Synthesis,spectroscopic and molecular docking studies on new schiff bases,nucleosides and α-aminophosphonate derivatives as antibacterial agents

New Nucleosides, analogues derived from 1, 3, 4-oxadiazole, arylidene analogues and α-aminophosphonate were prepared. Infrared (IR), elemental analysis and ¹HNMR elucidated nucleosides; arylidines and phosphonate derivatives. The prepared derivatives were purified and allowed to test against bacteria strains. Phosphonate derivative 12a showed the higher antibacterial against E. coli with inhibition zone 35 mm, P. aeruginosa with inhibition zone 30 and S. aureus with inhibition zone 22 while compounds 4, 6d, 9a, 9c and 12c showed moderate to weak activity against these bacteria species with inhibition zones ranged from 12 mm to 24 mm. The molecular docking studies was applied on compound 12a, which showed the binding at the active DNA Gyrase.     

Syntheses of 6-(2-hydroxy-6-phenylhexyl)-5,6-dihydro-2H-pyran-2-one derivatives and their cytotoxicities

The cytotoxicities against cancer cells (HL-60, HeLa) and insect cells (Sf9) of four stereoisomers of 6-(2-hydroxy-6-phenylhexyl)− 5,6-dihydro-2H-pyran-2-one (1) were evaluated, and then their structure-activity relationships examined. The 2′-dehydroxy derivative 5 of (6 R,2′R)- and (6 R,2′S)-1 showed the highest activity against HeLa cells (IC₅₀ = 1.4 μM). To evaluate the effect of the 2′-hydroxy group of 1, 6R-and 6S-oxetane derivatives were also synthesized and their activities examined. Against HeLa and HL-60 cells, the activities of the less potent stereoisomers were enhanced 3–4-fold by the introduction of the oxetane moieties at the 2′-position. Against the insect cell line (Sf9), phenyl derivative 7 showed the highest activity with an IC₅₀ value of 8.0 μM.     

X-ray crystallographic analysis of IMP-1 metallo-β-lactamase complexed with a 3-aminophthalic acid derivative,structure-based drug design,and synthesis of 3,6-disubstituted phthalic acid derivative inhibitors

3-(4-Hydroxypiperidine-1-yl) phthalic acid 1 shows potent inhibitory activity against metallo-β-lactamase, which is known to inactivate β-lactam antibiotics such as carbapenems. Here, the structure of co-crystals of the metallo-β-lactamase IMP-1 and 1 was first analyzed by X-ray crystallography, and then used for structure-based drug design. Four novel compounds bearing substituents at the 6-position were synthesized to produce 3,6-disubstituted phthalic acid derivatives, and their IMP-1 inhibitory activity and synergistic effect with the carbapenem biapenem (BIPM) were evaluated. 3,6-Disubstituted phthalic acid derivatives showed potent IMP-1 inhibitory activity. In particular, compound 13 showed 10-fold higher IMP-1 inhibitory activity as compared with the parent derivative 1.     

Design,synthesis and biological evaluations of novel 7-[3-(1-aminocycloalkyl)pyrrolidin-1-yl]-6-desfluoro-8-methoxyquinolones with potent antibacterial activity against multi-drug resistant Gram-positive bacteria

A series of novel 6-desfluoro [des-F(6)] and 6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methoxyquinolones bearing 3-(1-aminocycloalkyl)pyrrolidin-1-yl substituents at the C-7 position (1–6) was synthesized to obtain potent drugs for nosocomial infections caused by Gram-positive pathogens. The des-F(6) compounds 4–6 exhibited at least four times more potent activity against representative Gram-positive bacteria than ciprofloxacin or moxifloxacin. Among the derivatives, 7-[(3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl] derivative 4, which showed favorable profiles in preliminary toxicological and non-clinical pharmacokinetic studies, exhibited potent antibacterial activity against clinically isolated Gram-positive pathogens that had become resistant to one or more antibiotics.     

RE12 derivatives displaying Vaccinia H1-related phosphatase (VHR) inhibition in the presence of detergent and their anti-proliferative activity against HeLa cells

New derivatives of Vaccinia H1-related phosphatase (VHR) inhibitor RE12 (5) were designed by replacing the long straight alkyl chain with other hydrophobic functionalities containing two aromatic rings, with the aim of obtaining potent, cell-active inhibitors. We established a direct coupling reaction between tetronic acid derivative and thioimidate to prepare the RE derivatives 6a–6i efficiently. These compounds all showed VHR-inhibitory activity in the presence of 0.001% NP-40, whereas RE12 (5) was inactive under this condition, even at 100 μM. Further structure–activity studies focused on terminal substitution afforded trifluoromethyl derivative 6k (RE176) and nitro derivative 6l (RE177). The IC₅₀ value of 6l in the presence of NP-40 was almost equivalent to that of RE12 (5) in its absence. Compound 6k (RE176) potently inhibited proliferation of HeLa cells.     

Structure-Plant Phytotoxic Activity Relationship of 7,7′-epoxylignanes, (+)- and (−)-verrucosin: Simplification on the aromatic ring substituents

The synthesized 7-aryl derivatives of (7R,7′S,8S,8′S)-(+)-verrucosin were applied to growth inhibitory activity test against ryegrass at 1 mM. 7-(3-Ethoxy-4-hydroxyphenyl) derivative 12 and 7-(2-hydroxyphenyl) derivative 4 showed comparable activity to those of (+)-verrucosin against the root (−95%) and the shoot (−60%), respectively. The growth inhibitory activity test against lettuce using synthesized 7-aryl derivatives of (7S,7′R,8R,8′R)-(−)-verrucosin at 1 mM showed that the activities of 7-(3-hydroxyphenyl) derivative 20 and 7-(3-ethoxy-4-hydroxyphenyl) derivative 28 are similar to that of (−)-verrucosin against the root (−95%). Against the shoot, 7-(3-hydroxyphenyl) derivative 20 showed higher activity (−80%) than that of (−)-verrucosin (−60%). As the next step, (7S,7′R,8R,8′R)-7-(3-hydroxyphenyl)-7′-aryl-(−)-verrucosin derivatives, in which the most effective 3-hydroxyphenyl group is employed as 7-aromatic ring, were synthesized for the assay against lettuce. In this experiment, 7′-(2-hydroxyphenyl) derivative 37 and 7′-(3-hydroxyphenyl) derivative 38 showed similar activity to that of derivative 20. The effect of 7- and 7′-aryl structures of 7,7′-epoxylignanes on the plant growth inhibitory activity was clarified. The 7- and 7′-aryl structures were simplified to show comparable activity to or higher activity than that of (−)-verrucosin. The plant growth inhibitory activity of a nutmeg component, (+)-fragransin C_3b, was estimated as −80% inhibition at 1 mM against ryegrass roots.     

Synthesis and antimicrobial evaluation of some new substituted purine derivatives

A series of 8,9-disubstituted adenines (4, 5, 8), 6-substituted aminopurines (10–13) and 9-(p-fluorobenzyl/cyclopentyl)-6-substituted aminopurines (16, 17, 19–30) have been prepared and the antimicrobial activities of these compounds against Staphylococcus aureus, methicillin-resistant S. aureus (MRSA, standard and clinical isolate), Bacillus subtilis, Escherichia coli and Candida albicans were evaluated. 6-[(N-phenylaminoethyl)amino]-9H-purine (12) which has no substitution at N-9 position and 9-cyclopentyl-6-[(4-fluorobenzyl)amino]-9H-purine (24) exhibited excellent activity against C. albicans with MIC 3.12 μg/mL. These compounds displayed better antifungal activity than that of standard oxiconazole. Furthermore, compound 22 carrying 4-chlorobenzylamino group at the 6-position of the purine moiety exhibited comparable antibacterial activity with that of the standard ciprofloxacin against both of the drug-resistant bacteria (MRSA, standard and clinical isolate).     

Synthesis and the 5-HT6 receptor antagonistic effect of 3-arylsulfonylamino-5,6-dihydro-6-substituted pyrazolo[3,4]pyridinones for neuropathic pain treatment

A novel series of 3-arylsulfonylamino-5,6-dihydro-6-substituted-1H-pyrazolo[3,4-c]pyridine-7-ones was designed and synthesized as 5-HT₆ ligands. Among the derivatives synthesized, the lead compound, 12b, having piperidine functionality at the 6-position and (1-naphthyl)sulfonamino at the 3-position of the core structure showed the most potent 5-HT₆ inhibitory activity in vitro, good stability without CYP liability, and good neuropathic pain alleviation activity in a rat animal model.     

Impact of hydroxy moieties at the benzo[7]annulene ring system of GluN2B ligands: Design,synthesis and biological evaluation

In this study, the impact of one or two hydroxy moieties at the benzo[7]annulene scaffold on the GluN2B affinity and cytoprotective activity was analyzed. The key intermediate for the synthesis of OH-substituted benzo[7]annulenamines 11–13 and 17 was the epoxyketone 8. Reductive epoxide opening of 8 resulted with high regioselectivity in the 5-hydroxyketone 9 (Pd(OAc)₂, HCO₂H, phosphane ligand) or the 6-hydroxyketone 10 (H₂, Pd/C), whereas hydrolysis in aqueous dioxane led to the dihydroxyketone 14. Reductive amination of these ketones with primary amines and NaBH(OAc)₃ afforded the benzo[7]annulenamines 11–13 and 17. In receptor binding studies 5-OH derivatives 11 and 12 showed higher GluN2B affinity than 6-OH derivatives 13, which in turn were more active than 5,6-di-OH derivative 17a. The same order was found for the cytoprotective activity of the ligands. The tertiary amine 12a with one OH moiety in 5-position represents the most promising GluN2B negative allosteric modulator with a binding affinity of K_i = 49 nM and a cytoprotective activity of IC₅₀ = 580 nM. In the binding pocket 12a shows a crucial H-bond between the benzylic OH moiety and the backbone carbonyl O-atom of Ser132 (GluN1b). It was concluded that a 5-OH moiety is essential for the inhibition of the NMDA receptor associated ion channel, whereas a OH moiety in 6-position is detrimental for binding and inhibition. An OH or CH₂OH moiety at 2-position results in binding at the ifenprodil binding site, but very weak ion channel inhibition.     

The structure-activity relationship study on 2-, 5-, and 6-position of the water soluble 1,4-dihydropyridine derivatives blocking N-type calcium channels

In order to find an injectable and selective N-type calcium channel blocker, we have performed the structure–activity relationship (SAR) study on the 2-, 5-, and 6-position of 1,4-dihydropyridine-3-carboxylate derivative APJ2708 (2), which is a derivative of Cilnidipine and has L/N-type calcium channel dual inhibitory activities. As a consequence of the optimization, 6-dimethylacetal derivative 7 was found to have an effective inhibitory activity against N-type calcium channels with more than 170-fold lower activity for L-type channel compared to that of APJ2708.     

Combination of 4-anilinoquinazoline,arylurea and tertiary amine moiety to discover novel anticancer agents

In present study, 4-anilinoquinazolines scaffold, arylurea and tertiary amine moiety were combined to design, synthesize gefitinib analogs and discover novel anticancer agents. A series of 4-anilinoquinazoline derivatives (1, 2, 3 and 4) bearing arylurea and tertiary amine moiety at its 6-position were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against A431 cell and A549 cell. The SAR of the title compounds was discussed. The compounds 2d, 2i and 2j with potent antiproliferative activities were evaluated their inhibitory activity against EGFR-TK. Compound 2j displayed potent inhibitory activity against EGFR-TK. In addition, compound 2j, at 50 mg/kg, can completely inhibit cancer growth in established nude mouse A549 xenograft model in vivo. These results suggest that the 4-anilinoquinazoline derivatives bearing diarylurea and tertiary amino moiety at its 6-position can serve as anticancer agents and EGFR inhibitors.     

Constrained (l-)-S-adenosyl-l-homocysteine (SAH) analogues as DNA methyltransferase inhibitors

Potent SAH analogues with constrained homocysteine units have been designed and synthesized as inhibitors of human DNMT enzymes. The five membered (2S,4S)-4-mercaptopyrrolidine-2-carboxylic acid, in 1a, was a good replacement for homocysteine, while the corresponding six-member counterpart was less active. Further optimization of 1a, changed the selectivity profile of these inhibitors. A Chloro substituent at the 2-position of 1a, compound 1d, retained potency against DNMT1, while N⁶ alkylation, compound 7a, conserved DNMT3b2 activity. The concomitant substitutions of 1a at both 2- and N⁶ positions reduced activity against both enzymes.     

Novel purine benzimidazoles as antimicrobial agents by regulating ROS generation and targeting clinically resistant Staphylococcus aureus DNA groove

A novel series of purine benzimidazole hybrids were designed and synthesized for the first time with the aim to circumvent the increasing antibiotic resistance. Hexyl appended hybrid 3c gave potent activities against most of the tested bacteria and fungi especially against multidrug-resistant strains Staphylococcus aureus (MIC?=?4?µg/mL). Structure-activity relationships revealed that the benzimidazole fragment at the 9-position of purine played an important role in exerting potentially antibacterial activity. Both cell toxicity and ROS generation assays indicated that the purine derivative 3c showed low cytotoxicity and could be used as a safe agent. Molecular modeling suggested that hybrid 3c could bind with the residues of Topo IA through hydrogen bonds and electrostatic interactions. Quantum chemical studies were also performed on the target compound 3c to understand the structural features essential for activity. The active molecule 3c could effectively interact with S. aureus DNA to form 3c–DNA complex through groove binding mode, which might block DNA replication to display their powerful antimicrobial activity.     

Probing the binding pocket of the active site of aromatase with 2-phenylaliphatic androsta-1,4-diene-3,17-dione steroids

A series of 2-phenylaliphatic-substituted androsta-1,4-diene-3,17-diones (6) as well as their androstenedione derivatives (5) were synthesized as aromatase inhibitors to gain insights of structure–activity relationships of varying the alkyl moiety (C₁ to C₄) of the 2-phenylaliphatic substituents as well as introducing a methyl- or trifluoromethyl function to p-position of a phenethyl moiety to the inhibitory activity. The inhibitors examined showed a competitive type inhibition. The 2-phenpropylandrosta-1,4-diene 6c was the most powerful inhibitor (K_i: 16.1 nM) among them. Compounds 6c along with the phenethyl derivative 6b caused a time-dependent inactivation of aromatase (k_inact: 0.0293 and 0.0454 min^?1 for 6b and 6c, respectively). The inactivation was prevented by the substrate androstenedione, and no significant effect of l-cysteine on the inactivation was observed in each case. Molecular docking of the phenpropyl compound 6c to aromatase was conducted to demonstrate that the phenpropyl group orients to a hydrophobic binding pocket in the active site to result in the formation of thermodynamically stable enzyme–inhibitor complex.     

3-Aryl/Heteroaryl-5-amino-1-(3′,4′,5′-trimethoxybenzoyl)-1,2,4-triazoles as antimicrotubule agents. Design,synthesis, antiproliferative activity and inhibition of tubulin polymerization

Many natural and synthetic substances are known to interfere with the dynamic assembly of tubulin, preventing the formation of microtubules. In our search for potent and selective antitumor agents, a novel series of 1-(3′,4′,5′-trimethoxybenzoyl)-5-amino-1,2,4-triazoles were synthesized. The compounds had different heterocycles, including thiophene, furan or the three isomeric pyridines, and they possessed a phenyl ring bearing electron-releasing or electron-withdrawing substituents at the 3-position of the 5-amino-1,2,4-triazole system. Most of the twenty-two tested compounds showed moderate to potent antiproliferative activities against a panel of solid tumor and leukemic cell lines, with four (5j, 5k, 5o and 5p) showing strong antiproliferative activity (IC₅₀ < 1 μM) against selected cancer cells. Among them, several molecules preferentially inhibited the proliferation of leukemic cell lines, showing IC₅₀ values 2-100-fold lower for Jurkat and RS4;11 cells than those for the three lines derived from solid tumors (HeLa, HT-29 and MCF-7 cells). Compound 5k strongly inhibited tubulin assembly, with an IC₅₀ value of 0.66 μM, half that obtained in simultaneous experiments with CA-4 (IC₅₀ = 1.3 μM).     

Discovery of N-methyl-4-(4-methoxyanilino)quinazolines as potent apoptosis inducers. Structure–activity relationship of the quinazoline ring

As a continuation of our efforts to discover and develop apoptosis inducing N-methyl-4-(4-methoxyanilino)quinazolines as novel anticancer agents, we explored substitution at the 5-, 6-, 7-positions of the quinazoline and replacement of the quinazoline by other nitrogen-containing heterocycles. A small group at the 5-position was found to be well tolerated. At the 6-position a small group like an amino was preferred. Substitution at the 7-position was tolerated much less than at the 6-position. Replacing the carbon at the 8-position or both the 5- and 8-positions with nitrogen led to about 10-fold reductions in potency. Replacement of the quinazoline ring with a quinoline, a benzo[d][1,2,3]triazine, or an isoquinoline ring showed that the nitrogen at the 1-position is important for activity, while the carbon at the 2-position can be replaced by a nitrogen and the nitrogen at the 3-position can be replaced by a carbon. Through the SAR study, several 5- or 6-substituted analogs, such as 2a and 2c, were found to have potencies approaching that of lead compound N-(4-methoxyphenyl)-N,2-dimethylquinazolin-4-amine (1g, EP128495, MPC-6827, Azixa®).     

Antibacterial and antioxidant activities of flavonoids from Lannea alata (Engl.) Engl. (Anacardiaceae)

Two new prenylated flavonoids, lanneaflavonol (1) and dihydrolanneaflavonol (2) together with the known compounds myricetin-3-O-α-rhamnopyranoside (myricitrin) (3) and myricetin-3-O-α-arabinofuranoside (betmidin) (4), lupeol (5) and sitosterol (6) were isolated from the roots of Lannea alata. Compounds 1–4 exhibited good antibacterial and radical scavenging activity with the glycosides 3 and 4 showing better antioxidant activity than the aglycones 1 and 2 and myricetin-3-O-α-arabinofuranoside (4) showing the best antimicrobial activity followed by the aglycones 1 and 2. Betmidin (4) with an arabinose moiety at the 3-O-position showed the best antibacterial activity against Gram-positive bacteria, followed by the prenylated dihydroflavonol (2), whilst the prenylated linear flavonol (1) showed limited activity against Gram-negative bacteria. The arabinofuranoside (4) followed by the rhamnopyranoside (3) showed the best antioxidant activity comparable to that of ascorbic acid. The biological activities justify the ethnomedicinal uses of the plant in the management of diseases associated with Gram-positive bacteria, such as being used to treat injuries and wounds.     

Design,synthesis and biological activity evaluation of novel 2,6-difluorobenzamide derivatives through FtsZ inhibition

Novel series of 3-substituted 2,6-difluorobenzamide derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their in vitro antibacterial activity against various phenotype of Gram-positive and Gram-negative bacteria, and their cell division inhibitory activity against three representative strains. As a result, 3-chloroalkoxy derivative 7, 3-bromoalkoxy derivative 12 and 3-alkyloxy derivative 17 were found to exhibit the best antibacterial activity against Bacillus subtilis with MICs of 0.25–1 μg/mL, and good activity (MIC < 10 μg/mL) against both susceptible and resistant Staphylococcus aureus. Additionally, all the three compounds displayed potent cell division inhibitory activity with MIC values of below 1 μg/mL against Bacillus subtilis and Staphylococcus aureus.     

Ultrasonication-ionic liquid synergy for the synthesis of new potent anti-tuberculosis 1,2,4-triazol-1-yl-pyrazole based spirooxindolopyrrolizidines

The aim of the study is to design and synthesis of a new series of potent anti-TB 1,2,4-triazol-1-yl-pyrazole based spirooxindolopyrrolizidines with their safety profile. A synergetic effect of ultrasonication and ionic liquid was shown successfully as a green methodology for the synthesis of title compounds 6a–t. These derivatives were obtained in shorter reaction time with good yields and well characterized by various spectroscopic methods, single-crystal X-ray diffraction (6f). The in vitro anti-tuberculosis activity for newly-synthesized derivatives has been screened against Mycobacterium tuberculosis. Among all, six compounds 6e, 6k, 6l, 6n, 6q and 6r exhibited equal potent activity compared to standard drug ethambutol (MIC: 1.56 µg/mL) and another compound 6h exhibited outstanding activity (MIC: 0.78 µg/mL) than the standard drug ethambutol. Cytotoxic nature of the anti-TB active compounds was evaluated against RAW 264.7 cells. The 6h, 6e, 6k, 6l, 6n, 6q and 6r exhibited lower toxicity which could be promising hits for anti-tuberculosis.     

Synthesis and biological evaluation of rhodanine derivatives bearing a quinoline moiety as potent antimicrobial agents

Three series of rhodanine derivatives bearing a quinoline moiety (6a–h, 7a–g, and 8a–e) have been synthesized, characterized, and evaluated as antibacterial agents. The majority of these compounds showed potent antibacterial activities against several different strains of Gram-positive bacteria, including multidrug-resistant clinical isolates. Of the compounds tested, 6g and 8c were identified as the most effective with minimum inhibitory concentration (MIC) values of 1 μg/mL against multidrug-resistant Gram-positive organisms, including methicillin-resistant and quinolone-resistant Staphylococcus aureus (MRSA and QRSA, respectively). None of the compounds exhibited any activity against the Gram-negative bacteria Escherichia coli 1356 at 64 μg/mL. The cytotoxic activity assay showed that compounds 6g, 7g and 8e exhibited in vitro antibacterial activity at non-cytotoxic concentrations. Thus, these studies suggest that rhodanine derivatives bearing a quinoline moiety are interesting scaffolds for the development of novel Gram-positive antibacterial agents.