Microbial transformation of azaarenes and potential uses in pharmaceutical synthesis

Pyridine, quinoline, acridine, indole, carbazole, and other heterocyclic nitrogen-containing compounds (azaarenes) can be transformed by cultures of bacteria and fungi to produce a variety of new derivatives, many of which have biological activity. In many cases, the microbial biotransformation processes are regio- and stereoselective so that the transformation products may be useful for the synthesis of new candidate drugs.     

Carboline derivatives based on natural pityriacitrin as potential antifungal agents

Carboline alkaloids are a class of important heterocyclic natural products, which usually present extensive bioactivities. During the course of our research for active compounds from natural products, the pityriacitrin and pityriacitrin B belonged carboline alkaloids have been isolated from a Chinese Burkholderia sp. NBF227, which indicated potential antifungal activities. So, in order to develop these carboline alkaloids as potential fungicidal agents, a series of pityriacitrin derivatives were investigated for their antifungal activities against Phytophthora capsici, Sclerotinia sclerotiorum, Botrytis cinerea and Rhizoctonia solani, and the results demonstrated that compounds 4, 10 and 19 displayed broad-spectrum antifungal activities. In addition, in vivo bioassay also indicated that compounds 4 and 10 could protect the pepper leaves and grape fruits against infection by P. capsici and B. cinerea, respectively. The possible mechanism of antifungal action for these compounds was also explored.     

Synthesis and in vitro antiproliferative activities of (5-aryl-1,2,4-oxadiazole-3-yl) methyl d-ribofuranosides

The emergence of multidrug resistance cell lines is one of the major obstacles in the success of cancer chemotherapeutic treatment. Therefore, it remains a big challenge the development of new and effective drugs to defeat cancer. The presence of nitrogen heterocycles in the architectural design of drugs has led to the discovery of new leading compounds. Herein, we report the synthesis, characterization and in vitro antiproliferative activity against six cancer cell lines of d-ribofuranoside derivatives bearing a 1,2,4-oxadiazolic ring, with the aim of developing new active compounds. Most of these derivatives exhibit significant antiproliferative activities in the micromolar range. Noteworthy, the most potent compound of the series showed better selectivity towards the more resistant colon cancer cell line WiDr.     

Derivatives of imidazotriazine and pyrrolotriazine C-nucleosides as potential new anti-HCV agents

Previous investigations identified 2′-C-Me-branched ribo-C-nucleoside adenosine analogues, 1, which contains a pyrrolo[2,1-f][1,2,4]triazin-4-amine heterocyclic base, and 2, which contains an imidazo[2,1-f][1,2,4]triazin-4-amine heterocyclic base as two compounds with promising anti-HCV in vitro activity. This Letter describes the synthesis and evaluation of a series of novel analogues of these compounds substituted at the 2-, 7-, and 8-positions of the heterocyclic bases. A number of active new HCV inhibitors were identified but most compounds also demonstrated unacceptable cytotoxicity. However, the 7-fluoro analogue of 1 displayed good potency with a promising cytotherapeutic margin.     

Searching for multi-target antipsychotics: Discovery of orally active heterocyclic N-phenylpiperazine ligands of D2-like and 5-HT1A receptors

We described herein the design, synthesis, and pharmacological evaluation of N-phenylpiperazine heterocyclic derivatives as multi-target compounds potentially useful for the treatment of schizophrenia. The isosteric replacement of the heterocyclic ring at the biaryl motif generating pyrazole, 1,2,3-triazole, and 2-methylimidazole[1,2-a]pyridine derivatives resulted in 21 analogues with different substitutions at the para-biaryl and para-phenylpiperazine positions. Among the compounds prepared, 4 (LASSBio-579) and 10 (LASSBio-664) exhibited an adequate binding profile and a potential for schizophrenia positive symptoms treatment without cataleptogenic effects. Structural features of this molecular scaffold are discussed regarding binding affinity and selectivity for D₂-like, 5-HT_1A, and 5-HT_2A receptors.     

Design,synthesis, and biological evaluation of 4-chloro-2H-thiochromenes featuring nitrogen-containing side chains as potent antifungal agents

A series of 4-chloro-2H-thiochromenes featuring nitrogen-containing side chains were designed, synthesized and tested in vitro for their antifungal activities. The results of preliminary antifungal tests showed that most target compounds exhibited good inhibitory activities against Candida albicans, Cryptococcus neoformans, Candida tropicalis. Notably, compounds 10e and 10y showed most potent activity in vitro against a variety of fungal pathogens with low MICs. Meanwhile, low cytotoxicity on mammalian cells has been observed for compounds 10e and 10y in the tested concentrations by the MTT assay. Therefore, the 4-chloro-2H-thiochromenes with nitrogen-containing groups provide new lead structures in the search for novel antifungal agents.     

4,5-Dihydro-1H-pyrazole: an indispensable scaffold

Abstract

Pyrazoles, categorized as nitrogen-containing heterocycles, are well known for their interminable participation in the field of perpetual research and development of therapeutical active agents. As a consequence pyrazoles became an inevitable core of numerous drugs having diverse activities. The broad spectrum of activities portrayed by the pyrazoles instigated the researchers to modify the pyrazole ring as 4,5-dihydro-1H-pyrazoles commonly known as 2-pyrazolines. The present review is a concerted effort to retrace compounds covered from 2009-till date which owe diverse biological activities to the 2-pyrazoline scaffold and also condenses the retro-synthetic approaches employed for their synthesis. This endeavor culminated in revelation that inhibitory potential varied when the substituents in particular N-substituents of 2-pyrazolines were altered.     

Design and synthesis of new phthalazine-based derivatives as potential EGFR inhibitors for the treatment of hepatocellular carcinoma

Searching for new leads in the battle of cancer will never ends, we herein disclose the design and synthesis of new phthalazine derivatives and their in vitro and in vivo testing for their antiproliferative activity. Phthalazine was selected as a privilege moiety that is incorporated in a big number of anticancer drugs in clinical use or that are still under clinical or preclinical studies. We utilized the drug extension strategy to tailor the designed compounds to fit the EGFR hydrophobic sub pocket and cleft region. The designed phthalazine derivatives was synthesized by linking phthalazine moiety with 1,3,4-oxadiazole-thione and 1,2,4-triazole-thione. Alkylation and glycosylation of the new heterocyclic systems were successfully performed to be used in the drug extension. Coupling of some phthalazine derivatives with different amino acids was also performed to improve the drug selectivity.The synthesized compounds were tested for their antiproliferative activity against cancer cells both in vivo and in vitro. The in vitro activity against hepatocellular carcinoma (HepG2 cell line) ranged from 5.7 µg/mL to 43.4 µg/mL. Compounds 31a and 16 were the most active with an IC₅₀ 5.7 µg/mL and 7.09 µg/mL, respectively compared to the standard compound doxorubicin (4.0 µg/mL). In vivo, compounds 10 and 16 showed IC₅₀ values 7.25 μg/mL and 7.5 μg/mL, respectively compared to the standard compound cisplatin (IC₅₀ 9.0 μg/mL). In silico, testing of the phthalazine derivatives showed that they are good inhibitors for EGFR. The docking studies substantiated compounds 4, 10, 16 and 31a as new lead compounds and identified Arg841 as a key residue in the cleft region for binding stronger inhibitors.     

Preparation of New Spiropyrazole,Pyrazole and Hydantoin Derivatives and Investigation of Their Antioxidant and Antibacterial Activities.

In this study, the synthesis of new spiropyrazoles, pyrazole and hydantoin heterocycles is reported by three component reactions of parabanic acids, hydrazine derivatives, and phenacyl bromides in the presence of triphenylphosphine as a nucleophile and triethylamine as a base in good to high yields (69–91 %). Evaluation of the synthesized compounds revealed a good to excellent antioxidant activities (37.6–96.2 %) using DPPH inhibitory potency. Among these compounds, hydantoin derivatives displayed higher antioxidant activities (93.7–96.2 %) comparing with spiropyrazoles and pyrazoles. The obtained results showed that Cl and Br substituents on the phenyl ring increased antioxidant activities of the related heterocycles. The antibacterial activities of the synthesized compounds were examined against two Gram-negative (Escherichia coli and Pseudomonas aeruginosa) and two Gram-positive (Staphylococcus aureus and Bacillus subtilis) bacteria. Among the synthesized heterocycles, 2-[1,3-dimethyl-2,5-dioxo-4-(2-oxo-2-phenylethyl)imidazolidin-4-yl]hydrazine-1-carbothioamide exhibited the excellent antibacterial activity against both Gram-positive and Gram-negative bacteria.     

Lysosomes-targeting imaging and anticancer properties of novel bis-naphthalimide derivatives

A series of novel N,N-bis(3-aminopropyl)methylamine bridged bis-naphthalimide derivatives NI1–NI8 containing saturated nitrogenous heterocycles were designed and synthesized, their cytotoxic activities against Hela, MCF-7, A549 and MGC-803 cells were investigated, Compounds NI1–NI4 modified with piperidine and piperazine exhibited good and selective cytotoxic activity, for instance, compounds NI1 and NI4 showed potent cytotoxic activity against Hela cells and MGC-803 cells with the IC₅₀ values of 2.89, 060, 2.73 and 1.60?μM, respectively, better than the control drug (Amonafide). However, compounds NI5–NI8 conjugated with pyrrole derivatives showed weak cytotoxic activities against the all tested cell lines. Furthermore, their DNA binding properties, fluorescence imaging and cell cycle were investigated. Interestingly, compounds NI1 and NI4 showed fluorescence enhancement because of the strong binding with Ct-DNA, and exhibited fluorescence imaging with Hela cells on the lysosomes.     

Heterocyclic lactam derivatives containing piperonyl moiety as potential antifungal agents

To study the novel functionalized heterocyclic molecules with highly potential biological activity, two series of heterocyclic lactam derivatives containing the piperonyl moiety were designed and synthesized. The newly obtained compounds have been identified on the basis of analytical spectral data, including ¹H NMR, ¹³C NMR, and ESI-MS. The target compounds were evaluated for their potential antifungal activities in vitro against twelve species of the plant pathogen fungi (Sclerotinia sclerotiorum, Rhizoctonia solani, Rap Sclerotinia stemrot, Fusarium graminearum, Phomopsis adianticola, Pestallozzia theae, Pestalotiopsis guepinii, Alternaria tenuis Nees, Monilinia fructicola, Colletotrichum gloeosporioides, Phytophthora capsici, Magnaporthe oryzae). Preliminary bioassays suggested that all prepared compounds I1–14 displayed broad-spectrum and moderate antifungal activities compared with the positive control hymexazol, especially for Sclerotinia sclerotiorum, Rap Sclerotinia stemrot, and Monilinia fructicola. In particular, the inhibition rate of compound I9 exhibited good inhibition activity reached 95.16% against Sclerotinia sclerotiorum, and compounds I5, I12 against Phytophthora capsici were 93.44%, 91.25%. Further studies revealed that compounds I5 (IC₅₀ = 19.13 µM) and I12 (IC₅₀ = 9.12 µM) exhibited obviously antifungal activities against Phytophthora capsici, which were better than that of commercial agricultural fungicide hymexazol (IC₅₀ = 325.45 µM). Therefore, these target compounds could be further studied and explored as a lead skeleton for discovery of novel antifungal agents.     

Synthesis and preliminary pharmacological characterisation of a new class of nitrogen-containing bisphosphonates (N-BPs)

A new series of bisphosphonates bearing either the nitrogen-containing NO-donor furoxan (1,2,5-oxadiazole 2-oxide) system or the related furazan (1,2,5-oxadiazole) in lateral chain has been developed. pK_a values and affinity for hydroxyapatite were determined for all the compounds. The products were able to inhibit osteoclastogenesis on RAW 246.7 cells at 10 μM concentration. The most active compounds were further assayed on human PBMC cells and on rat microsomes. Unlike most nitrogen-containing bisphosphonates which target farnesyl pyrophosphate synthase, experimental and theoretical investigations suggest that the activity of our derivatives may be related to different mechanisms. The furoxan derivatives were also tested for their ability to relax rat aorta strips in view of their potential NO-dependent vasodilator properties.     

Synthesis and reactions of some new pyrrolylthieno[2,3-D]quinoxaline and pyrrolopyrazinothienoquinoxalines

The synthesis of 3-pyrrolyl-2-substituted thieno[2,3-b]quinoxalines from the precursor 3-amino derivatives are described. Synthesized compounds were subjected to reactions with other reagents to synthe-size polyfused heterocyclic incorporated thienoquinoxaline moiety. Some of the synthesized compounds were screened for their antibacterial and antifungal activities.     

Synthesis and cellular characterization of novel isoxazolo- and thiazolohydrazinylidene-chroman-2,4-diones on cancer and non-cancer cell growth and death

Coumarins are extensively studied anticoagulants that exert additional effects such as anticancerogenic and even anti-inflammatory. In order to find new drugs with anticancer activities, we report here the synthesis and the structural analysis of new coumarin derivatives which combine the coumarin core and five member heterocycles in hydrazinylidene-chroman-2,4-diones. The derivatives were prepared by derivatization of the appropriate heterocyclic amines which were used as electrophiles to attack the coumarin ring. The structures were characterized by spectroscopic techniques including IR, NMR, 2D-NMR and MS. These derivatives were further characterized especially in terms of a potential cytotoxic and apoptogenic effect in several cancer cell lines including the breast and prostate cancer cell lines MCF-7, MDA-MB-231, PC-3, LNCaP, and the monocytic leukemia cell line U937. Cell viability was determined after 48 h and 72 h of treatment with the novel compounds by MTT assay and the 50% inhibitory concentrations (EC₅₀ values) were determined. Out of the 8 novel compounds screened for reduced cell viability, 4c, 4d and 4e were found to be the most promising and effective ones having EC₅₀ values that were several fold reduced when compared to the reference substance 4-hydroxycoumarin. However, the effects were cancer cell line dependent. The breast cancer MDA-MB-231 cells, the prostate cancer LNCaP cells, and U937 cells were most sensitive, MCF-7 cells were less sensitive, and PC-3 cells were more resistant. Reduced cell viability was accompanied by increased apoptosis as shown by PARP-1 cleavage and reduced activity of the survival protein kinase Akt.In summary, this study has identified three novel coumarin derivatives that in comparison to 4-hydroxycoumarin have a higher efficiency to reduce cancer cell viability and trigger apoptosis and therefore may represent interesting novel drug candidates.     

Synthesis and biological evaluation of novel N-substituted nipecotic acid derivatives with an alkyne spacer as GABA uptake inhibitors

In this study, we present the synthesis and structure–activity relationships (SAR) of novel N-substituted nipecotic acid derivatives closely related to (S)-SNAP-5114 (2) in the pursuit of finding new and potent mGAT4 selective inhibitors. By the use of iminium ion chemistry, a series of new N-substituted nipecotic acid derivatives containing a variety of heterocycles, and an alkyne spacer were synthesized. Biological evaluation of the prepared compounds showed, how the inhibitory potency and subtype selectivity for the murine GABA transporters (mGATs) were influenced by the performed modifications.     

Ring cleavage of sulfur heterocycles: how does it happen?

Sulfur heterocycles are common constituents of petroleum and liquids derived from coal, and they are found in some secondary metabolites of microorganisms and plants. They exist primarily as saturated rings and thiophenes. There are two major objectives driving investigations of the microbial metabolism of organosulfur compounds. One is the quest to develop a process for biodesulfurization of fossil fuels, and the other is to understand the fates of organosulfur compounds in petroleum- or creosote-contaminated environments which is important in assessing bioremediation processes. For these processes to be successful, cleavage of different types of sulfur heterocyclic rings is paramount. This paper reviews the evidence for microbial ring cleavage of a variety of organosulfur compounds and discusses the few well-studied cases which have shown that the C-S bond is most susceptible to breakage leading to disruption of the ring. In most cases, the introduction of one or more oxygen atom(s) onto the adjacent C atom and/or onto the S atom weakens the C-S bond, facilitating its cleavage. Although much is known about the thiophene ring cleavage in dibenzothiophene, there is still a great deal to be learned about the cleavage of other sulfur heterocycles.     

Synthesis and antibacterial activity of novel enolphosphate derivatives

A new class of enolphosphates derivatives, the 1-alkenyldiphosphates, was designed and a rapid and efficient synthesis for these compounds was developed. These new molecules showed interesting in vitro antibacterial activities (MIC) against Gram-positive bacteria (Staphylococcus aureus) and Gram-negative pathogens including Pseudomonas aeruginosa and Escherichia coli.     

Discovery of γ-lactam derivatives containing 1,3-benzodioxole unit as potential anti-phytopathogenic fungus agents

A series of γ-lactam analogs containing 1,3-benzodioxole moiety were designed, and these derivatives were synthesized from the lead compound of lactam via a structural diversity-oriented synthesis, their structures were confirmed by ¹HNMR,¹³CNMR, ESI-MS spectrum. Their antifungal activities were evaluated against four serious and typically crop-threatening agricultural fungi, including Rhizoctonia solani, Alternaria tenuis Nees, Gloeosporium theae-sinensis, and Fusarium graminearum. Some of these derivatives exhibited activity against Alternaria tenuis Nees higher than that of commercial fungicides carbendazim, such as compounds 7a, 7b, and 7i, compared with the blank control, some of these derivatives showed good antifungal activities against Gloeosporium theae-sinensis and Fusarium graminearum. The systematic study provides evidences for further structural modification and application of lactam analogues as antifungal agents for agriculture.     

Antimicrobial activity of Araucaria cunninghamii Sweet and the chemical constituents of its twigs and leaves

The present study was aimed at the identification of antimicrobial components from Araucaria cunninghamii with an activity-guided purification process. Eight compounds were obtained from the most active n-BuOH fraction and identified as the new compound 4-n-butoxyl-phenylpropanetriol (1), together with seven known compounds (2–8). These compounds were tested for antimicrobial activities against five bacteria and four plant pathogenic fungi. Within the series of compounds tested, compound 2 was the most active, particularly displaying moderate antibacterial activities against Erwinia carotovora and Bacillus subtilis with MICs 7.8 and 15.5 μg/ml. Moreover, this compound exhibited inhibitory activities against four plant pathogenic fungi: Helminthosporium sativum, Rhizoctonia solani, Fusarium oxysporum f. sp. Niveum and Fusarium oxysporum f. sp. Cubense, with EC₅₀ values of 42.3, 90.0, 62.7 and 100.2 μg/ml. To our knowledge, this is the first report that the n-BuOH fraction and compound 2 from A. cunninghamii showed inhibitory activity against plant pathogenic fungi.     

Biotechnological production of feed nucleotides by microbial strain improvement

Sodium salts of inosine monophosphate (IMP) and guanosine monophosphate (GMP) are potent flavour enhancers. They are widely used as food additives in combination with monosodium glutamate (MSG) to synergistically increase umami flavour. In recent years, both inosine and guanosine derivatives have gained further importance because of their beneficial effects, related to their antioxidant, neuroprotective, cardiotonic and immunomodulatory properties. The industrial production of both IMP and GMP is mainly achieved either by RNA breakdown and nucleotide extraction or by microbial fermentation using different microorganisms such as Corynebacterium, Bacillus, or Escherichia coli. This work reviews the metabolic pathways and regulatory networks of purine synthesis, including both IMP and GMP, and the biotechnological processes applied to the production of these compounds, ranging from classical random mutagenesis to rational design by metabolic engineering. Recent advances of systems biology approaches, along with the rapid development of synthetic biology, may offer a basis for future manipulations to further increase the productivity of the fermentation processes.