Synthesis and in vitro antimicrobial activity of novel N-(6-chlorobenzo[d]thiazol-2-yl) hydrazine carboxamide derivatives of benzothiazole class

In this study, a series of novel 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole (6a–g) and 1,3,4-oxadiazole (7a–g, 8) were synthesized from N-(6-chlorobenzo[d]thiazol-2-yl) hydrazine carboxamide derivatives of benzothiazole class. Antimicrobial properties of the title compound derivatives were investigated against one Gram (+) bacteria (Staphylococcus aureus), three Gram (?) bacteria (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae) and five fungi (Candida albicans, Aspergillus niger, Aspergillus flavus, Monascus purpureus and Penicillium citrinum) using serial plate dilution method. The investigation of antibacterial and antifungal screening data revealed that all the tested compounds showed moderate to good inhibition at 12.5–100?µg/mL in DMSO. It has been observed that triazolo-thiadiazole derivatives are found to be more active than 1,3,4-oxadiazole derivatives against all pathogenic bacterial and fungal strains.     

Synthesis of a novel class of some 1,3,4-oxadiazole derivatives as antimicrobial agents

In an effort to discover new candidates with improved antimicrobial activities we report here the synthesis and in vitro biological evaluation of various series of 2-{(3,4,5-trimethoxy phenyl-1,3,4-oxadiazolyl)-5-thio}-4-(morpholino)-6-(phenyl ureido)-s-triazine (7a-i) and 2-{(3,4,5-trimethoxy phenyl-1,3,4-oxadiazolyl)-5-thio}-4-(morpholino)-6-(phenyl thioureido)-s-triazine (8a-g). Antimicrobial properties of the title compounds were investigated against two Gram ( + ve) bacteria (S. aureus, B. subtilis), two Gram ( ? ve) bacteria (P. aeruginosa, E. coli) and yeast-like fungi (C. albicans) using the broth microdilution method.     

Design and synthesis of (5-amino-1, 2, 4-triazin-6-yl)(2-(benzo[d] isoxazol-3-yl) pyrrolidin-1-yl)methanone derivatives as sodium channel blocker and anticonvulsant agents

Abstract

A series of novel (5-amino-3-substituted-1, 2, 4-triazin-6-yl) (2-(6-halo-substituted benzo[d]isoxazol-3-yl) pyrrolidin-1-yl) methanone 5a–5r was synthesized. Their anticonvulsant activities were evaluated by the maximal electroshock (MES) test and neurotoxicity was evaluated by the rotorod test. The MES test showed that (5-amino-3-phenyl-1, 2, 4-triazin-6-yl)(2-(6-fluorobenzo[d]isoxazol-3-yl) pyrrolidin-1-yl) methanone 5c was found to be the most potent compound with ED₅₀ value of 6.20?mg/kg (oral/rat) and a protective index (PI?=?ED₅₀/TD₅₀) value of >48.38, which was much higher than the PI of the reference drug phenytoin. To explain the possible mechanism of action of selected derivatives 5b, 5c, 5i and 5o, their influence on sodium channel was evaluated in vitro.     

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.     

DNA binding,prominent photonuclease activity and antibacterial PDT of cobalt(II) complexes of phenanthroline based photosensitizers

Abstract

The chemistry of Co(II) complexes showing efficient light induced DNA cleavage activity, binding propensity to calf thymus DNA and antibacterial PDT is summarized in this article. Complexes of formulation [Co(mqt)(B)₂]ClO₄ 1–3 where mqt is 4-methylquinoline-2-thiol and B is N,N-donor heterocyclic base, viz. 1,10-phenanthroline (phen 1), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq 2) and dipyrido[3,2-a:2′,3′-c]phenazine (dppz 3) have been prepared and characterized. The DNA-binding behaviors of these three complexes were explored by absorption spectra, viscosity measurements and thermal denaturation studies. The DNA binding constants for complexes 1, 2 and 3 were determined to be 1.6?×?10³?M^?1, 1.1?×?10⁴?M^?1 and 6.4?×?10⁴?M^?1 respectively. The experimental results suggest that these complexes interact with DNA through groove binding mode. The complexes show significant photocleavage of supercoiled (SC) DNA proceeds via a type-II process forming singlet oxygen as the reactive species. Antimicrobial photodynamic therapy was studied using photodynamic antimicrobial chemotherapy (PACT) assay against E. coli and all complexes exhibited significant reduction in bacterial growth on photoirradiation.     

A convenient synthesis and molecular modeling study of novel pyrazolo[3,4-d]pyrimidine and pyrazole derivatives as anti-tumor agents

Abstract

An efficient method to obtain ethyl 5-amino-1-tosyl-1H-pyrazole-4-carboxylate (3) was outlined using condensation reactions of 4-methylbenzenesulfonylhydrazide with (E)-ethyl 2-cyano-3-ethoxyacrylate. The cyclocondensation reaction of this substrate and its hydrazide derivative with urea, thiourea, formamide, formic acid, d-glucose, o-phenylenediamine, 4-dimethylaminobenzaldehyde, anthracene-9-carbaldehyde, thioglycolic acid and carbon disulphide then with hydrazine hydrate analogues furnished a series of pyrazolo[3,4-d]pyrimidine, pyrazolo[3,4-d]oxazin-4-one, pyrazole-4-glucoside, 4-benzo[d]imidazole, 1,3-thiazolidinone, 1,3,4-oxadiazol-2(3H)-thione and 1,2,4-triazol-5(4H)-thione derivatives respectively. The structure of the compound 3 was supported by X-Ray crystallographic data. Orally administrated, one of each of the series of pyrazoles showed significant effects in mouse tumor model cancer cell lines (EAC) and two human cancer cell lines of Colon cancer (HCT-29) and Breast cancer (MCF-7) with docking studies.     

Synthesis of novel sulfonamide analogs containing sulfamerazine/sulfaguanidine and their biological activities

Sulfamerazine and sulfaguanidine are clenched with p-nitrobenzoyl chloride and the products obtained are reduced to Na_xS in ethanol–water. Novel sulfonamides (6a–g and 9a–g) were synthesized by the reaction of these reduced products (4 and 8) with various sulfonyl chlorides (5a–g). The structures of these compounds were characterized using spectroscopic analysis (IR, ¹H-NMR, ¹³C-NMR and HRMS) technique. Antimicrobial activity of sulfonamides (3, 4, 7, 8, 6a–g and 9a–g) was evaluated by the agar diffusion method. These compounds showed antimicrobial activity against tested microorganism strains (Gram-positive bacteria, clinic isolate and yeast and mold). Compounds 9d, 9e, 9a, 6d and 6e showed particularly antimicrobial activity against tested Gram-positive (Bacillus cereus and B. subtilis) and Gram-negative (Enterobacter aerogenes) bacteria.     

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.     

In Vivo Antiviral Activity of 5-Amino-1-Methyl-3-β-D-Ribofuranosyl-Pyrazolo[4,3-d]Pyrimidin-7(6H)-One and Related Guanosine Analogues Prepared from Formycin

Abstract

A short and simple synthesis of 5-amino-3-β-D-ribofuranosylpyrazolo[4,3-d]pyrimidin-7(6H)-one, (7) was achieved from 7-amino-5-chloro-3-β-D-ribofuranosylpyrazolo[4,3-d]pyrimidine (5), in two steps, first deamination of 5 with NOCI, followed by amination of 6 with MeOH/NH₃. Also, an efficient synthesis of 5-amino-1(or 2)-methyl-3-β-D-ribofuranosylpyrazolo[4,3-d]pyrimidin-7(6H)-one was accomplished from the corresponding 1 (or 2)-methyloxoformycin B in four steps by a sequence consisting of (i) 2′,3′,5′ acetylation with AC₂O, (ii) 5,7-chlorination with PhP(O)Cl₂, (iii) selective hydrolysis of the 7-chloro group with aqueous Na₂CO₃, (iv) followed by amination of the 5-chloro group with MeOH/NH₃. Single crystal X-ray analysis off 11 confirmed position 7 as the site of selective hydrolysis with Na₂CO₃. The three guanosine C-nucleosides prepared were evaluated for their ability to inhibit certain RNA and DNA viral replication in vitro and Semliki Forest virus infection in vivo. Only 5-amino-1-methyl-3-β-D-ribofuranosylpyrazolo[4,3-d]pyrimidin-7(6H)-one (13) provided protection (67% survivors, compared to 0% for placebo controls) against a lethal dose of Semliki Forest virus infection in mice. The antiviral effect of 13 is believed to be due to the enhancement of the host immune function.     

Synthesis and antimycobacterial evaluation of various 6-substituted pyrazolo[3,4-d]pyrimidine derivatives

Various pyrazolo[3,4-d]pyrimidines carrying a variety of substituents in the 6-position have been synthesised and their ability to inhibit growth of Mycobacterium tuberculosis in vitro has been determined. Compounds 5a, 5b, 6c, 7a, 7b, 8d, 8e and 8f demonstrated a minimum inhibitory concentration (MIC) of <6.25?µg/mL and were found to be active against Mycobacterium tuberculosis strain H₃₇RV. Compound 8d was found to be the most active compound in vitro with a MIC of <6.25?µg/mL and inhibitory concentration IC₉₀ of 1.53?µg/mL.     

Insights into biological activity of ureidoamides with primaquine and amino acid moieties

Primaquine (PQ) ureidoamides 5a–f were screened for antimicrobial, biofilm eradication and antioxidative activities. Susceptibility of the tested microbial species towards tested compounds showed species- and compound-dependent activity. N-(diphenylmethyl)-2-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]-4-methylpentanamide (5a) and 2-(4-chlorophenyl)-N-(diphenylmethyl)-2-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]acetamide (5d) showed antibacterial activity against S. aureus strains (MIC?=?6.5?µg/ml). Further, compounds 5c and 5d had weak antibacterial activity against Escherichia coli and Pseudomonas aeruginosa. None of the tested compounds showed a wide spectrum of antifungal activity. In contrast, most of the compounds exerted strong activity in a biofilm eradication assay against E. coli, P. aeruginosa and Candida albicans, comparable to or even higher than gentamycin, amphotericin B or parent PQ. The most active compounds were 5a and 5b. Tested compounds were inactive against biofilm formation by C. parapsylosis, Enterococcus faecalis, C. tropicalis and C. krusei. Compounds 5b–f significantly inhibited lipid peroxidation (80–99%), whereas compound 5c presented interesting LOX inhibition.     

Synthesis and Antimicrobial Screening of Novel Thioglycosides and Acyclonucleoside Analogs Carrying 1,2,3-Triazole and 1,3,4-Oxadiazole Moieties

The solvent-free 1,3-dipolar cycloaddition reaction of dimethylacetylene dicarboxylate (1) with 2-chlorophenyl azide (2) afforded 1,2,3-triazole diester 3 that upon hydrazinolysis, furnished the corresponding bis-acid hydrazide 4. The treatment of compound 4 with carbon disulfide in a refluxing potassium hydroxide solution furnished the desired bis-1,3,4-oxadiazole-2-thione 5 tethered to a 1,2,3-triazole moiety. The respective SOx-glycosides 9–11 were obtained by glycosylation of bis-oxadiazole 5 with 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide (6), 2,3,4,6-tetra-O-acetyl-α-d-galactopyranosyl bromide (7), and 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-d-glucopyranosyl chloride (8) in dry acetone in the presence of Et₃N, which acted as a base. However, alkylation of 5 with halogeno-alkanol 12 or 13, chloroglycerol 14, bromoethers 20 or 21, and epichlohydrin 22 in the presence of K₂CO₃ in DMF yielded the corresponding acyclonucleoside analogs 16–18 and 23–25. The isopropylidenes 19 and acetyl derivatives 26–28 of the products were also prepared. The newly synthesized compounds were characterized by ¹H NMR, ¹³C NMR, 2D NMR, and mass spectra. The compounds were screened for their antibacterial and antifungal activities. A number of the tested compounds exhibited significant antimicrobial activity compared to the reference drugs.     

Synthesis,characterization, and antimicrobial evaluation of some new hydrazinecarbothioamide, 1,2,4-triazole and 1,3,4-thiadiazole derivatives

In this work, we reported the synthesis and evaluation of antibacterial and antifungal activities of three new compound series obtained from 6-(phenyl/4-chlorophenyl)imidazo[2,1-b]thiazole-3-acetic acid hydrazide: 2-{[6-(phenyl/4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl]acetyl}-N-alkyl/arylhydrazinecarbothioamides (2a–d), 4-alkyl/aryl-2,4-dihydro-5-{[6-(phenyl/4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl]methyl}-3H-1,2,4-triazole-3-thiones (3a–n), and 2-alkyl/arylamino-5-{[6-(phenyl/4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl]methyl}-1,3,4-thiadiazoles (4a–g). The newly synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR (APT), mass and elemental analysis. Their antibacterial and antifungal activities were evaluated against Staphylococcus aureus ATCC 29213, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, Candida albicans ATCC 10231, C. parapsilosis ATCC 22019, C. krusei ATCC 6258, Trichophyton mentagrophytes var. erinacei NCPF 375, Microsporum gypseum NCPF 580, and T. tonsurans NCPF 245. 3c, 3f, 3m, 3n, and 4e showed the highest antibacterial activity. Particularly 3c, 3f, 3g, 3k, 3n, 4a, 4e, and 4g showed the highest antifungal activity against tested fungi.     

Synthesis of new thieno[2,3-b]pyridine derivatives as pim-1 inhibitors

Three series of 5-bromo-thieno[2,3-b]pyridines bearing amide or benzoyl groups at position 2 were prepared as pim-1 inhibitors. All the prepared compounds were tested for their pim-1 enzyme inhibitory activity. Two compounds (3c and 5b) showed moderate pim-1 inhibitory activity with IC₅₀ of 35.7 and 12.71?μM, respectively. Three other compounds (3d, 3g and 6d) showed poor pim-1 inhibition. The most active compounds were tested for their cytotoxic activity on five cell lines [MCF7, HEPG2, HCT116, A549 and PC3]. Compound 3g was the most potent cytotoxic agent on almost all the cell lines tested.     

Design,synthesis, neuroprotective,antibacterial activities and docking studies of novel thieno[2,3-d]pyrimidine-alkyne Mannich base and oxadiazole hybrids

A series of thieno[2,3-d]pyrimidine alkyne Mannich base derivatives (7a-e, 8a-e) and thieno[2,3-d]pyrimidine 1,3,4-oxadiazole derivatives (9a-e, 10a-e) have been synthesized and evaluated for their neuroprotective and neurotoxicity activities where 9a, 10d displayed good neuroprotection 10.6 and 11.88?µg/mL respectively against the H₂O₂ induced cell death at the EC₅₀ values and 9b, 9d showed respective toxic effects on PC12 cells at CC₅₀ 86.12 and 94.16?µg/mL. Compounds 9a, 9e, 10a and 10b showed strong antibacterial activity against two gram positive (S. aureus, B. subtilis) and two gram-negative strains (E. coli, P. aeruginosa) and showed good binding affinities with C(30) carotenoid dehydrosqualene synthase, Gyrase A and LpxC. This is the first report for the demonstration of thieno[2,3-d] pyrimidine derivatives as promising neuroprotective agents against H₂O₂ induced neurotoxicity on PC12 cells.     

Microwave-Assisted Synthesis and Anti-HIV Activity of New Acyclic C-Nucleosides of 3-(D-Ribo-Tetritol-1-yl)-5-Mercapto-1,2,4-Triazoles. Part 1

Microwave-assisted synthesis of novel acyclic C-nucleosides of 6-alkyl/aryl-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (5–12) and the 6-aryl-thiomethyl analogues 25–27 has been described. Deblocking of 5–12 and 25–27 afforded the free acyclic C-nucleosides 13–20, and 28–30, respectively. All of the synthesized compounds showed no inhibition against HIV-1 and HIV-2 replication in MT-4 cells. However, 6-(3,4-dichlorophenyl)-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole (6) is a potent inhibitor, in vitro, of the replication of HIV-2. These results suggest that compound 6 should be considered as a new lead in the development of antiviral agent.     

Synthesis and bioactivity of 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-xylopyranosyl-1,3,4-oxa(thia)diazol-2-amines

A series of new N′-[N-(2,3,4-tri-O-acetyl-β-d-xylopyranosyl)thiocarbamoyl]-2-[(1-aryl-1H-tetrazol-5-yl)sulfanyl]acetohydrazides 5a–5e were synthesized rapidly in high yields from 2-(1-aryl-1H-tetrazol-5-ylsulfanyl)acetohydrazides 3a–3e and 2,3,4-tri-O-acetyl-β-d-xylopyranosyl isothiocyanate 4, then 5a–5e were converted to a series of new 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-(2,3,4-tri-O-acetyl-β-d-xylopyranosyl)-1,3,4-oxadiazole-2-amines 6a–6e and 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-(2,3,4-tri-O-acetyl-β-d-xylopyranosyl)-1,3,4-thiadiazole-2-amines 7a–7e, respectively under mercuric acetate/alcohol system or acetic anhydride/phosphoric acid system, then deacetylated in the solution of CH₃ONa/CH₃OH. All of the novel compounds were characterized by IR, ¹H NMR, ¹³C NMR, MS and elemental analysis. The structures of compounds 2e, 3e, 5a and 5c have been determined by X-ray diffraction analysis. Some of the synthesized compounds displayed PTP1B inhibition and microorganism inhibition.     

Diheteroarylurea derivatives as adventitious rooting adjuvants in mung bean shoots and M26 apple rootstock

The present research investigates the biological profile of eight symmetrical diheteroarylureas and phenylheteroarylureas, testing their hypothetical cytokinin-like activity and rooting activity. Cytokinin-like activity was assayed by the betacyanin (so-called amaranthin) accumulation test and by the tomato regeneration test. The rooting activity was assessed using the mung bean rooting test, the apple stem slice test and the rooting of apple microcuttings. Three compounds, 1,3-di(pyrazin-2-yl)urea (3a), 1,3-di(benzo[d]oxazol-5-yl)urea (3b) and 1,3-di(benzo[d]oxazol-6-yl)urea (3c), enhanced adventitious root formation in apple stem slice test, but only 3b and 3c were active in the mung bean rooting test. Compound 3b, that showed the best rooting activity, was also able to enhance the adventitious root formation in apple microcuttings. None of the compounds showed cytokinin-like activity.     

Synthesis of new pyridothienopyrimidinone derivatives as Pim-1 inhibitors

Four series of pyridothienopyrimidin-4-one derivatives were designed and prepared to improve the pim-1 inhibitory activity of the previously reported thieno[2,3-b]pyridines. Significant improvement in the pim-1 inhibition and cytotoxic activity was achieved using structure rigidification strategy via ring closure. Six compounds (6c, 7a, 7c, 7d, 8b and 9) showed highly potent pim-1 inhibitory activity with IC₅₀ of 4.62, 1.18, 1.38, 1.97, 8.83 and 4.18?μM, respectively. Four other compounds (6b, 6d, 7b and 8a) showed moderate pim-1 inhibition. The most active compounds were tested for their cytotoxic activity on three cell lines [MCF7, HCT116 and PC3]. Compounds 7a [the 2-(2-chlorophenyl)-2,3-dihydro derivative] and 7d [the 2-(2-(trifluoromethyl)-phenyl)-2,3-dihydro derivative] displayed the most potent cytotoxic effect on the three cell lines tested consistent with their highest estimated pim-1 IC₅₀ values.     

Synthesis of 2-Bromomethyl-3-Hydroxy-2-Hydroxymethyl-Propyl Pyrimidine and Theophylline Nucleosides Under Microwave Irradiation. Evaluation of Their Activity Against Hepatitis B Virus

Alkylation of 2-methylthiopyrimidin-4(1H)-one (1a) and its 5(6)-alkyl derivatives 1b–d as well as theophylline (7) with 2,2-bis(bromomethyl)-1,3-diacetoxypropane (2) under microwave irradia-tion gave the corresponding acyclonucleosides 1-[(3-acetoxy-2-acetoxymethyl-2-bromomethyl)prop-1-yl]-2-methyl-thio pyrmidin-4(1H)-ones 3a–d and 7-[(3-acetoxy-2-acetoxymethyl-2-bromomethyl)prop-1-yl]theophylline (8), which upon further irradiation gave the double-headed acyclonucleosides 1,1 ′-[(2,2-diacetoxymethyl)-1,3-propylidene]-bis[(2-(methylthio)-pyrimidin-4(1H)-ones] 4a–c, and 7,7 ′-[(2,2-diacetoxymethyl)-1,3-propylidene]-bis(theophylline) (9). The deacetylated derivatives were obtained by the action of sodium methoxide. The activity of deacetylated nucleosides against Hepatitis B virus was evaluated. Compound 5b showed moderate inhibition activity against HBV with mild cytotoxicity.