavonoids. Moreover, TM demonstrated the antimicrobial activity against all tested bacteria and all Gram-negative bacteria were sensitive with an high antimicrobial activity. The inhibitory activity showed a moderate effect on the growth of 72.7% of strains in presence of different extract MIC. Conclusion: The synergistic actions of bioactive compounds detected in the TM might be on the basis of the antioxidant and biological activities observed. These results can be applied in the pharmaceutical field and also in food preservation, alternative medicine and natural therapies.

Background: Cancer incidence and mortality have been increasing and cancer is still the leading cause of death all over the world. Despite the enormous progress in cancer treatment, many patients died of ineffective chemotherapy and drug resistance. Therefore, the design and development of anti-cancer drugs with high efficiency and low toxicity is still one of the most challenging tasks. Tricyclic heterocycles, such as phenothiazine, are always important sources of scaffolds for anti-cancer drug discovery. Methods: In this work, ten new urea-containing derivatives of phenothiazine coupled with different kinds of amine motifs at the endpoint through a three carbon long spacer were designed and synthesized. The structures of the synthesized compounds were elucidated and confirmed by 1H NMR and HRMS. All the synthesized compounds were tested for their antitumor activity in vitro against the proliferation of PC-3 cells, and the compounds with best potency entered further cytotoxicity evaluations against other 22 human tumor cell lines. Mechanism was also studied. Results: From all data, it showed that among all 10 target compounds, TTi-2 showed the best effect in inhibiting the proliferation of 23 human cancer cell lines while TTi-2 without obvious inhibitory effect on normal cell. Furthermore, our results also showed that TTi-2 could inhibit migration, invasion and colony formation of MDA-MB-231 cells. Finally, TTi-2 can induce arrest of cell cycle at G0/G1 phase and cell apoptosis by activating the caspase 3 activity. Conclusion: All these results suggested that TTi-2 might be used as a promising lead compound for anticancer drug development.

Background: Despite a variety of drugs used to stop acute pain, problems related to their insufficient efficacy and undesirable side effects have remained unresolved. Therefore, the search for analgesics of new structural types, which combine high activity with low toxicity, is a topical issue. It is known that a number of compounds with a hydrogenated 2H-chromene skeleton exhibit significant analgesic activity in in vivo tests. Methods: New hydro-2H-chromenols containing monoterpenoid moieties were obtained via one-pot synthesis by the interaction between para-menthane alcohols and commercially available monoterpene aldehydes: Citral, hydroxycitronellal, myrtenal, and perillaldehyde. The analgesic activity of these compounds wаs studied in the acetic acid-induced writhing test and hot plate test. Results: The target compounds were characterized using NMR and HR-MS. Most of them exhibited pronounced analgesic activity. Conclusion: Due to high analgesic activity, (2S,4aR,8R,8aR)-2-((E)-2,6-dimethylhepta-1,5-dien-1- yl)-4,7-dimethyl-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diol is considered as candidate compound to participate in further research.

Background: A wide range of biological activity, relatively low toxicity and multiple pharmacological effects of triterpenoids are major advantages of these compounds in the prevention and treatment of various diseases. They include the lupane- type triterpenoids that proved to be a promising platform for the synthesis of analogs with a wide range of biological activities, including anti-inflammatory, antitumor, antiparasitic and antiviral properties. The main disadvantage complicating the use of all known derivatives of lupane acids in medical practice is low bioavailability associated with poor solubility in biologic fluids, limiting their effective interaction with the biological targets. Objective: The objective of this study is the synthesis of new amphiphilic betulin derivatives on the base of pyridinium salts with antifungal and antibacterial activity. Methods: In this study we have developed an effective one-pot method for the preparation of new quaternized pyridine derivatives 4-6 of the betulinic series based on the reaction of the initial triterpenes 1-3 with the Tempo+Br3 - reagent in the pyridine. The synthesized and initial compounds were tested for their antimicrobial and antifungal activity. Results: The data presented in this document indicate that all synthesized compounds 4-6 exhibited high activity against both gram-positive Staphylococcus aureus bacteria and gram-negative Pseudomonas aeruginosa strains, as well as Candida albicans and Cryptococcus neoformans fungi with the >90% coverage of the inhibition zone. The best result in a series of compounds 4-6 was found for the derivative 6 at the minimum inhibitory concentration of 1 μg/ml against S. aureus bacteria, C. albicans and C. neoformans fungi at the concentration of 8 μg/ml. Conclusion: Thus, we have demonstrated the first example of the pyridine quaternization using the betulin triterpenoids as the lipophilic substrates and Tempo+Br3 - cation. The obtained quaternized pyridine analogs of betulin triterpenes showed high antibacterial and antifungal activity in comparison with the initial compounds.

Background: Xanthatin, fluoropyrimidine and thienopyrimidine, pyrazolopyrimidine, pyrimidine carboxamides, and SKLB1002 are reported as VEGFR2 tyrosine kinase inhibitors. Recently, many studies related to different heterocycles conjugated with dihydroquinazolinones are known to have very good biological activities. In this study, we are intended to explore the cytotoxic studies of piperidine conjugated dihydroquinazolinones against colorectal/colon cancer cell lines and along with molecular docking studies and DFT calculations. Methods: The colorectal/colon cell lines HCT116 and A549 cell lines were treated with these compounds and cytotoxic activities were evaluated by MTT dye uptake method. We performed molecular modelling for compound 3d using the Auto Dock software. The binding of compound 3d with target proteins was studied with the collection of experimentally determined PDB database. Optimized geometry by DFT calculations was performed with B3LYP/6-31G (d) basis set. Results: Piperidine-conjugated dihydroquinazolinone analogues displayed anticancer activity. Particularly, the compound 3d with electron-withdrawing substituents on a phenyl ring showed significant cytotoxicity against HCT116 and A549 cell lines. Molecular docking studies proved that the compound 3d has good fitting by forming hydrogen bonds with amino acid residues at the active sites of VEGFR2. The HOMO, LUMO, their energies and UV visible spectrum were predicted using DFT calculations. Conclusion: Four piperidine-conjugated dihydroquinazolinones were synthesized and evaluated against colorectal and colon cancer cell lines. Compound 3d significantly inhibited the growth of HCT116 and A549. Molecular docking studies displayed good fitting of compound 3d by forming different H-bonds with the amino acid at the active sites of the VEGFR2 target. Using a theoretical approach, we optimized HOMO and LUMO plots for the compound 3d.

Background: Thiohydantoins are an important class of heterocyclic compounds in drug discovery since they are related to a wide range of biological properties including antimicrobial activity. Objective: The objective of this study was to synthesize a series of thiohydantoins derived from Laminoacids and to evaluated their inhibitory effect on the growth of Gram-negative and Grampositive bacteria. Methods: All title compounds were synthetized by reaction of L-amino acids with thiourea or ammonium thiocyanate. Their antimicrobial activities were evaluated against bacterial strains by broth microdilution assays. The time-kill kinetics, the antibiofilm activity and the cytotoxicity to mammalian cells were determined for the compound that exhibited the best antimicrobial profile (1b). Results: Eleven thiohydantoins were readily obtained in good yields (52-95%). In general, thiohydantoins were more effective against Gram-positive bacteria. Compound 1b (derived from Lalanine) showed the best antibacterial activity against Staphylococcus epidermis ATCC 12228 and S. aureus BEC 9393 with MIC values of 940 and 1921 μM, respectively. The time-kill kinetics demonstrated time-dependent bactericidal effect in both strains for this derivative. Besides, 1b also exhibited antibacterial activity against biofilms of S. epidermidis ATCC 12228, leading to a 40% reduction in their metabolic activity compared to the untreated control. No cytotoxicity of 1b to mammalian cells was observed at MIC values. Conclusion: The data reported herein indicate relevant antimicrobial activity of thiohydantoins derived from L-aminoacid, mainly 1b, as potential pharmacophore to guide further chemical modification aiming at the search for new and improved antimicrobial agents.