Medicinal Chemistry - Volume 14, Issue 7, 2018

Background: Prostaglandins are a family of eicosanoids biosynthesized from arachidonic acid through cyclooxygenase (COX) pathway. Two isoforms of COX are well established: COX-1, COX-2. Evidence supports the notion that cyclooxygenase-2, plays a crucial role in some pathological conditions such as inflammation and cancer. Objective: A new group of 1,3-diphenyl-3-(phenylamino)propan-1-ones was designed and synthesized to investigate for their COX-2 inhibitory activity and inhibition of platelet aggregation. Method: Docking study was performed using AutoDock vina software. In vitro COX-1 and COX- 2 isozyme inhibition studies were accomplished to obtain structure activity relationship data. The in vitro antiplatelet aggregation activity was determined by turbidimetric procedure. Results: In vitro COX inhibition assay showed that except compound 8c, all derivatives were selective COX-2 inhibitors with IC50 values in the potent 0.20-0.35 μM range with high COX-2 selectivity indexes (SI). Molecular modeling and docking studies indicated that synthesized compounds had a binding similar to that of the known inhibitor SC-558 and the SO2Me group was inserted into the COX-2 secondary pocket (Val523, Phe518, Ile517, Arg513 and His90) and C=O of the central α, β-unsaturated-carbonyl moiety was oriented toward the entrance to the COX-2 binding site (Tyr355 and Arg120). Conclusion: The 1,3-diphenyl-3-(phenylamino)propan-1-ones are novel COX-2 inhibitors with good COX-2 inhibitory and low affinity for COX-1 isoenzyme. Also our results demonstrated that majority of these compounds inhibited AA-induced platelet aggregation.

Background: Non-steroidal anti-inflammatory drugs are widely used for many years, but the chronic use of NSAID's leads to gastric side effects, ulceration and kidney problems. These side effects are due to non-selective inhibition of COX-2 along with COX-1. Therefore, it is imperative to develop novel and selective COX-2 inhibitors. Objective: In this paper wehave synthesized a series of novel hybrids comprising of substituted-N- (3,4,5-trimethoxyphenyl)-benzo[d]oxazole derivatives and screened for the treatment of inflammation. Methods: The structures of the obtained compounds were elucidated by elemental and spectral analysis (ATR-FTIR, 1H NMR, 13C NMR, Mass spectroscopy). All of the compounds were evaluated for cyclooxygenase (COX-1/COX-2) inhibitory activity by in vitro enzymatic assay. The compound which showed COX-2 activity (3a - 3e, 3g – 3h, 3k, 3m and 3o) was further screened for in vivo anti-inflammatory activity and ulcerogenic liability. Molecular docking study was also performed with resolved crystal structure of COX-2 to understand the binding mechanism of newly synthesized inhibitors in the active site of COX-2enzyme. Results: The in vitro COX-1 and COX-2 inhibitory studies showed that the synthesized compounds potentially inhibited COX-2 (IC50 = 0.04 – 26.41 μM range) over COX-1 (IC50 = 0.98 – 33.33 μM range). The in vivo studies predicted that compounds 3c (70.9%, 0.6±0.22), 3m (68.1%, 1.9±0.41) and 3o (70.4%, 1.7±0.27) produced more efficacy against carrageenan induced paw edema and less ulcerogenic effect, as compared to standard ibuprofen (65.9%, 2.2±0.44). The results of docking studies were found to be concordant with the biological evaluation studies of the prepared compound. Conclusion: Among all the tested compounds, 2-Chloro-N-(2-(3,4,5-trimethoxyphenyl)- benzo[d]oxazol-5-yl)-benzamide (3c) was the most potent anti-inflammatory agent and has less ulcerogenic potential. This series of compound can be explored more for development of safer and more active anti-inflammatory agents.

Background: Inflammation is defined as the response of immune system cells to damaged or injured tissues. The major symptoms of inflammation include increased blood flow, cellular influx, edema, elevated cellular metabolism, reactive oxygen species (ROS) nitric oxide (NO) and vasodilation. This normally protective mechanism against harmful agents when this normal mechanism becomes dysregulated that can cause serious illnesses including ulcerative colitis, Crohn's disease, rheumatoid arthritis, osteoarthritis, sepsis, and chronic pulmonary inflammation. Method: In this study synthetic transformations on diclofenac were carried out in search of better non-steroidal antiinflammatory drugs (NSAIDs), non-acidic, antiinflammatory agents. For this purpose diclofenac derivatives (2-20) were synthesized from diclofenac (1). All derivatives (2-20) and parent diclofenac (1) were evaluated for their antiinflammatory effect using different parameters including suppression of intracellular reactive oxygen species (ROS), produced by whole blood phagocytes, produced by neutrophils, and inhibition of nitric oxide (NO) production from J774.2 macrophages. The most active compound also evaluated for cytotoxicity activity. Results: Diclofenac (1) inhibited the ROS with an IC50 of 3.9 ± 2.8, 1.2 ± 0.0 μg/mL respectively and inhibited NO with an IC50 of 30.01 ± 0.01 μg/mL. Among its derivatives 4, 5, 11, 16, and 20, showed better antiinflammatory potential. The compound 5 was found to be the most potent inhibitor of intracellular ROS as well as NO with IC50 values of 1.9 ± 0.9, 1.7 ± 0.4 μg/mL respectively and 7.13 ± 1.0 μg/mL, respectively, and showed good inhibitory activity than parent diclofenac. The most active compounds were tested for their toxic effect on NIH-3T3 cells where all compounds were found to be non-toxic compared to the standard cytotoxic drug cyclohexamide. Conclusion: Five derivatives were found to be active. Compound 5 was found to be the most potent inhibitor of ROS and NO compared to parent diclofenac 1 and standard drugs ibuprofen and L-NMMA, respectively. The most active compounds 1, 4, 5, 11 and 20 were found to be non-toxic on NIH-3T3 cells. Compound 4, 5, and 20 also showed good antiinflammatory potential, compound 11 and 16 showed moderate and low level of inhibition, respectively.

Background: Apelin receptor (APJ) is a G protein-coupled receptor (GPCR) activated by the endogenous peptide apelin. The apelin–APJ system has emerged as an important regulator of cardiovascular homeostasis. Recently, a potent benzimidazole-derived apelin peptidomimetic, CMF-019, was patented but without a comprehensive description of its synthesis and a complete spectroscopic characterization of the intermediates. Objective: Here, a detailed preparation of CMF-019 through a modified and improved synthetic pathway is described. Method: In particular, the benzimidazole ring in 7 was tailored by the condensation of methyl 3- amino-4-(pentan-3-ylamino)benzoate (4) with (thiophene-2-yl)acetimidate salt 6. Saponification of 7 and the subsequent condensation of the free acid 8 with the corresponding enantiopure β-amino acid methyl ester generated methyl (S)-5-methyl-3-{1-(pentan-3-yl)-2-(thiophen-2-ylmethyl)-1Hbenzo[ d]imidazole-5-carboxamido}hexanoate (9). Hydrolysis of the latter with KOH in THF/water, followed by HPLC-purification, afforded the desired product, CMF-019 (potassium salt) 10. Results & Conclusion: The approach reported herein enables preparation of 10 at a total yield of 12% over seven linear steps. Additionally, it does not require applying expensive designated microwave reactors and high-pressure hydrogenators. Thus, the elaborate synthesis provides a latent availability of potent agonist 10 for further exploring the physiologically essential apelin-APJ system.

Background: Phosphoinositide 3-kinase α (PI3Kα) is an attractive target for anticancer drug design. Objectives: Target compounds were designed to probe the significance of alcohol and imine moieties tailored on a benzoin scaffold to better understand the structure activity relation (SAR) and improve their biological activity as anticancer compounds. Methods: Chemical synthesis of the targeted compounds, biological evaluation tests against human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines, as well as Glide docking studies were employed in this investigation. Results: A new series of 1,2-diphenylimino ethanol was successfully synthesized and characterized by means of FT-IR, HRMS, NMR, and by elemental analysis. Biological screening revealed that the newly synthesized compounds inhibit PI3Kα activity in human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines. Results additionally showed that these compounds exhibit selective antiproliferative activity, induce apoptosis, and suppress the VEGF production. Compounds 2b, 2d, and 2g displayed promising inhibitory activity in HCT-116 suggesting that hydrophobic and/or hydrogen bond-acceptor mediate(s) ligand-receptor interaction on o- and mpositions. Furthermore, compounds 2g, 2i, 2j, and 2h, bearing hydrophobic moiety on m- and pposition, exerted high antiproliferative activity in T47D and MCF-7 cells, whereas compound 2e showed selectivity against T47D and MCF-7. Molecular docking studies against PI3Kα and caspase-3 demonstrated a strong correlation between the predicted binding affinity (ΔGobsd) and IC50 values of prepared compounds for the caspase-3 model, implying that the cellulous inhibitory activity was caspase-3-dependent. Moreover, Glide docking against PI3Kα identified Ser774, Lys802, E849, V851, and Asp933 as key binding residues. Conclusion: The series exerted a potential PI3Kα inhibitory activity in human carcinoma cell lines expressing PI3Kα.

Background: Structural component of proteins and peptides, amino acids have been used as building blocks in the synthesis of more complex molecules with antitumor activity against several types of cancer. Objective: The search for new anticancer compounds is ongoing, especially for cancers that are very aggressive and have poor prognoses, such as leukemia. Method: Here, we report a method to synthesize Tyr-Tyr dipeptides via sonochemistry reactions followed by functionalization of these Tyr-Tyr dipeptides with Suzuki-Miyaura and Sonogashira crosscoupling reactions in good yields. Twelve different Tyr-Tyr dipeptides were investigated against three cell lines: HaCaT; Jurkat-E6; and A2058. Results: Some of the Tyr-Tyr dipeptides showed activity against Jurkat-E6 leukaemia cells at low concentration, decreasing their viability, but not against non-tumor HaCaT cells, suggesting a cytotoxicity specific to tumor cells. Conclusion: All dipeptides were able to decrease the viability of Jurkat cell line, however the A2058 cell line did not respond well to treatment with the peptides. Some of the modified Tyr-Tyr dipeptides presented selective activity on leukemic tumor cells.

Background: R132H mutation of isocitrate dehydrogenase 1 (IDH1) is found in ~75% of low-grade gliomas and secondary glioblastomas as well as in several other types of cancer. More chemotypes of inhibitors of IDH1(R132H) are therefore needed. Objective: The study aimed to develop a new class of IDH1(R132H) inhibitors as potent antitumor agents. Method: A biochemical assay was developed to find inhibitors of IDH1(R132H) mutant enzyme. Chemical synthesis and structure-activity relationship studies were used to find compounds with improved potency. Antitumor activities of selected compounds were evaluated. Results: A series of aromatic sulfonamide compounds was found to be novel, potent inhibitors of IDH1(R132H) with Ki values as low as 0.6 μM. Structure-activity relationships of these compounds are discussed. Enzyme kinetics studies showed that one compound is a competitive inhibitor against the substrate α-KG and a non-competitive inhibitor against the cofactor NADPH. Several inhibitors were found to have no activity against wild-type IDH1, showing a high selectivity. Two potent inhibitors exhibited strong activity against proliferation of BT142 glioma cells with IDH1 R132H mutation, while these compounds did not significantly affect the growth of glioma cells without IDH1 mutation. Conclusion: This novel series of IDH1(R132H) inhibitors have potential to be further developed for the treatment of glioma with IDH1 mutation.

Background: Leishmaniasis is a protozoan parasitic vector-borne disease which is endemic in 88 tropical countries. Infected sandfly is the main vector of this disease, while there are several other vectors, parasites, and reservoirs involved in the transmission of this disease. Leishmania donovani, L. infantum, and L. chagasi are common disease causing species, transmitted through sandflies. Leishmaniasis is a neglected tropical disease with broad spectrum of clinical manifestations. Cutaneous leishmaniasis is prevalent in many countries, including Pakistan. Methods: Thiocarbohydrazones (1-20) were synthesized through one pot method by refluxing thiocarbahydrazide with different substituted benzaldehydes in ethanol in the presence of acetic acid as a catalyst. These synthetic compounds were evaluated for their potential antileishmanial activity in vitro against Leishmania major promastigotes. Results: Compounds 5-8, 11, 14, 16, 17, 19 and 20 were reported earlier, while compounds 2-4, 9, 10, 12, 13 and 15 were identified as were derivatives. Compounds 1-20 demonstrated antileishmanial activities with IC50 values between 1.63 ± 0.05 - 64.82 ± 0.17 μM, as compared to the standard drug pentamidine (IC50 = 5.09 ± 0.04 μM). Compounds 2 (IC50 = 1.63 ± 0.05 μM), 11 (IC50 = 2.33 ± 0.01 μM), 4 (IC50 = 11.03 ± 0.20 μM), and 10 (IC50 = 11.63 ± 0.06 μM) displayed comparable antileishmanial activities to the standard drug pentamidine. However, compounds 13, 15-17, and 20 with IC50 values 36.95 ± 0.025, 64.82 ± 0.17, 64.27 ± 0.38, 62.34 ± 0.38, and 40.47 ± 0.05 μM, respectively, showed a moderate antileishmanial activity. In contrast, compounds 1, 3, 5-9, 12, 14, 18, and 19 demonstrated less than 50% growth inhibition of promestigotes of L. major, and thus considered as inactive. Conclusion: In thiocarbohydrazone derivatives, different substituents at aryl part may be responsible for a varying degree of antileishmanial activity in vitro. Consequently, these compounds might have a potential for further studies as a new class of antileishmanial agents.

Background: The development of severe drug resistance caused by the extensive use of anti-HIV agents has resulted in a greatly extensive reduction in these drugs efficacy. Objectives: To identify the important pharmacophoric features and correlate 3D chemical structure of benzothiazinimines with their anti-HIV potential using 2D, 3D-QSAR and pharmacophore modeling studies. Methods: QSAR and pharmacophore mapping studies have been used to relate structural features. 2D QSAR and 3D QSAR studies were performed using partial least square and k-nearest neighbor methodology, coupled with various feature selection methods, viz. stepwise, genetic algorithm, and simulated annealing, to derive QSAR models which were further validated for statistical significance. Results: The physicochemical descriptor XAHydrophilicArea and SsOHE-index, and alignmentindependent descriptor T_C_Cl_6 showed significant correlation with the anti-HIV activity of benzothiazinimines in 2D QSAR. 3D QSAR results showed the significant effect of electrostatic and steric field descriptors in the anti-HIV potential of benzothiazinimines. The generated pharmacophore hypothesis demonstrated the importance of aromaticity and hydrogen bond acceptors. Conclusion: The significant models obtained in this study suggested that these techniques could be used as a guidance for designing new benzothiazinimines with enhanced anti-HIV potential.

Background: Antimicrobial peptides are on the first line of defense against pathogenic microorganisms of many living beings. These compounds are considered natural antibiotics that can overcome bacterial resistance to conventional antibiotics. Due to this characteristic, new peptides with improved properties are quite appealing for designing new strategies for fighting pathogenic bacteria. Methods: Sixteen designed peptides were synthesized using Fmoc chemistry; five of them are new cationic antimicrobial peptides (CAMPs) designed using a genetic algorithm that optimizes the antibacterial activity based on selected physicochemical descriptors and 11 analog peptides derived from these five peptides were designed and constructed by single amino acid substitutions. These 16 peptides were structurally characterized and their biological activity was determined against Escherichia coli O157:H7 (E. coli O157:H7), and methicillin-resistant strains of Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (P. aeruginosa) were determined. Results: These 16 peptides were folded into an α-helix structure in membrane-mimicking environment. Among these 16 peptides, GIBIM-P5S9K (ATKKCGLFKILKGVGKI) showed the highest antimicrobial activity against E. coli O157:H7 (MIC=10μM), methicillin-resistant Staphylococcus aureus (MRSA) (MIC=25μM) and Pseudomonas aeruginosa (MIC=10 μM). Peptide GIBIM-P5S9K caused permeabilization of the bacterial membrane at 25 μM as determined by the Sytox Green uptake assay and the labelling of these bacteria by using the fluoresceinated peptide. GIBIM-P5S9K seems to be specific for these bacteria because at 50 μM, it provoked lower than 40% of erythrocyte hemolysis. Conclusion: New CAMPs have been designed using a genetic algorithm based on selected physicochemical descriptors and single amino acid substitution. These CAMPs interacted quite specifically with the bacterial cell membrane, GIBIM-P5S9K exhibiting high antibacterial activity on Escherichia coli O157:H7, methicillin-resistant strains of Staphylococcus aureus and P. aeruginosa.