Antibacterial profiling of abietane-type diterpenoids

Abietic and dehydroabietic acid are interesting diterpenes with a highly diverse repertoire of associated bioactivities. They have, among others, shown antibacterial and antifungal activity, potentially valuable in the struggle against the increasing antimicrobial resistance and imminent antibiotic shortage. In this paper, we describe the synthesis of a set of 9 abietic and dehydroabietic acid derivatives containing amino acid side chains and their in vitro antimicrobial profiling against a panel of human pathogenic microbial strains. Furthermore, their in vitro cytotoxicity against mammalian cells was evaluated. The experimental results showed that the most promising compound was 10 [methyl N-(abiet-8,11,13-trien-18-yl)-d-serinate], with an MIC₉₀ of 60 μg/mL against Staphylococcus aureus ATCC 25923, and 8 μg/mL against methicillin-resistant S. aureus, Staphylococcus epidermidis and Streptococcus mitis. The IC₅₀ value for compound 10 against Balb/c 3T3 cells was 45 μg/mL.     

Novel 3-fluoro-6-methoxyquinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV

Novel (non-fluoroquinolone) inhibitors of bacterial type II topoisomerases (NBTIs) are an emerging class of antibacterial agents. We report an optimized series of cyclobutylaryl-substituted NBTIs. Compound 14 demonstrated excellent activity both in vitro (S. aureus MIC₉₀ = 0.125 μg/mL) and in vivo (systemic and tissue infections). Enhanced inhibition of Topoisomerase IV correlated with improved activity in S. aureus strains with mutations conferring resistance to NBTIs. Compound 14 also displayed an improved hERG IC₅₀ of 85.9 μM and a favorable profile in the anesthetized guinea pig model.     

Antileishmanial evaluation of clubbed bis(indolyl)-pyridine derivatives: One-pot synthesis,in vitro biological evaluations and in silico ADME prediction

A new series of bis(indolyl)-pyridine derivatives 6(a–m) were synthesized by Chichibabin reaction process and evaluated for antileishmanial and antibacterial activities to establish structure–activity relationship. The synthesis was carried out through one-pot multicomponent reaction of 3-acetylindole, aromatic aldehydes, and ammonium acetate in the presence of camphor-10-sulfonic acid as a catalyst. The compounds 6d (IC₅₀ = 102.47 μM) and 6f (IC₅₀ = 99.49 μM) had shown promising antileishmanial against L. donovani promastigotes when compared with standard sodium stibogluconate (IC₅₀ = 490.00 μM). All the synthesized compounds (MIC range = 41.35–228.69 μg/mL) had shown potent antibacterial activity than standard ampicillin (MIC range = 100.00–250.00 μg/mL) against all the tested bacterial strains. In silico ADME and metabolic site prediction studies were also held out to set an effective lead candidate for the future antileishmanial and antibacterial drug discovery initiatives.     

Design,synthesis, and bioactivities of novel oxadiazole-substituted pyrazole oximes

A series of novel pyrazole oxime derivatives containing a substituted oxadiazole group were designed and synthesized. The bioassay results indicated that some title compounds displayed good acaricidal and insecticidal activities against Tetranychus cinnabarinus, Aphis medicaginis, Oriental armyworm, and Nilaparvata lugens. Especially, compounds 7a, 7b, and 7c had 80%, 90%, and 90% insecticidal activities against A. medicaginis at 20 μg/mL, respectively. Interestingly, some of the designed compounds displayed wonderful fungicidal activities in vivo against cucumber Pseudoperonospora cubensis. Furthermore, compounds 7a (EC₅₀ = 4.97 μg/mL) and 7h (EC₅₀ = 0.51 μg/mL) showed excellent fungicidal activity against P. cubensis comparable or better than that of the control Pyraclostrobin (EC₅₀ = 4.59 μg/mL).     

Design,synthesis and in vitro anti-mycobacterial evaluation of gatifloxacin-1H-1,2,3-triazole-isatin hybrids

A set of novel gatifloxacin-1H-1,2,3-triazole-isatin hybrids 6a-l was designed, synthesized and evaluated for their in vitro anti-mycobacterial activities against M. tuberculosis (MTB) H₃₇Rv and MDR-TB as well as cytotoxicity. The results showed that all the targets (MIC: 0.025–3.12 μg/mL) exhibited excellent inhibitory activity against MTB H₃₇Rv and MDR-TB, but were much more toxic (CC₅₀: 7.8–62.5 μg/mL) than the parent gatifloxacin (GTFX) (CC₅₀: 125 μg/mL). Among them, 61 (MIC: 0.025 μg/mL) was 2–32 times more potent in vitro than the references INH (MIC: 0.05 μg/mL), GTFX (MIC: 0.78 μg/mL) and RIF (MIC: 0.39 μg/mL) against MTB H₃₇Rv. The most active conjugate 6 k (MIC: 0.06 μg/mL) was 16–>2048 times more potent than the three references (MIC: 1.0–>128 μg/mL) against MDR-TB. Both of the two hybrids warrant further investigations.     

Discovery of (R)-5-(benzo[d][1,3]dioxol-5-yl)-7-((1-(vinylsulfonyl)pyrrolidin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (B6) as a potent Bmx inhibitor for the treatment of NSCLC

Described as a Btk inhibitor, ibrutinib also potently inhibits Bmx and EGFR, two good targets for lung cancer. Owing to its high CLogP (4.07) and low aqueous solubility (<0.01 mg/ml), resulting in unfavorable bioavailability, ibrutinib requires high dosages to achieve good clinical response in the treatment of non-small cell lung cancer (NSCLC). In our effort to improve the CLogP of ibrutinib by structural optimization led to the discovery of a potent anti-cancer agent B6, with beneficial physicochemical parameters (CLogP = 2.56, solubility in water ≈ 0.1 mg/ml) meeting the principles of oral drugs. B6 exhibited anti-proliferation activities against EGFR-expressing cells, especially the mutant ones, such as H1975 (L858R/T790M, IC₅₀ = 0.92 ± 0.19 μM) and HCC827 (Del119 IC₅₀ = 0.014 ± 0.01 μM). Moreover, B6 significantly slowed down H1975 tumor growth with anti-tumor rate of 73.9% (p < 0.01). Enzyme potencies assay demonstrated B6 moderately selectively inhibited Bmx (IC₅₀ = 35.7 ± 0.1 nM) over other kinases. So, as a potent Bmx inhibitor, B6 has the potential to be an efficacious treatment for NSCLC with acquired drug resistance.     

Aspernolides F and G,new butyrolactones from the endophytic fungus Aspergillus terreus

Two new butyrolactones: aspernolides F (6) and G (7), together with three stigmasterol derivatives: (22E,24R)-stigmasta-5,7,22-trien-3-β-ol (1), stigmast-4-ene-3-one (2), and stigmasta-4,6,8(14), 22-tetraen-3-one (3), two meroterpenoids: terretonin A (4) and terretonin (5), and a butyrolactone derivative: butyrolactone VI (8) have been isolated from the endophytic fungus Aspergillus terreus isolated from the roots of Carthamus lanatus (Asteraceae). Their structures were determined by spectroscopic means (1D, 2D NMR, and HRESIMS), as well as optical rotation measurement and comparison with literature data. The isolated compounds were evaluated for their anti-microbial, anti-malarial, anti-leishmanial, and cytotoxic activities. Compound 1 displayed a potent activity against MRSA and C. neoformans with IC₅₀ values of 0.96 μg/mL and 4.38 μg/mL, respectively compared to ciprofloxacin (IC₅₀ 0.07 μg/mL) and amphotericin B (IC₅₀ 0.34 μg/mL), respectively. While, 6 showed good activity against C. neoformans (IC₅₀ 5.19 μg/mL) and mild activity against MRSA (IC₅₀ 6.39 μg/mL). Moreover, 1 and 2 exhibited very good anti-leishmanial activity towards L. donovani with IC₅₀ values of 4.61 and 6.31 μg/mL, respectively and IC₉₀ values of 6.02 and 16.71 μg/mL, respectively.     

Anti-diabetic xanthones from the bark of Garcinia xanthochymus

An ethyl acetate extract the bark of Garcinia xanthochymus exhibited strong inhibition towards α-glucosidase and PTP1B with IC₅₀ values of 0.3 ± 0.1 μg/mL and 2.3 ± 0.4 μg/mL, respectively. Chemical constituents of the extract were therefore examined, and two new compounds, xanthochymusxanthones A (1) and B (2), along with ten known xanthones (3–12), were isolated. Their structures were determined using spectroscopic methods, mainly 1D and 2D NMR. Inhibitory activity of the isolated compounds was then tested, and subelliptenone F (12) showed significant effect towards α-glucosidase with IC₅₀ value of 4.1 ± 0.3 μM (compared with acarbose, IC₅₀ = 900.0 ± 3.0 μM) whilst xanthochymusxanthone B (2) exhibited remarkable activity towards PTP1B with IC₅₀ value of 8.0 ± 0.6 μM (compared with RK682, IC₅₀ = 4.4 ± 0.3 μM).     

3-Aryl-4-acyloxyethoxyfuran-2(5H)-ones as inhibitors of tyrosyl-tRNA synthetase: Synthesis,molecular docking and antibacterial evaluation

Thirty-eight 3-aryl-4-acyloxyethoxyfuran-2(5H)-ones were designed, prepared and tested for antibacterial activities. Some of them showed significant antibacterial activity against Gram-positive organism, Gram-negative organism and fungus. Out of these compounds, 4-(2-(3-chlorophenylformyloxy)ethoxy)-3-(4-chlorophenyl)furan-2(5H)-one (d40) showed the widest spectrum of activity with MIC₅₀ of 2.0 μg/mL against Staphylococcus aureus, 4.3 μg/mL against Escherichia coli, 1.5 μg/mL against Pseudomonas aeruginosa and 1.2 μg/mL against Candida albicans. Our data disclosed that MIC₅₀ values against whole cell bacteria are positive correlation with MIC₅₀ values against tyrosyl-tRNA synthetase. Meanwhile, molecular docking of d40 into S. aureus tyrosyl-tRNA synthetase active site was also performed, and the inhibitor tightly fitting the active site might be an important reason why it has high antimicrobial activity.     

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.     

Biological activities of plant extracts from Ficus elastica and Selaginella vogelli: An antimalarial,antitrypanosomal and cytotoxity evaluation

The cytotoxic, antiplasmodial, and antitrypanosomal activities of two medicinal plants traditionally used in Cameroon were evaluated. Wood of Ficus elastica Roxb. ex Hornem. aerial roots (Moraceae) and Selaginella vogelii Spring (Selaginellaceae) leaves were collected from two different sites in Cameroon. In vitro cell-growth inhibition activities were assessed on methanol extract of plant materials against Plasmodium falciparum strain 3D7 and Trypanosoma brucei brucei, as well as against HeLa human cervical carcinoma cells. Criteria for activity were an IC₅₀ value < 10 μg/mL. The extract of S. vogelii did not significantly reduce the viability of P. falciparum at a concentration of 25 μg/mL but dramatically affected the trypanosome growth with an IC₅₀ of 2.4 μg/mL. In contrast, at the same concentration, the extract of F. elastica exhibited plasmodiacidal activity (IC₅₀ value of 9.5 μg/mL) and trypanocidal (IC₅₀ value of 0.9 μg/mL) activity. Both extracts presented low cytotoxic effects on HeLa cancer cell line. These results indicate that the selected medicinal plants could be further investigated for identifying compounds that may be responsible for the observed activities and that may represent new leads in parasitical drug discovery.     

New nemadectin congeners with acaricidal and nematocidal activity from Streptomyces microflavus neau3 Y-3

Two nemadectin congeners 1 and 2 were isolated from the fermentation broth of a mutant strain (Y-3) of Streptomyces microflavus neau3. Their structures were determined on the basis of extensive spectroscopic analysis and comparison with data from the literature. Compound 2 possessed a 5-membered ring lactone that is unprecedented among known milbemycins and avermectins. Both compounds 1 and 2 exhibited potent acaricidal activity and nematocidal activity. Especially, compound 2 demonstrated impressive acaricidal activity against adult mites with an IC₅₀ of 2.3 ± 0.9 μg/mL and mite eggs with an IC₅₀ of 17.5 ± 2.1 μg/mL and nematocidal activity against Caenorhabditis elegans with an IC₅₀ of 0.7 ± 0.2 μg/mL, which are higher than those of nemadectin and the known commercial acaricide and nematocide milbemycin A3/A4.     

New antiprotozoal agents: Synthesis and biological evaluation of different 4-(7-chloroquinolin-4-yl) piperazin-1-yl)pyrrolidin-2-yl)methanone derivatives

In an endeavor to develop efficacious antiprotozoal agents 4-(7-chloroquinolin-4-yl) piperazin-1-yl)pyrrolidin-2-yl)methanone derivatives (5–14) were synthesized, characterized and biologically evaluated for antiprotozoal activity. The compounds were screened in vitro against the HM1: IMSS strain of Entamoeba histolytica and NF54 chloroquine-sensitive strain of Plasmodium falciparum. Among the synthesized compounds six exhibited promising antiamoebic activity with IC₅₀ values (0.14–1.26 μM) lower than the standard drug metronidazole (IC₅₀ 1.80 μM). All nine compounds exhibited antimalarial activity (IC₅₀ range: 1.42–19.62 μM), while maintaining a favorable safety profile to host red blood cells. All the compounds were less effective as an antimalarial and more toxic (IC₅₀ range: 14.67–81.24 μM) than quinine (IC₅₀: 275.6 ± 16.46 μM) against the human kidney epithelial cells. None of the compounds exhibited any inhibitory effect on the viability of Anopheles arabiensis mosquito larvae.     

Synthesis and QSAR study of novel α-methylene-γ-butyrolactone derivatives as antifungal agents

Thirty-six new α-benzylidene-γ-lactone compounds based α-methylene-γ-butyrolactone substructure were prepared and characterized by spectroscopic analysis. All compounds were evaluated for antifungal activities in vitro against six plant pathogenic fungi and the half maximal inhibitory concentration (IC₅₀) against Botrytis cinerea and Colletotrichum lagenarium were investigated. Compounds 5c-3 and 5c-5 with the halogen atom exhibited excellent fungicidal activity against B. cinerea (IC₅₀ = 22.91, 18.89 μM). The structure-activity relationships (SARs) analysis indicated that the derivatives with electron-withdrawing substituents at the meta- or para-positions improves the activity. Via the heuristic method, the generated quantitative structure-activity relationship (QSAR) model (R² = 0.961) revealed a strong correlation of antifungal activity against B. cinerea with molecular structures of these compounds. Meanwhile, the cytotoxicity of 20 representative derivatives was tested in the human tumor cells line (HepG2) and the hepatic L02 cells line, the result indicated that the synthesized compounds showed significant inhibitory activity and limited selectivity. Compound 5c-5 has the highest fungicidal activity with IC₅₀ = 18.89 μM (against B. cinerea.) but low cytotoxicity with IC₅₀ = 35.4 μM (against HepG2 cell line) and IC₅₀ = 68.8 μM (against Hepatic L02 cell line). These encouraging results can be providing an alternative, promising use of α-benzylidene-γ-lactone through the design and exploration of eco-friendly fungicides with low toxicity and high efficiency.     

Synthesis,structure and antibacterial activity of new 2-(1-(2-(substituted-phenyl)-5-methyloxazol-4-yl)-3-(2-substitued-phenyl)-4,5-dihydro-1H-pyrazol-5-yl)-7-substitued-1,2,3,4-tetrahydroisoquinoline derivatives

A series of new 2-(1-(2-(substituted-phenyl)-5-methyloxazol-4-yl)-3-(2-substitued-phenyl)-4,5-dihydro-1H-pyrazol-5-yl)-7-substitued-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized. The results showed that compounds 9q and 10q can strongly inhibit Staphylococcus aureus DNA gyrase and Bacillus subtilis DNA gyrase (with IC_50s of 0.125 and 0.25 μg/mL against S. aureus DNA gyrase, 0.25 and 0.125 μg/mL against B. subtilis DNA gyrase). On the basis of the biological results, structure–activity relationships were also discussed.     

Preliminary SAR and biological evaluation of antitubercular triazolothiadiazine derivatives against drug-susceptible and drug-resistant Mtb strains

Following up the SAR study of triazolothiadiazoles for their antitubercular activities targeting Mt SD in our previous study, on the principle of scaffold hopping, the C3 and C6 positions of triazolothiadiazine were examined systematically to define a preliminary structure–activity relationship (SAR) with respect to biological activity. This study herein highlights the potential of two highly potent advanced leads 6c-3, 6g-3 and several other compounds with comparable potencies as promising new candidates for the treatment of TB (6c-3, MIC-H37Rv = 0.25 μg/mL; MIC-MDRTB = 2.0 μg/mL; MIC-RDRTB = 0.25 μg/mL; Mt SD-IC₅₀ = 86.39 μg/mL; and 6g-3, MIC-H37Rv = 1.0 μg/mL; MIC-MDRTB = 4.0 μg/mL; MIC-RDRTB = 2.0 μg/mL; Mt SD-IC₅₀ = 73.57 μg/mL). Compounds 6c-3 and 6g-3 possessed a para-nitro phenyl at the 6 position showed low Vero and HepG2 cells toxicity, turning out to be two excellent lead candidates for preclinical trials. In addition, in vitro Mt SD inhibitory assay indicates that Mt SD is at least one of the targets for their antitubercular activity. Thus, they may turn out to be promising multidrug-resistance-reversing agents.     

Isolation,structure, and bioactivities of abiesadines A–Y, 25 new diterpenes from Abies georgei Orr

Twenty-five new (abiesadines A–Y, 1–25) and 29 known (26–54) diterpenes were isolated from the aerial parts of Abies georgei. Abiesadine A (1) is a novel 8,14-seco-abietane, while abiesadine B (2) is a novel 9,10-seco-abietane. The structures of the new compounds were established on the basis of spectroscopic data analysis. Manool (52) showed the strongest effect against LPS-induced NO production in RAW264.7 macrophages with the IC₅₀ value of 11.0 μg/mL. In another anti-inflammatory assay against TNFα-triggered NF-κB activity, (12R,13R)-8,12-epoxy-14-labden-13-ol (54) exhibited the strongest effect (IC₅₀ = 8.7 μg/mL). For antitumor assays, pomiferin A (26) and 8,11,13-abietatriene-7α,18-diol (29) both showed the most significant activity against LOVO cells (IC₅₀ = 9.2 μg/mL). While 7-oxocallitrisic acid (46) exhibited significant cytotoxicity against QGY-7703 tumor cells (IC₅₀ = 10.2 μg/mL).     

Constituents of Nelumbo nucifera leaves and their antimalarial and antifungal activity

From the leaves of Nelumbo nucifera (an aquatic plant), one new compound, 24(R)-ethylcholest-6-ene-5α-ol-3-O-β-d-glucopyranoside (1), along with 11 known metabolites (2–12), were isolated and identified by spectroscopic methods including 1D- and 2D NMR. Antifungal activity for (R)-roemerine (3) (IC₅₀/MIC = 4.5/10 μg/mL against Candida albicans) and antimalarial activity for (R)-roemerine (3) and N-methylasimilobine (5) (IC₅₀ = 0.2 and 4.8 μg/mL for the D6 clone, respectively, and 0.4 and 4.8 μg/mL for the W2 clone, respectively) was observed. None of the compounds were cytotoxic to Vero cells up to a concentration of 23.8 μg/mL. NMR data for 10-eicosanol (7) and 7,11,15-trimethyl-2-hexadecanone (10) are presented for the first time. An analysis of the structure–activity relationship shows that the substituents in position C-1 and C-2 of aporphine alkaloids are crucial for the antimalarial activity.     

Design and synthesis of new triazoles linked to xanthotoxin for potent and highly selective anti-gastric cancer agents

Two series of xanthotoxin-triazole derivatives were designed, synthesized, and studied for their antiproliferative properties. The in vitro cytotoxicity of the compounds in the AGS cancer cell line and the L02 normal cell line was evaluated via MTT assay. Among the synthesized compounds, 9-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-7H-furo[3,2-g]chromen-7-one (6p) was found to have the greatest antiproliferative activity against AGS cells (IC₅₀ = 7.5 μM) and showed better activity than the lead compound (xanthotoxin, IC₅₀ > 100 μM) and the reference drug (5-fluorouracil, IC₅₀ = 29.6 μM) did. The IC₅₀ value of 6p in L02 cells was 13.3 times higher than that in the AGS cells. Therefore, the compound exhibited better therapeutic activity and specificity compared with the positive control 5-fluorouracil. Cell cycle analysis revealed that compound 6p inhibited cell growth via the induction of S/G2 phase arrest in AGS cells. Compound 6p was identified as a promising lead compound for the further development and identification of 1,2,3-triazole-based anticancer agents.     

Synthesis and biological evaluation of novel thiadiazole amides as potent Cdc25B and PTP1B inhibitors

A series of novel thiadiazole amide derivatives have been synthesized and evaluated for inhibitory activities against Cdc25B and PTP1B. Most of them showed inhibitory activities against Cdc25B (IC₅₀ = 1.18–8.01 μg/mL) and PTP1B (IC₅₀ = 0.85–8.75 μg/mL), respectively. Moreover, compounds 5b and 4l were most potent with IC₅₀ values of 1.18 and 0.85 μg/mL for Cdc25B and PTP1B, respectively, compared with reference drugs Na₃VO₄ (IC₅₀ = 0.93 μg/mL) and oleanolic acid (IC₅₀ = 0.85 μg/mL). The results of selectivity experiments showed that the target compounds were selective inhibitors against PTP1B and Cdc25B. Enzyme kinetic experiments demonstrated that compound 5k was a specific inhibitor with the typical characteristics of a mixed inhibitor.