Synthesis and evaluation of antitubercular activity of fluorinated 5-aryl-4-(hetero)aryl substituted pyrimidines

Various 5-(fluoroaryl)-4-(hetero)aryl substituted pyrimidines have been synthesized based on the Suzuki cross-coupling and nucleophilic aromatic substitution of hydrogen (S_N^H) reactions starting from commercially available 5-bromopyrimidine and their antitubercular activity against Mycobacterium tuberculosis H₃₇Rv has been explored. The outcome of the study disclose that, some of the compounds have showed promising activity in micromolar concentration against Mycobacterium tuberculosis H₃₇Rv, Mycobacterium avium, Mycobacterium terrae, and multidrug-resistant strains isolated from tuberculosis patients in Ural region (Russia). The data concerning the ‘structure–activity’ relationship for fluorinated compounds have been discussed.     

Synthesis of novel antimitotic agents based on 2-amino-3-aroyl-5-(hetero)arylethynyl thiophene derivatives

Microtubules are dynamic structures that play a crucial role in cellular division and are recognized as an important target for cancer therapy. In search of new compounds with strong antiproliferative activity and simple molecular structure, a new series of 2-amino-3-(3′,4′,5′-trimethoxybenzoyl)-5-(hetero)aryl ethynyl thiophene derivatives was prepared by the Sonogashira coupling reaction of the corresponding 5-bromothiophenes with several (hetero)aryl acetylenes. When these compounds were analyzed in vitro for their inhibition of cell proliferation, the 2- and 3-thiophenyl acetylene derivatives were the most powerful compounds, both of which exerted cytostatic effects at submicromolar concentrations. In contrast, the presence of a more flexible ethyl chain between the (hetero)aryl and the 5-position of the thiophene ring resulted in significant reduction in activity relative to the 5-(hetero)aryl acetylene substituted derivatives. The effects of a selected series of compounds on cell cycle progression correlated well with their strong antiproliferative activity and inhibition of tubulin polymerization. We found that the antiproliferative effects of the most active compounds were associated with increase of the proportion of cells in the G₂/M and sub-G₁ phases of the cell cycle.     

Synthesis and antiproliferative evaluation of 5-oxo and 5-thio derivatives of 1,4-diaryl tetrazoles

A series of 1,4-diaryl tetrazol-5-ones were synthesized by copper mediated N-arylation of 1-phenyl-1H-tetrazol-5(4H)-one with aryl boronic acids, o-R₁C₆H₄B(OH)₂ where R₁ = H, OMe, Cl, CF₃, Br, CCH. The 1,4-diaryl tetrazol-5-ones substituted with OMe, Cl, CF₃, Br underwent thionation with Lawesson’s reagent to yield the corresponding 5-thio derivatives. The 1-(2-bromophenyl)-4-phenyl-1H-tetrazole-5(4H)-thione so obtained was subjected to lithiation/protonation and Sonogashira coupling to produce 1,4-diphenyl-1H-tetrazole-5(4H)-thione and 1-(2-ethynylphenyl)-4-phenyl tetrazole-5-thione, respectively. The title compounds were found to be stable to strong Lewis acid conditions. Three of these novel compounds were found to inhibit L1210 leukemia cell proliferation and SK-BR-3 breast cancer cell growth over several days in culture in vitro. Shorter tetrazole derivative treatments also reduced the expression of the Ki-67 marker of cell proliferation in SK-BR-3 cells and the rate of DNA synthesis in L1210 cells.     

A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives

In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC₅₀ values ranging from 0.044 to 5.80?µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC₅₀ values of 0.058 and 0.044?µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC₅₀ values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.     

Design,synthesis and evaluation of 1,2,3-triazole-adamantylacetamide hybrids as potent inhibitors of Mycobacterium tuberculosis

A series of novel 1,2,3-triazole-adamantylacetamide hybrids 5a–u, designed by combining bioactive fragments from antitubercular I-A09 and substituted adamantyl urea, were synthesized using copper catalyzed click chemistry. N-(1-Adamantyl)-2-azido acetamide 3 prepared from 1-adamantylamine was reacted with a series of alkyl/aryl acetylenes in the presence of copper sulfate and sodium ascorbate to give new analogues 5a–u in very good yields. Evaluation of all new compounds for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv (ATCC27294), resulted N-(1-adamantan-1-yl)-2-(4-(phenanthren-2-yl)-1H-1,2,3-triazol-1-yl)acetamide (5t) as most promising lead MIC: 3.12 μg/mL) with selectivity index >15.     

Synthesis,Molecular Properties Prediction and Antimicrobial Activity of Imidazolyl Schiff Bases,Triazoles and Azetidinones

Benzylidenehydrazinyl imidazoles ( 3 ) are prepared from 2‐hydrazinyl imidazoles ( 2 ) on treatment with hydrazine. The imine functionality in 3 is utilized to develop 5′‐aryl‐N‐(4‐aryl‐1H‐imidazol‐2‐yl)‐1H‐1,2,3‐triazol‐1‐amines ( 5 ) by 1,3‐dipolar cycloaddition of diazomethane followed by aromatization with I₂ in DMSO. Compounds 3 are also explored to prepare 4′‐aryl‐1‐(4‐aryl‐1H‐imidazol‐2‐ylamino)‐3‐chloroazetidin‐2‐ones ( 6 ) on treatment with chloroacetyl chloride. The Molinspiration calculations predicted that 3 , 5 and 6 have molecular hydrophobicity, conformational flexibility, good intestinal absorption and bioactivity scores. The chloro, bromo and nitro substituted imidazolyl azetidinones ( 6c , 6d , 6f ) and nitro substituted imidazolyl triazole ( 5f ) exhibited excellent antibacterial activity on B. subtilis, whereas chloro and nitro substituted imidazolyl triazoles ( 5c , 5f ) showed prominent antifungal activity on A. niger.     

Synthesis and changes in affinity for NOP and opioid receptors of novel hexapeptides containing β2-tryptophan analogues

We report the synthesis and the biological activity of new analogues of Ac-RFMWMK-NH₂ and Ac-RYYRWK-NH₂, modified in position 4 and 5, respectively, with incorporation of newly synthesized β²-tryptophan analogues. Trp was substituted by the (S)-2-(1-methyl-1H-indol-3-yl)propionic residue or by (S)-2-(5-methoxy-1H-indol-3-yl)propionic residue. The biological activity (pEC₅₀ and E_max) of these compounds was tested on electrically stimulated preparations of rat vas deferens. The 5-methoxy β-tryptophan group reverses the affinity of the compounds.     

Effect of biginelli pyrimidines on production of reactive oxygen species by polymorphonuclear leukocytes

The action of six synthetic Biginelli pyrimidines on the production of reactive oxygen species (ROS) by polymorphonuclear leukocytes has been studied. It has been shown using the method of luminoldependent chemiluminescence that, at concentrations of 10–100 μM, these compounds stimulate the production of ROS by neutrophils stimulated by phorbol-12-myristate-13-acetate (PMA). The ROS production by PMA-stimulated neutrophils in the presence of 10 μM 1-(3,4-dimethoxyphenylethyl)-4-(alkyl/aryl) substituted Biginelli pyrimidines increased by 50–90%. The priming action of Biginelli pyrimidines on the ROS production by neutrophils has been shown to increase when the furyl radical was replaced by phenyl and isopropyl radicals by the C(4) pyrimidine cycle and replacement of the benzyl substitute at N(1) by 3,4-phenylethyl. At a concentration of 0.01–0.1 μM, 1-(3,4-dimethoxyphenylethyl)-4-(alkyl/aryl) substituted Biginelli pyrimidines had a high inhibitory activity. It has been found that 1-(2-[3,4-dimethoxyphenyl]-ethyl)-4-phenyl-5-carbethoxy-6-methyl-3,4-dihydro-2(1H)-pyrimidinethion at high concentrations (1 mM and more) is able to induce a respiratory burst of neutrophils without additional stimulation.     

Chromone-Fused Cytosine Analogues: Synthesis,Biological Activity,and Structure–Activity Relationship

The preparation of a series of novel chromone-fused cytosine analogues, i.e., chromeno[2,3-d]pyrimidines has been carried out from substituted 2-amino-4-oxo-4H-chromene-3-carbonitriles with urea, thiourea, and guanidine under different reaction conditions. These chromone-fused cytosine analogues were evaluated for their in vitro activity against Mycobacterium tuberculosis H₃₇Rv strain and different microbial pathogenic strains in cell culture for their structure–activity relationships, respectively. Among the synthesized compounds, 2d, 3a, and 4e showed better results against Mycobacterium tuberculosis H₃₇Rv. The compounds 2a, 2b, and 3a showed potential antibacterial activity against E. coli and P. aeruginosa, while the majority of compounds were found to be active against S. aureus as compared to ampicillin. The synthesized cytosine analogues having an imine (–C&dbnd;NH) have been less sensitive to the bacterial and fungal strains but have a more beneficial effect on Mycobacterium tuberculosis H₃₇Rv.     

Alkenyl substituted bicyclic nucleoside analogues retain nanomolar potency against Varicella Zoster Virus

Novel alkenyl substituted aryl bicyclic furano pyrimidines have been prepared and evaluated in vitro against Varicella Zoster Virus (VZV). The para-substituted analogues retain the nanomolar potency we have reported for p-alkyl analogues, while the ortho- and meta-alkenyl systems lose 3–4 orders of potency.     

Synthesis and analgesic effects of novel β2-tryptophan hexapeptide analogs

Aiming to develop more potent analgesic substances a new series of hexapeptides containing β²-tryptophan analogues was synthesized. The Trp in position 4 and 5, respectively in Ac-Arg-Phe-Met-Trp-Met-Lys-NH₂ (opioid receptor antagonist) and Ac-Arg-Tyr-Tyr-Arg-Trp-Lys-NH₂ (highly potent and selective NOP-receptor agonist) was substituted by the (S)-2-(1-methyl-1H-indol-3-yl)propionic residue or the (S)-2-(5-methoxy-1H-indol-3-yl)propionic residue. The analgesic effect of the four newly synthesized compounds has been evaluated in male Wistar rats by PP- and HP tests and compared to the native templates. Further estimation of the mechanisms of action of each compound was achieved using specific antagonists—naloxone for opioid and JTC801 for the NOP receptor. Replacement of Trp with β²-tryptophan analogues in 4th position (Ac-Arg-Phe-Met-Trp-Met-Lys-NH₂) led to increased and longer lasting analgesic effect. The results obtained permit us to assume that both opioid and NOP receptors take part in the newly synthesized compounds analgesic effects.     

The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor ligands. Part 2: Carboxamide derivatives with different spacer motifs

3,7-Diazabicyclo[3.3.1]nonane (bispidine) based nicotinic acetylcholine receptor (nAChR) ligands have been synthesized and evaluated for nAChRs interaction. Diverse spacer motifs were incorporated between the hydrogen bond acceptor (HBA) part and a variety of substituted (hetero)aryl moieties. Bispidine carboxamides bearing spacer motifs often showed high affinity in the low nanomolar range and selectivity for the α4β2¹ nAChR. Compounds 15, 25, and 47 with K_i values of about 1 nM displayed the highest affinities for α4β2¹ nAChR. All evaluated compounds are partial agonists or antagonists at α4β2¹, with reduced or no effects on α3β4¹ with the exception of compound 15 (agonist), and reduced or no effect at α7 and muscle subtypes.     

Synthesis, crystal structure, solution behavior and catalytic activity of a palladium(II)-allyl complex containing a 2-pyridyl-1,2,3-triazole bidentate ligand

The synthesis and characterization of the cationic complex [Pd(η³-C₃H₅)(2-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)pyridine)](BF₄) (2) are reported. The solid-state structure of 2 has been unambiguously confirmed by single-crystal X-ray diffraction analysis. ¹H NMR spectroscopy reveals that in solution complex 2 is dynamic and that syn-syn, anti-anti exchange of the allyl protons occurs. Complex 2 exhibits good activity in the Suzuki-Miyaura coupling of aryl bromides with phenyl boronic acid.     

Optically active iridium complexes with cyclopentadienyl-phosphine ligands: synthesis and oxidative addition of methyl iodide

The dimer [Ir(μ-Cl)(C₈H₁₄)₂]₂ reacts with the ligands (S)-(C₅H₄CH₂CH(Ph)PPh₂)Li and (R)-(C₅H₄CH(Cy)CH₂PPh₂)Li to give (S)-[Ir(η⁵-C₅H₄CH₂CH(Ph)PPh₂-κP)(C₈H₁₄)] and (R)-[Ir(η⁵-C₅H₄CH(Cy)CH₂PPh₂-κP)(C₈H₁₄)], which upon treatment with CH₃I at room temperature afford the cationic iridium(III) compounds (S,S_Ir)-[Ir(η⁵-C₅H₄CH₂CH(Ph)PPh₂-κP)(CH₃)(C₈H₁₄)][I] as a single diastereomer, and (R)-[Ir(η⁵-C₅H₄CH(Cy)CH₂PPh₂-κP)(CH₃)(C₈H₁₄)][I] as a 9:1 mixture of two diastereomers. If the oxidative addition reaction is performed at reflux in methylene chloride, the starting complexes convert to the neutral compounds (S)-[Ir(η⁵-C₅H₄CH₂CH(Ph)PPh₂-κP)(CH₃)(I)] and (R)-[Ir(η⁵-C₅H₄CH(Cy)CH₂PPh₂-κP)(CH₃)(I)] as 1.6:1 and 3.3:1 mixtures of diastereoisomers, respectively. Carbonyl iridium complexes are synthesized by reacting [IrCl(CO)(PPh₃)₂] with the ligands to afford (S)-[Ir(η⁵-C₅H₄CH₂CH(Ph)PPh₂-κP)(CO)] and (R)-[Ir(η⁵-C₅H₄CH(Cy)CH₂PPh₂-κP)(CO)]. They give upon treatment with CH₃I the cationic species (S)-[Ir(η⁵-C₅H₄CH₂CH(Ph)PPh₂-κP)(CH₃)(CO)][I] and (R)-[Ir(η⁵-C₅H₄CH(Cy)CH₂PPh₂-κP)(CH₃)(CO)][I] as 1.6:1 and 3:1 mixture of diastereomers, respectively. No migratory-insertion of the methyl group into the carbonyl-metal bond has been observed even after prolonged heating.     

Nature-inspired pyrrolo[2,3-d]pyrimidines targeting the histamine H3 receptor

Inspired by marine compounds the derivatization of the natural pyrrolo[2,3-d]pyrimidine lead scaffold led to a series of novel compounds targeting the histamine H₃ receptor. The focus was set on improved binding towards the receptor and to establish an initial structure-activity relationship for this compound class based on the lead structure (compound V, K_i value of 126 nM). As highest binding affinities were found with 1,4-bipiperidines as basic part of the ligands, further optimization was focused on 4-([1,4′-bipiperidin]-1′-yl)-pyrrolo[2,3-d]pyrimidines. Related pyrrolo[2,3-d]pyrimidines that were isolated from marine sponges like 4-amino-5-bromopyrrolo[2,3-d]pyrimidine (compound III), showed variations in halogenation pattern, though in a next step the impact of halogenation at 2-position was evaluated. The chloro variations did not improve the affinity compared to the dehalogenated compounds. However, the simultaneous introduction of lipophilic cores with electron-withdrawing substitution patterns in 7-position and dehalogenation at 2-position (11b, 12b) resulted in compounds with significantly higher binding affinities (K_i values of 7 nM and 6 nM, respectively) than the initial lead structure compound V. The presented structures allow for a reasonable structure-activity relationship of pyrrolo[2,3-d]pyrimidines as histamine H₃ receptor ligands and yielded novel lead structures within the natural compound library against this target.     

Design,synthesis and photoinduced DNA cleavage studies of [1,2,4]-triazolo[4,3-a]quinoxalin-4(5H)-ones

An expedient and eco-friendly synthesis of 1-aryl/heteroaryl-[1,2,4]-triazolo[4,3-a]quinoxalin-4(5H)-ones (4) has been accomplished via iodobenzene diacetate mediated oxidative intramolecular cyclization of 3-(2-(aryl/heteroarylidene)hydrazinyl)-quinoxalin-2(1H)-ones (3). Ten synthesized compounds 3 and 4 (10–40 μg) on irradiation with UV light at λ_max 312 nm could lead to cleavage of supercoiled pMaxGFP DNA (Form I) into the relaxed DNA (Form II) without any additive. Further, DNA cleaving ability of triazoles was quantitatively evaluated and was found to be dependent on its structure, concentration, and strictly on photoirradiation time. Mechanistic investigations using several additives as potential inhibitors/activator revealed that the DNA photocleavage reaction involves Type-I pathway leading to formation of superoxide anion radicals (O₂⁻) as the major reactive oxygen species responsible for photocleavage process.     

3(5)-Pyrazolyl substituted triphenylphosphines as ligands for the palladium catalyzed Heck reaction

3(5)-Pyrazolyl substituted triphenylphosphines have been investigated as ligands for the palladium catalyzed Heck reaction of aryl halides with styrene. Catalysts formed in situ from those phosphines and Pd^II(OAc)₂ are comparable in activity and selectivity with the corresponding pre-synthesized Pd(II) complexes, while Pd₂(dba)₃ has turned out to be a less suitable palladium source. Among the ligands investigated, the bidentate P,N-ligand 2-[3(5)-pyrazolylphenyl]diphenylphosphine has shown the highest activities for the coupling of bromobenzene with styrene in the presence of Pd^II(OAc)₂. In the presence of 1 equiv. of nBu₄NI as the additive, unreactive 4-chloroacetophenone also undergoes Heck coupling with styrene.     

Synthesis and pharmacological studies of new pyrazole analogues of podophyllotoxin

The pyrazole analogues of podophyllotoxin were synthesized by the chalcone route. This route attracts the attention because of its simple operating conditions and easy availability of the chemicals. Initially, benzylideneacetophenones (chalcones) were prepared in high yields by Claisen-Schmidt reaction of acetophenones with 4-(methylthio)benzaldehyde. The cyclopropyl ketones were prepared in good yields by the reaction of chalcones with trimethylsulfoxonium iodide. Tetralones were prepared in good yields by the Friedel-Craft’s intramolecular cyclization reaction of cyclopropyle ketones in the presence of anhyd. stannic chloride and acetic anhydride. The tetralones on formylation to give substituted hydroxylmethylene tetralones. Condensation of substituted hydroxylmethylene tetralones with hydrazine hydrate afforded target compounds. The structures of the synthesized compounds were confirmed by IR, ¹H NMR and Mass spectral technique. The title compounds were screened for their antimitotic and antimicrobial activities. Among the synthesized compounds cyclopropyl ketones and pyrazole analogues of podophyllotoxin, compound 7-(methylthio)-5-(4-(methylthio)phenyl)-4,5-dihydro-² H-benzo[g]indazole is more active than 5-(4-(methylthio)phenyl)-4,5-dihydro-² H-benzo[g]indazole, 7-methyl-5-(4-(methylthio)phenyl)-4,5-dihydro-² H-benzo[g]indazole, 7-methoxy-5-(4-(methylthio)phenyl)-4,5-dihydro-² H-benzo[g]indazole and the key intermediate tetralones in 100, 200 and 400 ppm at 12, 18 and 24 h and also showed very good activity against screened bacteria and fungi compared to their standard.     

Synthesis and characterization of some new quinoline based derivatives endowed with broad spectrum antimicrobial potency

The synthesis of a novel series of 2-(5-(2-chloro-6-fluoroquinolin-3-yl)-3-(aryl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-ones (4a–l) and N-(4-(2-chloro-6-fluoroquinolin-3-yl)-6-(aryl)pyrimidin-2-yl)-2-morpholinoacetamides (7a–l) are described in the present paper. The chemical structures of compounds have been elucidated by IR, ¹H NMR, ¹³C NMR and mass spectral data. Antimicrobial activity was measured against Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 1688), Staphylococcus aureus (MTCC 96), Streptococcus pyogenes (MTCC 442), Candida albicans (MTCC 227), Aspergillus niger (MTCC 282) and Aspergillus clavatus (MTCC 1323) by serial broth dilution. Evaluation of antimicrobial activity showed that several compounds exhibited greater activity than reference drugs and thus could be promising new lead molecules.     

Synthesis, crystal structures, cytotoxicity and qualitative structure-activity relationship (QSAR) of cis-bis{5-[(E)-2-(aryl)-1-diazenyl]quinolinolato}di-n-butyltin(IV) complexes, (n)Bu2Sn(L)2

A series of cis-bis{5-[(E)-2-(aryl)-1-diazenyl]quinolinolato}di-n-butyltin(IV) complexes has been synthesized and characterized by ¹H-, ¹³C-, ¹¹⁹Sn NMR, ESI-MS (electrospray ionization mass spectrometry), IR and ^119mSn Mössbauer spectroscopic techniques in combination with elemental analyses. The structures of four di-n-butyltin(IV) complexes, viz., ⁿBu₂Sn(L³)₂ (3), ⁿBu₂Sn(L⁴)₂ (4), ⁿBu₂Sn(L⁵)₂ (5) and ⁿBu₂Sn(L⁷)₂ · 0.5C₆H₆ (7) (LH = 5-[(E)-2-(aryl)-1-diazenyl)quinolin-8-ol) were determined by single crystal X-ray diffraction. In general, the complexes were found to adopt a distorted cis-octahedral arrangement around the tin atom. These complexes retain their solid-state structure in non-coordinating solvent as evidenced by ¹¹⁹Sn and ¹³C NMR spectroscopic results. The in vitro cytotoxicity of di-n-butyltin(IV) complexes (3-8) is reported against seven well characterized human tumour cell lines. The basicity of the two quinolinolato donor N and O atoms of the ligands are discussed in relation to the cytotoxicity data.