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.     

Synthesis,characterization, and in vitro antimicrobial activities of 5-alkenyl/hydroxyalkenyl-2-phenylamine-1,3,4-oxadiazoles and thiadiazoles

The long-chain alkenoic acid hydrazides (1a–d) on reaction with phenylisocyanate and phenylthiocyanate gave their corresponding semicarbazides (2a–d) and thiosemicarbazides (4a–d), which on further refluxing with POCl₃ and Ac₂O yielded corresponding 1,3,4-oxadiazoles (3a–d) and thiadiazoles (5a–d), respectively.The structure elucidation of synthesized compounds is based on the elemental analysis and spectral data (IR, ¹H NMR, ¹³C NMR and MS). The synthesized oxadiazoles and thiadiazoles have been screened for antibacterial and antifungal activities. The investigation of antimicrobial screening revealed that compounds 3c, 3d, 5c, 5d and compounds 3b, 5b, showed good antibacterial and antifungal activities, respectively.     

Design,synthesis, and biological evaluation of novel 1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide analogs in MCF-7 and MDA-MB-468 breast cancer cell lines

A series of novel 1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide analogs were designed and synthesized for developing pyrazinoindolone scaffolds as anti-breast cancer agents. Compounds 1h and 1i, having a furan-2-yl-methylamide and benzylamide group, respectively, exhibited more potent cytotoxicity in MDA-MB-468 triple-negative breast cancer (TNBC) cells than compounds possessing aliphatic groups. Compounds 2a and 2b, as (R)-enantiomers of 1h and 1i, also had inhibitory activity against MDA-MB-468 cells. Moreover, analogs (3a–b and 3d–e) bearing a benzyl group at the N-2 position showed more potent activity than gefitinib, as a potent EFGR-TK inhibitor. Especially, compound 3a exhibited selective cytotoxic activity against MDA-MB-468 cells; it also had a synergistic effect in combination with gefitinib against MDA-MB-468 cells. In addition, we confirmed that compounds 3a and 3d inhibit phosphorylation of Akt in MDA-MB-468 cells using western blot analysis. Therefore, these 1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide analogs may be helpful for investigating new anti-TNBC agents.     

Synthesis of novel celecoxib analogues by bioisosteric replacement of sulfonamide as potent anti-inflammatory agents and cyclooxygenase inhibitors

Two series of celecoxib analogues having 1,5-diaryl relationship were synthesized. The key strategy of the molecular design was oriented towards exploring bioisosteric modifications of the sulfonamide moiety of celecoxib. First series (2a–2i) of celecoxib analogues bearing cyano functionality in place of sulfonamide moiety was synthesized by the reaction of appropriate trifluoromethyl-β-diketones (5a–5i) with 4-hydrazinylbenzonitrile hydrochloride (4) in ethanol. Cyano moiety of pyrazoles 2 was then converted into corresponding carbothioamides 3 by bubbling H₂S gas in the presence of triethylamine. All the synthesized compounds (2a–2i and 3a–3i) were screened for their in vivo anti-inflammatory (AI) activity using carrageenan-induced rat paw edema assay. COX-1 and COX-2 inhibitory potency was evaluated through in vitro cyclooxygenase (COX) assays. Compounds 2a, 2b, 2c, 2e and 3c showed promising AI activity at 3–4 h after the carrageenan injection that was comparable to that of the standard drug indomethacin. Although compounds 3d, 3e and 3f exhibited more pronounced COX-2 inhibition but they also inhibit COX-1 effectively thus being less selective against COX-2. Three compounds 2a, 2f and 3a were found to have a COX profile comparable to the reference drug indomethacin. However 2e, 3b, 3c and 3i compounds were the most potent selective COX-2 inhibitors of this study with 3b showing the best COX-2 profile. In order to better rationalize the action and the binding mode of these compounds, docking studies were carried out. These studies were in agreement with the biological data.     

Novel indolizine derivatives with unprecedented inhibitory activity on human farnesyltransferase

The rational structural modification of new substituted indolizin-3-yl(phenyl)methanones 1a–i, 2a–i and 3a–i has greatly improved human farnesyltransferase inhibition. The para-bromophenyl analog 2f bearing an ester unit on the indolizine ring demonstrates the highest inhibition potential, with IC₅₀ value of 1.3 ± 0.2 μM. The amidic series 1a–i proves to be the most promising for future modulations, particularly at the triple bond level.     

Synthesis and biological screening of a combinatorial library of β-chlorovinyl chalcones as anticancer,anti-inflammatory and antimicrobial agents

A combinatorial library of β-chlorovinyl chalcones (4) were synthesized by Claisen–Schmidt condensation reaction. Catalytic reaction of substituted 3-chloro-3-phenyl-propenal (2) and 1-(2,4-dimethoxy-phenyl)-ethanone or 1-(4-methoxy-phenyl)-ethanone (3) in alkaline conditions furnished the target compound 5-chloro-1-(2,4-dimethoxy-phenyl)-5-phenyl-penta-2,4-dien-1-one (4). The synthesized compounds were screened for their biological activity viz. anticancer, anti-inflammatory and antimicrobial activities. Synthesized compounds 4g and 4h revealed promising anti-inflammatory activity (66–67% TNF-α and 95–97% IL-6 inhibitory activity at 10 μM). Cytotoxicity of the compounds checked using CCK-8 cell lines and found to be nontoxic to slightly toxic. Furthermore, the anticancer activity (30–40%) was shown by compounds 4d, 4e, 4h and 4b at 10 μM concentrations against ACHN followed by Calu 1, Panc1, HCT116 and H460 cell lines. Some of the compounds 4d, 4e, 4a, 4i and 4b revealed promising antimicrobial activity at MIC 50–100 μg/mL against selected pathogenic bacteria and fungi.     

Synthesis of novel 2-amino-4-(5′-substituted 2′-phenyl-1H-indol-3′-yl)-6-aryl-4H-pyran-3-carbonitrile derivatives as antimicrobial and antioxidant agents

As a part of systematic investigation of synthesis and biological activities of indole analogues linked to various heterocyclic systems, we have synthesized new compounds viz., 2-amino-4-(5′-substituted 2′-phenyl-1H-indol-3′-yl)-6-aryl-4H-pyran-3-carbonitriles (2a–i), 4,5-diamino-6-(5′-substituted 2′-phenyl-1H-indol-3′-yl)-8-aryl-2-oxo-2,6-dihydrodipyrano [2,3-b:3,2-e]pyridine-3-carbonitriles (3a–i), 4-amino-5-(5′-substituted 2′-phenyl-1H-indol-3-yl)-7-aryl-1H-pyrano[2,3-d]pyrimidin-2(5H)-ones (4a–i), 4-amino-5-(5′-substituted 2′-phenyl-1H-indol-3′-yl)-7-aryl-1H-pyrano[2,3-d]pyrimidin-2(5H)-thiones (5a–i), 4-(5′-subtituted 2′-phenyl-1H-indol-3′-yl)-6-aryl-1,4-dihydropyrano[2,3-c]pyrazol-3-amines (6a–i) and 5-(5′-substituted 2′-phenyl-1H-indol-3′-yl)-7-aryl-3H-pyrano[2,3-d]pyrimidin-4(5H)-ones (7a–i). Antibacterial activity results revealed that, compound 6a showed promising activity versus Escherichia coli, Staphylococcus aureus and Klebsiella pneumoniae. Compound 6d exhibited good activity against S. aureus, K. pneumoniae and Pseudomonas aeruginosa. Antifungal activity results indicated that, compound 4d exhibited maximum zone of inhibition against Aspergillus oryzae and Aspergillus flavus. In case of antioxidant activity, compound 4a showed promising radical scavenging activity, ferric ions (Fe³⁺) reducing antioxidant power (FRAP) and metal chelating activity.     

Novel pyrazoline amidoxime and their 1,2,4-oxadiazole analogues: Synthesis and pharmacological screening

A novel series of pyrazoline amidoxime (2a–d) and pyrazoly-1,2,4-oxadiazole (3a–p) and (4) of pharmacological significance have been synthesised. Structures of newly synthesised compounds were characterized by spectral studies. New compounds were screened for their in vitro antioxidant, antimicrobial and antiinflammatory activities. Among the synthesized compounds, compound 2a, 3l and 3o were found to be active antimicrobial agents in addition to having potent antioxidant activity, while the compound 3f showed promising antiinflammatory activity in comparison with standard drug.     

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.     

Synthesis of novel 1,2,3-triazole/isoxazole functionalized 2H-Chromene derivatives and their cytotoxic activity

A series of novel 2-(1,2,3-triazolylmethoxy) 5a–q and isoxazole tagged 6a–g 2H-Chromene derivatives were prepared starting from salicylaldehyde and ethyl-4,4,4-trifluoroacetoacetate via cyclization to form ethyl 2-hydroxy-2-(trifluoromethyl)-2H-Chromene-3-carboxylate 3. Compound 3 on reaction with propargyl bromide resulted compound 4 and was independently reacted with aryl/alkyl azides and aryl aldoximes obtained 2-(1,2,3-triazolylmethoxy) and isoxazole tagged 2H-Chromene derivatives 5a–q, 6a–i, respectively. Compounds 6 were further hydrolysed to acid derivatives 7a–g. All the products 5a–q, 6a–i, 7a–g were screened for cytotoxic activity against four human cancer cell lines and among all the compounds, 5f, 5g, 5l, 5q showed promising activity at <20 μM concentration.     

4-Functionalized 1,3-diarylpyrazoles bearing 6-aminosulfonylbenzothiazole moiety as potent inhibitors of carbonic anhydrase isoforms hCA I,II, IX and XII

A series of 24 novel heterocyclic compounds—functionalized at position 4 with aldehyde (5a–5f), carboxylic acid (6a–6f), nitrile (7a–7f) and oxime (8a–8f) functional groups—bearing 6-aminosulfonybenzothiazole moiety at position 1 of pyrazole has been synthesized and investigated for the inhibition of four isoforms of the α-class carbonic anhydrases (CAs, EC 4.2.1.1), comprising hCAs I and II (cytosolic, ubiquitous isozymes) and hCAs IX and XII (transmembrane, tumor associated isozymes). Against the human isozyme hCA I, compounds 6a–6f showed medium-weak inhibitory potential with K_i values in the range of 157–690 nM with 6a showing better potential than the standard drug acetazolamide (AZA). Against hCA II, all the compounds showed excellent to moderate inhibition with K_i values of compounds 5a, 5d, 5f, 6a–6f, 8d and 8f lower than 12 nM (K_i of AZA). Against hCA IX, all the compounds showed moderate inhibition with the exception of 6e which showed nearly 9 fold a better profile compared to AZA, whereas against hCA XII, four compounds 6e, 7a, 7b and 7d showed K_i in the same order as that of AZA. Carboxylic acid 6e was found to be an excellent inhibitor of both hCA IX and XII, with K_i values of 2.8 nM and 5.5 nM, respectively.     

Novel 3-substituted-1-aryl-5-phenyl-6-anilinopyrazolo[3,4-d]pyrimidin-4-ones: Docking,synthesis and pharmacological evaluation as a potential anti-inflammatory agents

Novel 3-substituted-1-aryl-5-phenyl-6-anilino-pyrazolo[3,4-d]pyrimidin-4-ones of pharmacological significance were synthesized by the reaction of ethyl-(5-amino-3-methylthio-1-aryl-5-phenyl-2H-pyrazole)-4-carboxylates 3a–c with S-methyl diphenyl thiourea independently to produce 1-aryl-3-thiomethyl-5-phenyl-pyrazolo[3,4-d]pyrimidines 4a–c in DMF with catalytic amount of K₂CO₃, which on further treatment with different aromatic amines independently under same reaction conditions generated for compounds 5a–l. The compounds were screened for the anti-inflammatory activity and evaluated for ulcerogenic potential. The compounds 5i exhibited superior anti-inflammatory activity in comparison with diclofenac sodium and comparable activity with celecoxib at a dose of 25 mg/kg. The other compounds 4c, 5c, 5f and 5l were found as active with inhibition of edema in the range of 35–39 after 3 h of administration of test compounds. The ulcerogenic potential of active compounds was observed to be quite lesser as compared to standard. COX-2 docking score of the active compound 5i was found to be better than standard celecoxib.     

Novel anti-viability ceramide analogs: Design,synthesis, and structure–activity relationship studies of substituted (S)-2-(benzylideneamino)-3-hydroxy-N-tetradecylpropanamides

A group of novel l-serinamides, substituted (S)-2-(benzylideneamino)-3-hydroxy-N-tetradecylpropanamides (3a–o) and substituted (S)-2-(benzylamino)-3-hydroxy-N-tetradecyl propanamides (4c, 4i, 4l, and 4o), were synthesized as potential anti-tumor lead compounds. In vitro cell viability assay results indicate treatment with 3a–o compounds resulted in significant inhibition of cell viability in the chemoresistant breast cancer cell line, MCF-7TN-R. Compounds 3i and 3l, both ortho-substituted analogs, show the greatest efficacy with IC₅₀ values of 10.3 μM and 12.5 μM, respectively. The SAR analysis indicate that the imine functional group of 3a–o is critical for the cellular anti-viability effect, and the partial atomic charge (PAC) value of imine C atom is a valuable structural parameter for predicting the activity of these ceramide analogs.     

New carboxamides bearing benzenesulphonamides: Synthesis,molecular docking and pharmacological properties

Ten new derivatives of benzenesulphonamide bearing carboxamide functionality were synthesized and investigated for their in vitro antimicrobial, antioxidant and in vivo anti-inflammatory activities. Compound 9d inhibited carrageenan induced rat-paw oedema at 93.81, 88.79 and 86.09% at 1 h, 2 h and 3 h administration respectively. In the antimicrobial activity, compound 9a (6.54, 6.69 and 6.64 mg/mL) was most potent against S. aureus, B. subtilis and C. albicans respectively, compound 9e (6.45 and 6.46 mg/mL) was most active against P. aeruginosa and A. niger respectively while compound 9i (6.24 mg/mL) was most active against E. coli. Only compound 9a (IC₅₀ 0.3052 mg/mL) had comparable activity with Vitamin C (IC₅₀ 0.2090 mg/mL) in the antioxidant assay.     

Synthesis,antioxidant, and antimicrobial evaluation of some 2-arylbenzimidazole derivatives

A series of 2-arylbenzimidazole derivatives (3a–3p and 4a–4i) were synthesized and evaluated as potential antioxidant and antimicrobial agents. Their antioxidant properties were evaluated by various in vitro assays including hydroxyl radical (HO) scavenging, superoxide radical anion (O₂^?) scavenging, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging, and ferric reducing antioxidant power. Results demonstrated that compounds with hydroxyl group at the 5-position of benzimidazole ring had a comparable or better antioxidant activity in comparison to standard antioxidant tert-butylhydroquinone (TBHQ). Markedly, compound 4h that showed the highest HO scavenging activity (EC₅₀ = 46 μM) in vitro had a significant reduction of 2,2′-azobis(2-amidinopropane) dihydrochloride (AAPH)-induced intracellular oxidative stress and H₂O₂-induced cell death. In addition, these compounds showed moderate to good inhibitory activity against Staphylococcus aureus selectively at noncytotoxic concentrations.     

Design,synthesis, and evaluation of l-cystine diamides as l-cystine crystallization inhibitors for cystinuria

To overcome the chemical and metabolic stability issues of l-cystine dimethyl ester (CDME) and l-cystine methyl ester (CME), a series of l-cystine diamides with or without N^α-methylation was designed, synthesized, and evaluated for their inhibitory activity of l-cystine crystallization. l-Cystine diamides 2a–i without N^α-methylation were found to be potent inhibitors of l-cystine crystallization while N^α-methylation of l-cystine diamides resulted in derivatives 3b–i devoid of any inhibitory activity of l-cystine crystallization. Computational modeling indicates that N^α-methylation leads to significant decrease in binding of the l-cystine diamides to l-cystine crystal surface. Among the l-cystine diamides 2a–i, l-cystine bismorpholide (CDMOR, LH707, 2g) and l-cystine bis(N′-methylpiperazide) (CDNMP, LH708, 2h) are the most potent inhibitors of l-cystine crystallization.     

Dihydrothiophene-condensed chromones from a marine-derived fungus Penicillium oxalicum and their structure–bioactivity relationship

Four dihydrothiophene-condensed chromones including two new compounds oxalicumones D–E (1–2) and known oxalicumones A–B (3–4), along with five other known chromones were isolated from a culture broth of the marine gorgonian-associated fungus Penicillium oxalicum SCSGAF 0023. The structures of 1–2 were elucidated by spectroscopic analysis. Eleven derivatives 3a–3i and 4a–4b were obtained from the acylation of 3 and 4, respectively. Compounds 1–4, 3a–3e, 3g–3h, and 4b showed significant cytotoxicity against several carcinoma cell lines with IC₅₀ ⩽ 10 μM. And their structure–bioactivity relationship was discussed.     

Characterization of new PPARγ agonists: Benzimidazole derivatives—importance of positions 5 and 6, and computational studies on the binding mode

In this and previous studies we investigated the importance of partial structures of Telmisartan on PPARγ activation. The biphenyl-4-ylmethyl moiety at N1 and residues at C2 of the central benzimidazole were identified to be essential for receptor activation and potency of receptor binding. Now we focused our attention on positions 5 and 6 of the central benzimidazole and introduced bromine (3b–5/6, 3c), phenylcarbonyl (3d–5/6), hydroxy(phenyl)methyl (3g–5/6), hydroxymethyl (3h–5/6) and formyl (3i) groups. The selection of these moieties was inspired by the structure of Losartan and its metabolite EXP3179. In order to increase the hydrophobicity of the central part of the molecule, the benzimidazole was exchanged by a naphtho[2,3-d]imidazole (5). The compounds 3a–3i and 5 were tested in a differentiation assay using 3T3-L1 preadipocytes and a luciferase assay using COS-7 cells, transiently transfected with pGal4-hPPARγDEF, pGal5-TK-pGL3 and pRL-CMV, as established models for the assessment of cellular PPARγ activation. An enhanced effect on PPARγ activation could be observed if lipophilic moieties are introduced in these positions. 4′-[(2-Propyl-1H-naphtho[2,3-d]imidazol-1-yl)methyl]biphenyl-2-carboxylic acid (5) was identified as the most potent compound with an EC₅₀ of 0.26 μM and the profile of a full agonist.Together with compounds of the former structure–activity relationship study (position 2-substituted benzimidazole derivatives 4a–4j), the binding mode of Telmisartan and its derivatives have been analyzed in 3D pharmacophore-driven docking experiments.     

In vitro antitubercular and antimicrobial activities of 1-substituted quinoxaline-2,3(1H,4H)-diones

1-((Substituted)methyl)quinoxaline-2,3(1H,4H)-dione (2a–e) and 1-((substituted)acryloyl)quinoxaline-2,3(1H,4H)-dione (4a–c) were synthesized from quinoxaline-2,3(1H,4H)-dione 1 and evaluated for their antimicrobial activities. Results of the antitubercular screening against Mycobacterium tuberculosis H₃₇Rv showed that the compounds 2b, 3, and 4a were the most effective, with minimum inhibitory concentrations of 8.012, 8.561, and 8.928 μg/ml, respectively. All the compounds exhibited significant antibacterial and considerable antifungal activities.     

Lactones 34 [1]. Application of alcohol dehydrogenase from horse liver (HLADH) in enantioselective synthesis of δ- and ɛ-lactones

The ability of horse liver alcohol dehydrogenase (HLADH) to the enantioselective oxidation of primary–primary, primary–secondary and primary-tertiary aliphatic 1,5- and 1,6-diols 1a–i was studied. No enantioselectivity of the transformations of primary–primary 1,6-diols 1a–d to ɛ-lactones 4a–d was observed. Regioselective oxidation of primary–secondary 1,6-diols 1e,f and 1,5-diols 1h,i afforded enantiomerically enriched ɛ-lactones 4e,f and δ-lactones 4h,i. ɛ-Lactones 4e,f were formed with higher enantiomeric excesses (e.e. = 85–99%). Enzymatic oxidation of primary–tertiary 1,6-diol 1g did not give lactone product.