Synthesis and antiviral evaluation of novel 1,3,4-oxadiazole/thiadiazole-chalcone conjugates

A series of novel 1,3,4-oxadiazole/thiadiazole–chalcone conjugates were synthesized and their in vitro and in vivo antiviral activities were evaluated via microscale thermophoresis method and half-leaf method, respectively. The in vitro results indicated that compounds 7g, 7l, 8h, and 8l displayed good antiviral activity against TMV, with the binding constant values of 5.93, 6.15, 6.02, and 5.04 μM, respectively, which were comparable to that of Ninnanmycin (6.78 μM) and even better than that of Ribavirin (99.25 μM). The in vivo results demonstrated that compounds 7g, 7l, 8h, and 8l exhibited remarkable anti-TMV activity with the EC₅₀ values of 33.66, 33.97, 33.87 and 30.57 µg/mL, respectively, which were comparable to that of Ningnanmycin (36.85 µg/mL) and superior to that of Ribavirin (88.52 µg/mL). Interestingly, the trend of antiviral activity in vivo was consistent with the in vitro results.     

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 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.     

Sulfonamide-based non-alkyne LpxC inhibitors as Gram-negative antibacterial agents

We attempted to optimize sulfonamide-based non-alkyne LpxC inhibitors by focusing on improvements in enzyme inhibitory and antibacterial activity. It was discovered that inhibitors possessing 2-aryl benzofuran as a hydrophobe exhibited good activity. In particular, compound 21 displayed impressive antibacterial activity (E. coli MIC = 0.063 μg/mL, K. pneumoniae MIC = 0.5 μg/mL, and P. aeruginosa MIC = 0.5 μg/mL), and is a promising lead for further exploration as an antibacterial agent.     

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.     

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.     

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).     

Broad spectrum anti-infective properties of benzisothiazolones and the parallels in their anti-bacterial and anti-fungal effects

Various mono- and bis-benzisothiazolone derivatives were synthesized and screened against different strains of bacteria and fungi in order to understand the effect of multiple electrophilic sulfur atoms and substitution pattern in the immediate vicinity of reactive sulfur. Staphyllococcus aureus-ATCC 7000699, MRSA and S. aureus-ATCC 29213 (Quality Control strain) were more susceptible to this class of compounds, and the most potent derivative 1.15 had MIC₅₀ of 0.4 μg/mL (cf. Gentamicin = 0.78 μg/mL). CLogP value, optimally in the range of 2.5–3.5, appeared to contribute more to the activity than the steric and electronic effects of groups attached at nitrogen. By and large, their anti-fungal activities also followed a similar trend with respect to the structure and CLogP values. The best potency of IC₅₀ = 0.1 μg/mL was shown by N-benzyl derivative (1.7) against Aspergillus fumigatus; it was also potent against Candida albicans, Cryptococcus neoformans, Sporothrix schenckii, and Candida parapsilosis with IC₅₀ values ranging from 0.4 to 1.3 μg/mL. Preliminary studies also showed that this class of compounds have the ability to target malaria parasite with IC₅₀ values in low micromolar range, and improvement of selectivity is possible through structure optimization.     

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.     

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).     

Design,synthesis and in vitro cytotoxicity studies of novel β-carbolinium bromides

A series of novel β-carbolinium bromides has been synthesized from easily accessible β-carbolines and 1-aryl-2-bromoethanones. The newly synthesized compounds were evaluated for their in vitro anticancer activity. Among the synthesized derivatives, compounds 16l, 16o and 16s exhibited potent anticancer activity with IC₅₀ values of <10 μM against tested cancer cell lines. The most potent analogue 16l was broadly active against all the tested cancer cell lines (IC₅₀ = 3.16–7.93 μM). In order to test the mechanism of cell death, we exposed castration resistant prostate cancer cell line (C4-2) to compounds 16l and 16s, which resulted in increased levels of cleaved PARP1 and AO/EB staining, indicating that β-carbolinium salts induce apoptosis in these cells. Additionally, the most potent β-carbolines 16l and 16s were found to inhibit tubulin polymerization.     

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.     

Synthesis,anticancer, and docking studies of salicyl-hydrazone analogues: A novel series of small potent tropomyosin receptor kinase A inhibitors

A series of novel salicyl-hydrazone analogues were synthesized and evaluated for their in vitro cytotoxic activities in five human cancer cell lines, namely, lung cancer (A549), ovarian cancer (SK-OV-3), skin cancer (SK-MEL-2), colon cancer (HCT15) and pancreatic cancer (MIA-PaCa-2) cells, and for their in vitro tropomyosin receptor kinase A (TrkA) inhibitory activities. Each of the compounds showed significant cytotoxicity against all cancer cells. Compound 3i was found to be most potent against all cancer cell lines with IC₅₀ values of 2.46 (A549), 0.87 (SK-OV-3), 1.43 (SK-MEL-2), 0.89 (HCT15), and 0.48 μM (MIA-PaCa-2), followed by compound 3l. Cytotoxicity of 3i was similar to that of doxorubicin (0.87 μM) against HCT15 cells. Compounds 3i and 3l also showed highest TrkA inhibitory activities with IC₅₀ values of 0.231 and 0.380 μM, respectively. A SAR study of the series revealed that compounds with hydroxyl groups showed better cytotoxicity and TrkA inhibitory potency (in the following order 2,4-OH > 2,3,4-OH > 3,4-OH > 4-OH) than compounds possessing electron donating or withdrawing groups on the benzylidenephenyl ring. Docking studies of compounds 3i and 3l conducted on the crystal structure of TrkA receptor (a promising target for anticancer agents) showed both had a high docking score and similar order of experimental TrkA inhibitory activities. The formation of several hydrogen bonds involving N and O containing moieties contributed most significantly to ligand binding and stabilization at the active site of the receptor. In addition, ligand-receptor complexes were further stabilized by π-cation, π-anion, amide-π stacked, and van der Waal’s interactions. Conformational analyses showed ligand molecules adopted similar conformations at the receptor active site during interactions, but that the low energy optimized conformations of compounds 3i and 3l differed.     

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.     

Synthesis and antibacterial activity of benzyl-[3-(benzylamino-methyl)-cyclohexylmethyl]-amine derivatives

A series of benzyl-[3-(benzylamino-methyl)-cyclohexylmethyl]-amine derivatives with different substitution pattern on the aromatic ring have been prepared and evaluated for their antibacterial activity against Gram-positive and Gram-negative bacterial strains. Most of the compounds exhibit potent activity against Pseudomonas aeruginosa and Staphylococcus epidermidis while compounds 6l and 6m showed antibacterial activity against all the four bacterial strains with MIC values ranging from 0.002 to 0.016 μg/mL and no hemolytic activity up to 512 μg/mL in mammalian erythrocytes was observed.     

Activity of caffeic acid derivatives against Candida albicans biofilm

The aim of this study was to evaluate the caffeic acid (1) and ester derivatives (2–10) against Candida albicans biofilm and to investigate whether these compounds are able to inhibit the biofilm formation or destroy pre-formed biofilm.Caffeic acid ester 7, cinnamic acid ester 8 and 3,4-dihydroxybenzoic acid ester 10 are more active than fluconazole, used as reference drug, both on biofilm in formation with MIC₅₀ values of 32, 32 and 16 μg/mL, respectively, and in the early stage of biofilm formation (4 h) with MIC₅₀ values of 64, 32 and 64 μg/mL, respectively. These esters result also more active than fluconazole on mature biofilm (24 h), especially 8 and 10 with MIC₅₀ values of 64 μg/mL.     

Anti-tubercular agents. Part 8: Synthesis,antibacterial and antitubercular activity of 5-nitrofuran based 1,2,3-triazoles

A series of 5-nitrofuran–triazole conjugates were synthesized and evaluated for their antimicrobial activity against both Gram-positive and Gram-negative bacterial strains. All the compounds exhibited promising inhibition towards Gram-positive pathogenic strains, while mild inhibitory effects were observed towards Gram-negative bacterial strains. Some of the compounds 8a, 8b, 8e, 8f, 8h are most active among the series exhibiting MIC value of 1.17 μg/ml against different bacterial strains. The bactericidal activity is found to be in accordance with the bacterial growth inhibition data. Compound 8e was found to be equipotent to the standard drug Ciprofloxacin displaying MBC value of 1.17 μg/ml against the bacterial strain Bacillus subtilis. The compounds have also demonstrated promising antibacterial activity against the resistant strain MRSA and were found to be effective inhibitors of biofilm formation. The compound 8b exhibited excellent anti-biofilm activity with IC₅₀ value as low as 0.8 μg/ml. These conjugates were also screened for antitubercular activity against Mycobacterium tuberculosis H₃₇Rv strain. Compound 8e showed promising antitubercular activity with MIC value of 0.25 μg/ml. Most of these compounds are less toxic to normal mammalian cells than the widely used antibacterial drug Ciprofloxacin.     

Syntheses of benzophenone-xanthone hybrid polyketides and their antibacterial activities

Muchimangins are benzophenone-xanthone hybrid polyketides produced by Securidaca longepedunculata. However, their biological activities have not been fully investigated, since they are minor constituents in this plant. To evaluate the possibility of muchimangins as antibacterial agent candidates, five muchimangin analogs were synthesized from 2,4,5-trimethoxydiphenyl methanol and the corresponding xanthones, by utilizing p-toluenesulfonic acid monohydrate for the Brønsted acid-catalysis. The antibacterial assays against Gram-positive bacteria, Staphylococcus aureus and Bacillus subtilis, and Gram-negative bacteria, Klebsiella pneumoniae and Escherichia coli, revealed that the muchimangin analogs (±)-1,3,6,8-tetrahydroxy-4-(phenyl-(2′,4′,5′-trimethoxyphenyl)methyl)-xanthone (1), (±)-1,3,6-trihydroxy-4-(phenyl-(2′,4′,5′-trimethoxyphenyl)methyl)-xanthone (2), and (±)-1,3-dihydroxy-4-(phenyl-(2′,4′,5′-trimethoxyphenyl)methyl)-xanthone (3) showed significant activities against S. aureus, with MIC values of 10.0, 10.0, and 25.0 μM, respectively. Analogs (±)-1 and (±)-2 also exhibited antibacterial activities against B. subtilis, with MIC values of 50.0 and 12.5 μM, respectively. Furthermore, (+)-3 enhanced the antibacterial activity against S. aureus, with a MIC value of 10 μM.     

Synthesis of new morpholine-connected pyrazolidine derivatives and their antimicrobial,antioxidant, and cytotoxic activities

A simple and convenient one-pot four-component synthesis of morpholine-connected pyrazolidine derivatives 2a–f and 4a–f was developed using direct metal-free catalysis, with the identities of the synthesized compounds confirmed by IR, NMR (¹H and ¹³C), mass spectrometry, and elemental analysis. The prepared compounds were inspected for antimicrobial, antioxidant, and cytotoxic activities.Antimicrobial and antifungal activities against five bacterial and four fungal pathogens, respectively, were investigated using the disc diffusion technique. In antibacterial activity, compounds 2d and 2f (MIC = 2 μg/mL) exhibited significantly higher activity than the standard ciprofloxacin. The results of antifungal assay showed that the activity of compound 4a (MIC = 0.5 μg/mL) was significantly higher than the standard clotrimazole. Antioxidant activity was screened based on ABTS⁺ radical scavenging and linoleic acid peroxidation performance. Compound 4a showed substantial antioxidant (91.3%) activities, as compared with the Trolox standard. Cytotoxicity was evaluated using HepG2 (liver), HeLa (cervical), and MCF-7 (breast) cancer cell lines, with high toxicities observed for 2b (GI₅₀ = 12.2 μm) and 4a (GI₅₀ = 07.8 μm).     

Novel α,β-unsaturated amide derivatives bearing α-amino phosphonate moiety as potential antiviral agents

Based on flexible construction and broad bioactivity of ferulic acid, a series of novel α,β-unsaturated amide derivatives bearing α-aminophosphonate moiety were designed, synthesized and systematically evaluated for their antiviral activity. Bioassay results indicated that some compounds exhibited good antiviral activities against cucumber mosaic virus (CMV) and tobacco mosaic virus (TMV) in vivo. Especially, compound g18 showed excellent curative and protective activities against CMV, with half-maximal effective concentration (EC₅₀) values of 284.67 μg/mL and 216.30 μg/mL, which were obviously superior to that of Ningnanmycin (352.08 μg/mL and 262.53 μg/mL). Preliminary structure-activity relationships (SARs) analysis revealed that the introduction of electron-withdrawing group at the 2-position or 4-position of the aromatic ring is favorable for antiviral activity. Present work provides a promising template for development of potential inhibitor of plant virus.