Medicinal Chemistry - Volume 17, Issue 9, 2021

Background: Diabetes mellitus is a serious global health issue, currently affecting 425 million people and is set to affect over 690 million people by 2045. It is a chronic disease characterized by hyperglycemia due to relative or absolute insulin hormone deficiency. Dipeptidyl peptidase- IV (DPP-IV) inhibitors are hypoglycemic agents augmenting the action of the incretin hormones that stimulate insulin secretion from the pancreatic beta cells. Objective: In this study, synthesis and biological evaluation of seven piperazine derivatives 3a-g was carried out. Methods: The synthesized molecules were characterized using proton-nuclear magnetic resonance, carbon-nuclear magnetic resonance, infrared spectroscopy and mass spectrometry. Results: In vitro biological evaluation study showed comparable DPP-IV inhibitory activity for the targeted compounds ranging from 19%-30% at 100 μM concentration. Furthermore, the in vivo hypoglycemic activity of 3d was evaluated using streptozotocin-induced diabetic mice. It was found that compound 3d significantly decreased the blood glucose level when the diabetic group treated with 3d was compared to the control diabetic group. Quantum–Polarized Ligand Docking (QPLD) studies demonstrate that 3a-g fit the binding site of DPP-IV enzyme and form H-bonding with the backbones of R125, E205, E206, K554, W629, Y631, Y662, R669, and Y752. Conclusion: Piperazine derivatives were successfully found to be new scaffolds as potential DPP-IV inhibitors.

Background: Natural naphthoquinones have shown diversified biological activities including antibacterial, antifungal, antimalarial, and cytotoxic activities. However, they are also compounds with acute cytotoxicity, immunotoxicity, carcinogenesis, and cardio- and hepatotoxicity, and the modification at their redox center is an interesting strategy to overcome such harmful activity. Objective: In this study, four novel semisynthetic hydrazones, derived from the isomers α- and β- lapachones (α and β, respectively) and coupled with the drugs hydralazine (HDZ) and isoniazid (ACIL), were prepared, evaluated by electrochemical methods and assayed for anticancer activity. Methods: The semisynthetic hydrazones were obtained and had their molecular structures established by NMR, IR, and MS. Anticancer activity was evaluated by cell viability determined by reduction of 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (MTT). The electrochemical studies, mainly cyclic voltammetry, were performed, in aprotic and protic media. Results: The study showed that the compounds 2, 3, and 4 were active against at least one of the cancer cell lines evaluated, compounds 3 and 4 being the most cytotoxic. Toward HL-60 cells, compound 3 was 20x more active than β-lapachone, and 3x more cytotoxic than doxorubicin. Furthermore, 3 showed an SI value of 39.62 for HL-60 cells. Compound 4 was active against all cancer cells tested, with IC50 values in the range 2.90–12.40 μM. Electrochemical studies revealed a profile typical of self-protonation and reductive cleavage, dependent on the supporting electrolyte. Conclusion: These results therefore indicate that compounds 3 and 4 are strong candidates as prototypes of new antineoplastic drugs.

Background: Ligustrazine and chalcones have been reported previously for various biological activities including anticancer effects. Objectives: Based on the multitargeted biological activities approach of ligustrazine-based chalcones, in the current study 18 synthetic ligustrazine-containing α, β-unsaturated carbonyl-based 1, 3- Diphenyl-2-propen-1-one derivatives were evaluated for their inhibitory effects on the growth of five different types of cancer cells. Methods: All the compounds were evaluated for anticancer effects on various cancer cell lines by propidium iodide fluorescence assay and various other assays were performed for mechanistic studies. Results: A majority of compounds exhibited strong inhibition of cancer cells, especially synthetic compounds 4a and 4b, bearing 1-Pyridin-3-yl-ethanone as a ketone moiety in the main structural backbone were found to be most powerful inhibitors of cancer cell growth. Nine most active compounds among the whole series were selected for further studies related to different cancer targets, including EGFR TK kinases, tubulin polymerization, KAF and BRAF^V600E. Conclusion: Synthetic derivatives, including 4a-b and 5a-b showed a multitarget approach and strong inhibitory effects on EGFR, FAK and BRAF while three compounds, including 3e bearing methoxy substitution, 4a and 4b with 1-pyridin-3-yl-ethanone moiety showed the inhibition of tubulin polymerization.

Background: Reactive oxygen species are involved in the etiology and progress of many kinds of diseases such as cancer, cardiovascular diseases, inflammatory and neurodegenerative disorders. Epidemiological studies reported that fruits, vegetables, and wines containing a high percentage of phenolics and flavonoids showed a positive impact in treating inflammatory diseases, reducing cancer risk, and increasing life expectancy. Objective: Some Mongolian medicinal plants were studied for their antioxidant activity and anticancer effects. Methods: Selected Mongolian medicinal plant extracts were examined for their antioxidant activity by the DPPH-radical scavenging assay, the content of phenolics and flavonoids by Folin-Ciocalteu and the Dowd method, respectively, and anti-cancer activities in human hepatoma cell line HepG2 cells by MTT assay. Results: Methanol extract from Hippophae rhamnoides L. leaf and ethanol extract from Artemisia macrocephala Jacq. ex Bess. showed the highest efficiency to scavenge free radicals. Ethanol extracts from Hippophae rhamnoides L. grain and Paeonio anomala L. leaf showed the highest total phenolics content, whereas Hippophae rhamnoides L. fruit methanol extract and ethanol extract from Caragana leucophloea pojark. mentioned the highest flavonoids content. The Artemisia macrocephala Jacq. ex Bess seed wallet and Paeonia anomala L. seed wallet showed the most potent antiproliferative effects against human liver cancer HepG2 cell line. Gnetin-H compound was isolated from the Paeonio anomala L. seed wallet extract, and its molecular structure was determined by 1H and 13C NMR spectrum and IR spectroscopy methods. Conclusion: The screening study on anti-oxidative effects of 21 extracts from 15 Mongolian medicinal plants showed anti-oxidative activities and was rich in phenolics and flavonoids. Among these, methanol extract of the Hippophae rhamnoides L. leaf showed a better anti-oxidative effect than the ethanol extract. Artemisia macrocephala Jacq. ex Bess and Paeonia anomala L. seed wallet mentioned the best anti-cancer effects. Gnetin-H, methyl gallate, ethylgallate were the major components in the extract from the Paeonio anomala L. seed wallet. Finally, the molecular structure of gnetin-H was determined by NMR and IR spectroscopy. Further investigation, especially in vivo antioxidant activity, is needed to justify the use of a natural source of antioxidants to prevent the progression of diseases such as cancer.

Background: Schisandronic acid (SA), a triterpenoid from fruits of Schisandra sphenanthera, inhibited pan-genotypic HCV entry into human hepatocytes by interfering with virion-cell membrane fusion. It was a promising lead compound for the development of novel HCV entry inhibition agents. Objective: The aim of the present study is to search for compounds with more potent anti-HCV and antitumor activities and explore SARs. A series of novel derivatives of SA were designed and synthesized and evaluated for in vitro, their anti-HCV and antitumor activities. Methods: SA derivatives were synthesized by reduction, condensation, esterification or amidation. The anti-HCV activity of title compounds was tested by inhibition on HCVcc infection of Huh7 cells, and a preliminary MOA study was conducted by determining inhibition on HCVpp entry into Huh7 cells. The antitumor activity in vitro was determined by MTT methods. Results: In total, 24 novel derivatives were synthesized. Most of the compounds inhibited HCVcc infection. Compounds 5h and 6 showed the most potent anti-HCVcc activities and inhibition of HCVpp entry into Huh7 cells without obvious cytotoxicity. Most of the title compounds showed potent in vitro antitumor activities against Bel7404 and SMMC7721 tumor cell lines. Compounds 5j and 6 exhibited more potent antitumor activity than positive control SA and DOX. Conclusion: Structural modification of SA could lead to the discovery of potent anti-HCV or antitumor agents. Compounds 5h, 5j and 6 were promising lead compounds for development of novel HCV entry inhibition or antitumor agents.

Background: Inflammation involves a dynamic network that is highly regulated by signals that initiate the inflammation process as well as signals that downregulate it. However, an imbalance between the two leads to tissue damage. Throughout the world, inflammatory disease becomes common in the aging society. The drugs which are used clinically have serious side effects. Natural products or compounds derived from natural products show diversity in structure and play an important role in drug discovery and development. Objective: Oreganum Vulgare is used in traditional medicine for various ailments including respiratory and rheumatic disorders, severe cold, suppression of tumors. The current study aims to evaluate the anti-inflammatory potential by evaluating various in vitro parameters. Methods: Inflammation-induced in macrophages via LPS is the most accepted model for evaluating the antiinflammatory activity of various plant extracts and lead compounds. Results: The extracts (OVEE, OVEAF) as well as the isolated compound(OVRA)of Oreganum Vulgare inhibit the pro-inflammatory cytokines (IL-6 and TNF-α) and NO without affecting cell viability. Conclusion: Our study established that the leaf extracts of Oreganum vulgare L. exhibit anti-inflammatory activity and thus confirm its importance in traditional medicine.

Background: NSAIDs are the most widely prescribed medications worldwide for their anti-inflammatory, antipyretic, and analgesic effects. However, their chronic use can lead to several adverse drug events including GI toxicity. The selective COX-2 inhibitors developed as gastrosparing NSAIDs also suffer from serious adverse effects which limit their efficacy. Objective: Local generation of reactive oxygen species is implicated in NSAID-mediated gastric ulceration and their combination with H2 antagonists like famotidine reduces the risk of ulcers. The objective of this work was to design and synthesize novel methanesulphonamido isoxazole derivatives by hybridizing the structural features of NSAIDs with those of antiulcer drugs (ranitidine, famotidine, etc.) to utilize a dual combination of anti-inflammatory activity and reducing (antioxidant) potential. Methods: The designing process utilized three dimensional similarity studies and utilized an isoxazole core having a potential for anti-inflammatory as well as radical scavenging antioxidant activity. The compounds were assayed for their anti-inflammatory activity in established in vivo models. The in vitro antioxidant activity was assessed in potassium ferricyanide reducing power (PFRAP) assay employing ascorbic acid as the standard drug. Results: Compounds 5, 6, 9 and 10 showed antiinflammatory activity comparable to the standard drugs and were also found to be non-ulcerogenic at the test doses. Compounds 6-10 exhibited good antioxidant effect in the concentration range of 1.0- 50.0 μmol/ml. The test compounds were also found to comply with the Lipinski rule suggesting good oral absorption. Conclusion: A new series of isoxazole based compounds is being reported with good antiinflammatory activity coupled with antioxidant potential as gastro-sparing anti-inflammatory agents.

Background: Over the years, transition metal complexes have exhibited significant antimicrobial and antitumor activity. It all started with cisplatin discovery, but due to the large number of side effects it shows, there is a growing need to find a new metal-based compound with higher selectivity and activity on more tumors. Objectives: Two novel trans-palladium(II) complexes with organoselenium compounds as ligands, [Pd(L1)2Cl2] (L1 = 5-(phenylselanylmethyl)-dihydrofuran-2(3H)-one) and [Pd(L2)2Cl2] (L2 = 2- methyl-5-(phenylselanylmethyl)- tetrahydrofuran) were synthesized, in the text referred to as Pd-Se1 and Pd-Se2. Also, a structurally similar trans-palladium(II) complex, [Pd(L3)2Cl2] (L3= 2,2- dimethyl-3-(phenylselanylmethyl)-tetrahydro-2H-pyran) was synthesized according to an already published work and is referred to as Pd-Se3. The interaction of synthesized complexes with DNA and bovine serum albumin was observed. Also, antimicrobial activity and in vitro testing, cell viability, and cytotoxic effects of synthesized ligands and complexes on human epithelial colorectal cancer cell line HCT-116 were studied. Molecular docking simulations were performed to understand better the binding modes of the complexes reported in this paper with DNA and BSA, as well as to comprehend their antimicrobial activity. Methods: The interactions of the synthesized complexes with DNA and bovine serum albumin were done using UV-Vis and emission spectral studies as well as docking studies. Antimicrobial activity was tested by determining the minimum inhibitory concentrations (MIC) and minimum microbicidal concentration (MMC) using the resazurin microdilution plate method. Cytotoxic activity on cancer cells was studied by MTT test. Results: The Pd(II) complexes showed a significant binding affinity for calf thymus DNA and bovine serum albumin by UV-Vis and emission spectral studies. The intensity of antimicrobial activity varied with the complexes Pd-Se1 and Pd-Se3, showing significantly higher activity than the corresponding ligand. The most significant activity was shown on Pseudomonas aeruginosa. Under standardized laboratory conditions for in vitro testing, cell viability and cytotoxic effects of synthesized ligands and complexes were studied on human epithelial colorectal cancer cell line HCT-116, where Pd-Se2 showed some significant cytotoxic effects. Conclusion: The newly synthesized complexes have the potential to be further investigated as metallodrugs.

Background: Anticonvulsants are drugs used in the treatment of seizures; their pharmacology includes promoters of brain inhibition and inhibitors of brain activity. Of the latter, voltagedependent sodium channel blockers (VGSCB) are the most widely used in therapeutics. Objective: The study aimed at proposing the structural requirements of VGSC blockers through a quantitative structure-activity relationship analysis of drugs with proven activity. Methods: IC50 values of anticonvulsant drugs on VGSCs were considered under similar experimental conditions; some physicochemical properties of the molecules that were correlated with their biological activity were determined in silico. Results: Relationships were observed between the dipole moment, pKa, EHOMO, and MR with the biological activity, which infers that between greater polarity and basicity of the drugs, their activity as blockers will increase. Subsequently, the structural subclassification of the drugs was carried out, based on the urea derivation, the groups of which were: Group 1 (direct and bioisostere derivatives) and Group 2 (homologue and vinylogue derivatives of urea). Conclusion: The biological activity depends on the polarity, basicity, and electronic density of the drugs. The derivation of urea is essential, which is present in its original substituted form or a bioisosteric form. Urea can be in the form of a homologue or a vinylogue at the ends of the molecule. Aromatic substitution to the urea portion is necessary.

Background: Thiourea is a classical urease inhibitor which is usually used as a positive control, and many N,N'-disubstituted thioureas have been determined as urease inhibitors. However, due to steric hindrance, N,N'-disubstituted thiourea motif could not bind urease as thiourea. On the contrary, N-monosubstituted thiourea with a tiny thiourea motif could theoretically bind into the active pocket as thiourea. Objective: A series of N-monosubstituted aroylthioureas were designed and synthesized for evaluation as urease inhibitors. Methods: Urease inhibition was determined by the indophenol method and IC50 values were calculated using computerized linear regression analysis of quantal log dose-probit functions. The kinetic parameters were estimated via surface plasmon resonance (SPR) and by nonlinear regression analysis based on the mixed type inhibition model derived from Michaelis-Menten kinetics. Results: Compounds b2, b11, and b19 reversibly inhibited urease with a mixed mechanism, and showed excellent potency against both cell-free urease and urease in the intact cell, with IC50 values being 90- to 450-fold and 5- to 50-fold lower than the positive control acetohydroxamic acid, respectively. The most potent compound b11 showed an IC50 value of 0.060 ± 0.004μM against cell-free urease, which bound to urea binding site with a very low KD value (0.420±0.003nM) and a very long residence time (6.7 min). Compound b11 was also demonstrated to have very low cytotoxicity to mammalian cells. Conclusion: The results revealed that N-monosubstituted aroylthioureas bound to the active site of urease as expected, and represent a new class of urease inhibitors for the development of potential therapeutics against infections caused by urease-containing pathogens.

Background: HIV-1 integrase (IN) has been considered as an important target for the development of novel anti-HIV-1 drugs. Objective: The aim of this study was to design novel groups of HIV IN inhibitors. Methods: In this study, we presented a novel series of 4-oxo-4,10-dihydrobenzo[4,5]imidazo[1,2- a]pyrimidine-3-carboxylic acid derivatives by structural modification of N-arylindole β-diketoacids as a well-known group of IN inhibitors. Results: Based on in-vitro anti-HIV-1 activity in a cell-based assay, compounds 5, 6a and 6k displayed moderate to good inhibitory activity with EC50 values of 4.14, 1.68 and 0.8 μM, respectively. However, integrase inhibition assay showed that most of the analogues did not have significant effects against integrase enzyme except compound 5 with an IC50 value of 45 μM. Our results indicated that compound 6k was the best one among synthesized compounds with an EC50 of 0.8 μM and SI of 175. Docking and molecular dynamics simulation studies were also performed to provide some insights into the probable mechanism of tested compounds. Conclusion: These findings suggest that 4-oxo-4,10-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3- carboxylic acid derivatives may consider as promising lead compounds for the development of new anti-HIV-1 drugs.