Novel pyrazole integrated 1,3,4-oxadiazoles: Synthesis,characterization and antimicrobial evaluation

A novel series of 2-(5-methyl-1,3-diphenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazoles 7(a–m) were synthesized either by cyclization of N′-benzoyl-5-methyl-1,3-diphenyl-1H-pyrazole-4-carbohydrazide 4a using POCl₃ at 120 °C or by oxidative cyclization of hydrazones derived from various arylaldehyde and (E)-N′-benzylidene-5-methyl-1,3-diphenyl-1H-pyrazole-4-carbohydrazide 5(a–d) using chloramine-T as oxidant. Newly synthesized compounds were characterized by analytical and spectral (IR, ¹H NMR, ¹³C NMR and LC–MS) methods. The synthesized compounds were evaluated for their antimicrobial activity and were compared with standard drugs. The compounds demonstrated potent to weak antimicrobial activity. Among the synthesized compounds, compound 7m emerged as an effective antimicrobial agent, while compounds 7d, 7f, 7i and 7l showed good to moderate activity. The minimum inhibitory concentration of the compounds was in the range of 20–50 μg mL⁻¹ against bacteria and 25–55 μg mL⁻¹ against fungi. The title compounds represent a novel class of potent antimicrobial agents.     

Steroidal saponins with cytotoxic activities from the rhizomes of Anemarrhena asphodeloids Bge.

Two new steroidal saponins, named timosaponin R (1) and S (2), together with seven known compounds (3-9) were isolated from the rhizomes of Anemarrhena asphodeloides Bge. Their structures were elucidated on the basis of NMR spectroscopy and mass spectrometry. All the compounds were evaluated for cytotoxic activities against the four human cancer cell lines MCF7, SW480, HepG2 and SGC7901 in vitro. Compounds 7-9 showed moderate activities against all the cell lines.     

Microwave assisted one pot synthesis of some novel 2,5-disubstituted 1,3,4-oxadiazoles as antifungal agents

Sodium bisulfite has been reported first time for the synthesis of 2,5-disubstituted 1,3,4-oxadiazole using microwave and conventional method in ethanol-water. The yields obtained are in the range of 90-95% using microwave and 87-91% using conventional method. All the synthesized compounds (8a-8s) are novel and were evaluated for their in vitro antifungal activity. SAR for the series has been developed by comparing their MIC values with miconazole and fluconazole. Some of the compounds from the series like 8k was equipotent with miconazole against Candida albicans and Fusarium oxysporum. Also compound 8n was equipotent with miconazole against F. oxysporum.     

Synthesis of fluorinated carbazoles via C–H arylation catalyzed by Pd/Cu bimetal system and their antibacterial activities

An effective intramolecular C–H arylation reaction catalyzed by a bimetallic catalytic system Pd(OAc)₂/CuI for the synthesis of fluorine-substituted carbazoles from corresponding N-phenyl-2-haloaniline derivatives under ligand free conditions is demonstrated. The established method is effective for both N-phenyl-2-bromoaniline and N-phenyl-2-chloroaniline, and requires the low loading of Pd(OAc)₂ (0.5 mol %). A series of new fluorinated carbazoles were synthesized in excellent yields using the protocol (>83%, 19 examples) and were fully characterized by ¹H, ¹³C and ¹⁹F NMR spectral data, HRMS and elemental analysis. All compounds were evaluated for their antibacterial activities against four bacteria (Bacillus subtilis, Staphylococcus aureus, Escherichia coli and methicillin-resistant S. aureus with resistance to gentamicin) by serial dilution technique. All tested compounds showed antibacterial activity against three test strains (S. aureus, B. subtilis and MRSA), and most of these compounds displayed pronounced antimicrobial activities against these three strains with low MIC values ranging from 0.39 to 6.25 μg/mL. Among them, compounds 7 and 14 exhibited potent inhibitory activity better than reference drugs meropenem and streptomycin. Three compounds (2, 4 and 5) showed antibacterial activity against E. coli. with MIC values from 12.5 to 25 μg/mL.     

Ecdysteroids from the flowers of Aerva javanica

Four new ecdysteroids (1–4), along with three known steroids, β-ecdysone (5), 5-β-2-deoxyintegristerone A (6) and 24-epi-makisterone A (7) (Fig. 1), were isolated from the methanolic extract of the flowers of Aerva javanica by using normal and reverse phase chromatography. The structures of the new compounds (1–4) were determined due to 1D (¹H and ¹³C), 2D NMR (HSQC, HMBC, COSY, NOESY) techniques and high resolution mass spectrometry (HREIMS). The known compounds (5–7) were characterized based on the 1D NMR spectroscopy and mass spectrometry and by comparison with the literature values. All isolates were evaluated for their inhibitory activities against enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and lipoxygenase (LOX).     

Design and synthesis of positional isomers of 5 and 6-bromo-1-[(phenyl)sulfonyl]-2-[(4-nitrophenoxy)methyl]-1H-benzimidazoles as possible antimicrobial and antitubercular agents

In this Letter, we report the structure–activity relationship (SAR) studies on series of positional isomers of 5(6)-bromo-1-[(phenyl)sulfonyl]-2-[(4-nitrophenoxy)methyl]-1H-benzimidazoles derivatives 7(a–j) and 8(a–j) synthesized in good yields and characterized by ¹H NMR, ¹³C NMR and mass spectral analyses. The crystal structure of 7a was evidenced by X-ray diffraction study. The newly synthesized compounds were evaluated for their in vitro antibacterial activity against Staphylococcus aureus, (Gram-positive), Escherichia coli and Klebsiella pneumoniae (Gram-negative), antifungal activity against Candida albicans, Aspergillus flavus and Rhizopus sp. and antitubercular activity against Mycobacterium tuberculosis H37Rv, Mycobacterium smegmatis, Mycobacterium fortuitum and MDR-TB strains. The synthesized compounds displayed interesting antimicrobial activity. The compounds 7b, 7e and 7h displayed significant activity against Mycobacterium tuberculosis H37Rv strain.     

Synthesis,identification and in vitro biological evaluation of some novel quinoline incorporated 1,3-thiazinan-4-one derivatives

The present study describes the synthesis of two new series of 3-hydroxy-N-(4-oxo-2-phenyl-1,3-thiazinan-3-yl)-8-(trifluoromethyl)quinoline-2-carboxamide derivatives (4a–j) and 3-((7-chloroquinolin-4-ylamino)methyl)-2-phenyl-1,3-thiazinan-4-one derivatives (5a–7j). All the compounds were synthesized in moderate to good yield by one-pot three component cyclo-condensation reaction. The newly synthesized compounds were characterized by FT-IR, ¹H, ¹³C NMR and elemental analysis. The compounds were screened for their in vitro antibacterial activity against a panel of pathogenic bacterial strains, antitubercular activity against Mycobacterium tuberculosis H₃₇Rv and also for their in vitro antimalarial activity against Plasmodium falciparum. Among the synthesized compounds two of them (4f and 5f) showed excellent antibacterial activity against C. tetani at 15.6 μg/mL. Some of them exhibited excellent antitubercular (4f & 5f) and good antimalarial (4f, 5f & 6f) activity compared with the first line drugs.     

Isolation and structural elucidation of novel cholestane glycosides and spirostane saponins from Polygonatum odoratum

Much attention has been paid to cholestane-type steroidal glycosides because of their importance from the perspectives of both chemical diversity and significant biological activities. A phytochemical investigation of the rhizomes of Polygonatum odoratum (Liliaceae) resulted in the isolation of three novel cholestane-type steroidal glycosides (1–3) with unique Δ^14,16-unsaturated D-ring structures as well as two novel spirostane-type steroidal saponins (4 and 5) and three known steroidal glycosides (6–8). Their structures were determined by various spectroscopic methods and chemical reactions. Steroidal saponin 7 showed significant antifungal activity against Candida albicans JCM1542 (MIC 3.1 μg/mL) and Aspergillus fumigatus JCM1738 (MIC 6.3 μg/mL).     

Indolylmethylene benzo[h]thiazolo[2,3-b]quinazolinones: Synthesis,characterization and evaluation of anticancer and antimicrobial activities

A series of novel 10-((1H-indol-3-yl)methylene)-7-aryl-7,10-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-ones (8a–t) have been synthesized in good yields by the reaction of benzo[h]quinazoline-2(1H)-thiones (4a–f) with 2-chloro-N-phenylacetamide (5) followed by Knoevenagel condensation with various indole-3-carbaldehydes (7a–d) under conventional method. All the synthesized compounds were characterized by spectral studies and screened for their in vitro anticancer and antimicrobial activities. Compound 8c has exhibited excellent activity against MCF-7 (breast cancer cell line) than the standard drug Doxorubicin. Compound 8d against both the cancer cell lines, 8q against MCF-7 and 8c, 8h against HepG2 have also shown good activity. Remaining compounds have shown moderate activity against both the cell lines. Antimicrobial activity revealed that, the compound 8q and 8t against Staphylococcus aureus and 8i, 8k, 8l, 8q & 8t against Klebsiella pneumoniae have shown equipotent activity on comparing with the standard drug Streptomycin. Remaining compounds have shown significant antibacterial and comparable antifungal activities against all the tested microorganisms.     

One pot three components microwave assisted and conventional synthesis of new 3-(4-chloro-2-hydroxyphenyl)-2-(substituted) thiazolidin-4-one as antimicrobial agents

A one-pot, three-component, microwave assisted and conventional synthesis of new 3-(4-chloro-2-hydroxyphenyl)-2-(substituted) thiazolidin-4-one (4a–n) was carried out by using N,N-dimethylformamide as a solvent with high product yield. Among these synthesized compounds (4f, 4g, 4l and 4m) were found to be a broad spectrum molecule active against all bacterial and fungus strains tested, except fungus Aspergillus niger. Amongst the compounds (4g, 4l and 4m) were found to be more potent than respective standard drugs used in the experiment against Candida albicans, Staphylococcus aureus and Aspergillus flavus, respectively. All synthesized compounds were also tested for their cytotoxic activity against HeLa and MCF-7 cell lines by the sulforhodamine B (SRB) assay. This study shows that all compounds were non-cytotoxic in nature, and confirmed their antimicrobial specificity apart from any general cytotoxicity.     

Bioactive butylphthalide derivatives from Ligusticum chuanxiong

Seven new butylphthalide derivatives, ligusticumolide A-G (1–7), together with two known butylphthalide derivatives (8–9) were isolated from an ethanol extract of Ligusticum chuanxiong Hort. The structures of these derivatives were elucidated from analysis of 1D/2D NMR, UV, IR and HRESIMS data. The absolute configurations of these derivatives were determined by electronic circular dichroism (ECD) calculations and Mosher′s method. Ligusticumolide A (1) and ligusticumolide B (2) are enantiomers that were obtained by chiral separation. Ligusticumolide C (3) and ligusticumolide D (4) are diastereomers. All of the compounds were evaluated for their hepatoprotective activity against N-acetyl-p-aminophenol-induced HepG2 cell injury. Compounds 4, 5, and 7–9 showed more significant hepatoprotective activity than that of the positive control drug (bicyclol) at a concentration of 10 μM (p < 0.01).     

Microwave assisted nano (ZnO–TiO2) catalyzed synthesis of some new 4,5,6,7-tetrahydro-6-((5-substituted-1,3,4-oxadiazol-2-yl)methyl)thieno[2,3-c]pyridine as antimicrobial agents

Combined nano zinc oxide and titanium dioxide [nano (ZnO–TiO₂)] has been reported first time for the synthesis of novel series of 4,5,6,7-tetrahydro-6-((5-substituted-1,3,4-oxadiazol-2-yl)methyl)thieno[2,3-c]pyridine. All the synthesized compounds (7a–7m) are novel and were screened for their antimicrobial activity against four different strains like Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis and antifungal activity was determined against two strains Candida albicans and Aspergillus niger. SAR for the newly synthesised derivatives has been developed by comparing their MIC values with ampicillin, ciprofloxacin and miconazole for antibacterial and antifungal activities, respectively. Among the synthesized compounds, 2,6 dichlorophenyl analogue (7f), 4 fluorophenyl analogue (7k) and 2,6 dichlorophenyl analogue (7l) shows promising antibacterial as well as antifungal activity whereas thiophene substituted compound (7j) shows promising antibacterial activity.     

DFT/B3LYP calculations,in vitro cytotoxicity and antioxidant activities of steroidal pyrimidines and their interaction with HSA using molecular docking and multispectroscopic techniques

As a part of our continuing program on the synthesis of steroidal heterocycles, it has been prepared a series of novel steroidal pyrimidine derivatives 4–6 via TMSCl, steroidal ketones (1c–3c), urea and benzaldehyde. The systems presented here, are novel scaffolds and have not been described before at 6th position of steroidal-6-one (1c–3c). Structural assignment of newly synthesized compounds was performed by DFT/B3LYP calculations as well as spectral and analytical data. The interactions of compounds (4–6) with HSA were studied by fluorescence spectroscopy, DLS, CD and molecular docking, under imitated physiological conditions. The antitumor activity has been tested in vitro against three cancer cell lines MDA-MB231 (breast carcinoma), HeLa (human cervical carcinoma), HepG2 (hepatic carcinoma) and one non-cancer normal cell lines, PBMCs (peripheral blood mononuclear cell) by MTT assay. In addition, in vitro antioxidant activity and apoptosis assay of the synthesized compounds (4–6) have also been investigated.     

Steroidal glycosides from Marsdenia tenacissima

Three new compounds 1–3 as C₂₁ steroidal glycosides of diester derivatives of tenacigenin B were isolated from the ethanolic extract of stems of Marsdenia tenacissima. All compounds were prepared and evaluated inhibitory activity of nitric oxide in RAW276.4 macrophages. Compounds 1–3 exhibited inhibitory effects against nitric oxide (NO).     

Design,synthesis and antibacterial activities of thiouracil derivatives containing acyl thiourea as SecA inhibitors

A series of novel thiouracil derivatives containing an acyl thiourea moiety (7a–7x) have been synthesized by structural modification of a lead SecA inhibitor, 2. All the compounds have been evaluated for their antibacterial activities against Bacillus amyloliquefaciens, Staphylococcus aureus, and Bacillus subtilis. Compounds 7c, 7m, 7u, 7v exhibited promising activities against above bacteria. Such four compounds were further tested for their inhibitory activity against SecA ATPase, and the results showed that compounds 7c and 7u had higher inhibitory activities than that of compound 2. Molecular docking work suggests that compound 7u might bind at a pocket close to the ATPase ATP-binding domain.     

Design,synthesis and antiplasmodial activity of novel imidazole derivatives based on 7-chloro-4-aminoquinoline

A series of short chain 4-aminoquinoline-imidazole derivatives have been synthesized in one pot two step multicomponent reaction using van leusen standard protocol. The diethylamine function of chloroquine is replaced by substituted imidazole derivatives containing tertiary terminal nitrogen. All the synthesized compounds were screened against the chloroquine sensitive (3D7) and chloroquine resistant (K1) strains of Plasmodium falciparum. Some of the compounds (6, 8, 9 and 17) in the series exhibited comparable activity to CQ against K1 strain of P. falciparum. All the compounds displayed resistance factor between 0.09 and 4.57 as against 51 for CQ. Further, these analogues were found to form a strong complex with hematin and inhibit the β-hematin formation, therefore these compounds act via heme polymerization target.     

Iodine mediated pyrazolo-quinoline derivatives as potent anti-proliferative agents

A novel series of substituted pyrazolo-quinoline derivatives 7pa–7qg were synthesized efficiently by using molecular iodine in DMSO and further characterized based on ¹H NMR, ¹³C NMR, IR and HRMS spectral studies. All the synthesized derivatives were screened for their in vitro cytotoxic activity against a panel of five different cancer cell lines such as A549, HeLa, SKNSH, HepG2 and MCF7. The compounds 7pc, 7pd, and 7pj exhibited considerable to promising anti-proliferative activity with IC₅₀ values of 3.76, 3.87 and 3.83?µM against SKNSH cancer cell line. It was revealed that the compounds 7pa and 7pg have shown very close IC₅₀ values of 2.43 and 6.01?µM, against A549 and MCF7 cancer cell lines respectively, which compared to positive control of Doxorubicin. This is the first report on the synthesis and in vitro anti-proliferative evaluation of pyrazolo-quinoline derivatives.     

New amide linked dimeric 1,2,3-triazoles bearing aryloxy scaffolds as a potent antiproliferative agents and EGFR tyrosine kinase phosphorylation inhibitors

A search for potent antiproliferative agents has prompted to design and synthesize aryloxy bridged and amide linked dimeric 1,2,3-triazoles (7a–j) by using 1,3-dipolar cycloaddition reaction between 2-azido-N-phenylacetamides (4a–e) and bis(prop-2-yn-1-yloxy)benzenes (6a–b) via copper (I)-catalyzed click chemistry approach with good to excellent yields. All the newly synthesized compounds have been screened for their in vitro antiproliferative activities against two human cancer cell lines. The compounds 7d, 7e, 7h, 7i and 7j have revealed promising antiproliferative activity against human breast cancer cell line (MCF-7), whereas, the compounds 7a, 7b, 7c, 7i and 7j were observed as potent antiproliferative agents against human lung cancer cell line (A-549). The active compounds against MCF-7 have been also analysed for their mechanism of action by the enzymatic study, which shows that the compounds 7d, 7h and 7j were acts as active EGFR tyrosine kinase phosphorylation inhibitors. In support to this biological study, the molecular docking as well as in silico ADME properties of all the newly synthesized hybrids were predicted.     

Synthesis and biological evaluation of a novel series of aryl S,N-ketene acetals as antileishmanial agents

A series of aryl S,N-ketene acetals 7(a–f) was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani. All the 6 compounds exhibited significant in vitro activity against intracellular amastigotes of L. donovani with IC₅₀ values ranging from 1.2 to 3.5 μM and were found promising as compared with reference drugs, sodium stibogluconate (SSG) and paromomycin. On the basis of good selectivity indices (SI), they were further tested for their in vivo potential against L. donovani/hamster model. Two compounds 7a and 7b showed significant inhibition of parasite multiplication, 72% and 83%, respectively. These compounds were comparable with SSG and superior to paromomycin. Preliminary in vitro metabolic investigations were also performed to assess the metabolic stability and in vitro hepatic intrinsic clearance (Cl_int) of compound 7b in hamster liver microsomes.