Structures of pulvinone derivatives from Aspergillus terreus

The structures were established of six pulvinone derivatives, together with 3-(p-hydroxyphenyl)-4-hydroxy-5-(p-hydroxybenzylidene)-2(5H)-furanone (dihydroxy pulvinone), which were all isolated from a culture of Aspergillus terreus. Dihydroxy pulvinone is the fundamental structure for the six new compounds, which have one more hydroxyl group and/or two 3,3-dimethylallyll or related groups substituted on the aryl nuclei.     

Synthesis and activity of polyacetylene substituted 2-hydroxy acids,esters, and amides against microbes of clinical importance

A series of novel polyacetylene substituted 2-hydroxy acids and derivatives were prepared and characterized. Alkylation of butane-2,3-diacetal (BDA) protected glycolic acid with iodoalkyl substituted polyacetylene compounds gave the corresponding diacetal protected polyacetylene substituted 2-hydroxy acids. Diacetal deprotection through acid mediated hydrolysis, transesterification or aminolysis afforded the 2-hydroxy-polyacetylenic acid, ester or amide derivatives. Twenty one of these novel compounds were tested against 10 microbes of clinical importance and several of them showed good antimicrobial activity, in particular against Pseudomonas aeruginosa.     

Antibacterial activity of quinoxalines,quinazolines, and 1,5-naphthyridines

Several phenyl substituted naphthalenes and isoquinolines have been identified as antibacterial agents that inhibit FtsZ-Zing formation. In the present study we evaluated the antibacterial of several phenyl substituted quinoxalines, quinazolines and 1,5-naphthyridines against methicillin-sensitive and methicillin-resistant Staphylococcus aureus and vancomycin-sensitive and vancomycin-resistant Enterococcus faecalis. Some of the more active compounds against S. aureus were evaluated for their effect on FtsZ protein polymerization. Further studies were also performed to assess their relative bactericidal and bacteriostatic activities. The notable differences observed between nonquaternized and quaternized quinoxaline derivatives suggest that differing mechanisms of action are associated with their antibacterial properties.     

Synthesis and evaluation of novel 2,3,5-triaryl-4H,2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-diones for advanced glycation end product formation inhibitory activity

The synthesis of some biologically interesting pyrrolo-isoxazolidine derivatives was accomplished by the 1,3-dipolar cycloaddition reaction of substituted azomethine N-oxides 1 with substituted N-aryl maleimides 2 leading to the formation of new stereoisomeric 2,3,5-triaryl-4H,2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione derivatives 3 in excellent yields. The synthesized compounds have been screened for their advanced glycation end (AGE) product formation inhibitory activity on the basis of their ability to inhibit the formation of AGEs in the bovine serum albumin (BSA)-glucose assay. All the synthesized compounds have been found to exhibit significant activity against AGE formation.     

Modification of imidazothiazole derivatives gives promising activity in B-Raf kinase enzyme inhibition; synthesis,in vitro studies and molecular docking

B-Raf mutation was identified as a key target in cancer treatment. Based on structural features of dabrafenib (potent FDA approved B-Raf inhibitor), the design of new NH₂-based imidazothiazole derivatives was carried out affording new highly potent derivatives of imidazothiazole-based scaffold with amino substitution on the terminal phenyl ring as well as side chain with sulfonamide group and terminal substituted phenyl ring. In vitro enzyme assay was investigated against V600E B-Raf kinase. Compounds 10l, 10n and 10o showed higher inhibitory activities (IC₅₀ = 1.20, 4.31 and 6.21 nM, respectively). In vitro cytotoxicity evaluation was assessed against NCI-60 cell lines. Most of tested derivatives showed cytotoxic activities against melanoma cell line. Compound 10k exhibited most potent activity (IC₅₀ = 2.68 µM). Molecular docking study revealed that the new designed derivatives preserved the same binding mode of dabrafenib with V600E B-Raf active site. It was investigated that the new modification in the synthesized derivatives (substituted with NH₂) had a significant inhibitory activity towards V600E B-Raf. This core scaffold is considered a key compound for further structural and molecular optimization.     

Synthesis and Topoisomerase I inhibitory properties of klavuzon derivatives

Klavuzon is a naphthalen-1-yl substituted α,β-unsaturated δ-lactone derivative, and is one of the anti-proliferative members of this class of compounds. Asymmetric and racemic syntheses of novel α,β-unsaturated δ-lactone derivatives are important to investigate their potential for the treatment of cancer. In this study, asymmetric and racemic syntheses of heteroatom-substituted klavuzon derivatives are reported. The syntheses were completed by a well-known three-step procedure. Anti-proliferative activity of seven novel racemic klavuzon derivatives were reported against MCF-7, PC3, HCT116 p53+/+ and HCT116 p53−/− cancer cell lines. Topoisomerase I inhibitory properties of 5,6-dihydro-2H-pyran-2-one derivatives were also studied.     

Synthesis and structure–activity relationship of a novel class of 15-membered macrolide antibiotics known as ‘11a-azalides’

Macrolide antibiotics are widely prescribed for the treatment of respiratory tract infections; however, the increasing prevalence of macrolide-resistant pathogens is a public health concern. Therefore, the development of new macrolide scaffolds with activities against resistant pathogens is urgently needed. An efficient method for reconstructing the erythromycin A macrolactone skeleton has been established. Based on this methodology, novel 15-membered macrolides, known as ‘11a-azalides’, with substituents at the C12, C13, or C4″ positions were synthesized and their antibacterial activities were evaluated. These derivatives showed promising antibacterial activities against erythromycin-resistant Streptococcus pneumoniae. Among them, the C4″ substituted derivatives had the most potent activity against erythromycin-resistant S. pneumoniae.     

Novel urea and thiourea derivatives of thiazole-glutamic acid conjugate as potential inhibitors of microbes and fungi

Since discovery and development of effective as well as safe drugs has brought a progressive era in human healthcare that is accompanied by the appearance of drug resistant bacterial strains, there is constant need of new antibacterial agent having novel mechanisms of action to act against the harmful pathogens. In the present study, several N-terminal substituted urea/thiourea derivatives were synthesized by the reaction of glutamic acid and 3-(1-piperazinyl)-1,2-benzisothiazole with various substituted phenyl isocyanates/isothiocyanates. Elemental analysis, IR, ¹H NMR, ¹³C NMR and mass spectral data confirmed the structure of the newly synthesized compounds. The derivatives were investigated for their antibacterial and antifungal activities against various pathogens of human origin by agar well diffusion method and microdilution method. The preliminary antimicrobial bioassay reveals that the compounds containing fluoro and bromo as substituents showed promising antimicrobial activity.     

Synthesis and antiproliferative activity of pyrrolo[3,2-b]pyridine derivatives against melanoma

Synthesis of a new series of diarylureas and amides having pyrrolo[3,2-b]pyridine scaffold is described. Their in vitro antiproliferative activity against human melanoma cell line A375 and HS 27 human fibroblast cell line was tested and the effect of substituents on the pyrrolo[3,2-b]pyridine was investigated. The newly synthesized compounds, except meta-substituted derivatives (Ij–k and Iv–w), generally showed superior or similar activity against A375 to Sorafenib. Among all of these derivatives, compounds Ir and It having 5-benzylamide substituted 4′-amide moieties showed the most potent antiproliferative activity against A375.     

Structure–activity relationship of indoline-2-carboxylic acid N-(substituted)phenylamide derivatives

Chroman derivatives exhibited potent inhibitory activity of NF-κB. For SAR, the chroman scaffold was modified with an indoline moiety. A series of indoline-2-carboxylic acid N-(substituted)phenylamide derivatives were synthesized to explore their inhibitory activities of NF-κB and they were also evaluated for cytotoxicity against various cancer cell lines. Since intermediates with Boc showed outstanding results, various substituents in place of the Boc group were introduced additionally and these compounds were also evaluated for SAR.     

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.     

Metallo-β-lactamase inhibitory activity of phthalic acid derivatives

4-Butyl-3-methylphthalic acid was recognized as a metallo-β-lactamase inhibitor. The structure–activity relationship study of substituted phthalic acids afforded 3-phenylphthalic acid derivatives as potent IMP-1 inhibitors. On the other hand, 3-substituted with 4-hydroxyphenyl phthalic acid derivative displayed a potent combination effect with biapenem (BIPM) against Pseudomonas aeruginosa that produce IMP-1.     

Diversity-oriented synthesis of pyrazoles derivatives from flavones and isoflavones leads to the discovery of promising reversal agents of fluconazole resistance in Candida albicans

Diversity-oriented synthesis of derivatives of natural products is an important approach for the discovery of novel drugs. In this paper, a series of novel 3,4-diaryl-1H-pyrazoles and 3,5-diaryl-1H-pyrazoles derivatives were synthesized through the one-pot reaction of flavones and isoflavones with the hydrazine hydrate and substituted hydrazine hydrate. Some of these novel compounds exhibited antifungal effects against Candida albicans SC5314, and displayed more potent inhibitory activities against the efflux-pump-deficient strain DSY654. In addition, compounds 25, 28 and 32a displayed outstanding reversal activity of azole resistance against clinical azole-resistant Candida albicans in combination with fluconazole (FLC), with FICI values ranging from 0.012 to 0.141. The preliminary structure-activity relationship (SAR) of these compounds was also discussed. In conclusion, this study provides several novel agents that displayed potent antifungal activities alone or together with fluconazole, which makes progress for development of antifungal drugs.     

Chemical modification and antitumor activities of two polysaccharide–protein complexes from Pleurotus tuber-regium

Two water-soluble polysaccharide-protein complexes, extracted from Pleurotus tuber-regium sclerotia, were modified chemically to obtain their sulfated and carboxymethylated derivatives. While C6 position of glucan was fully substituted, C2, C3, and C4 were only partially substituted by sulfate groups. C3, C4, and C6 position of glucan were partially substituted during the carboxymethylation. Chain conformation and antitumor activity of the native samples and their derivatives were studied. The native samples and derivatives existed in sphere conformation, and showed potent in vitro antitumor activities. Water-solubility and introduction of ionic groups played important roles in enhancing the antitumor activities of the polysaccharide–protein complexes.     

New salicylamide and sulfonamide derivatives of quinoxaline 1,4-di-N-oxide with antileishmanial and antimalarial activities

Continuing with our efforts to identify new active compounds against malaria and leishmaniasis, 14 new 3-amino-1,4-di-N-oxide quinoxaline-2-carbonitrile derivatives were synthesized and evaluated for their in vitro antimalarial and antileishmanial activity against Plasmodium falciparum Colombian FCR-3 strain and Leishmania amazonensis strain MHOM/BR/76/LTB-012A. Further computational studies were carried out in order to analyze graphic SAR and ADME properties. The results obtained indicate that compounds with one halogenous group substituted in position 6 and 7 provide an efficient approach for further development of antimalarial and antileishmanial agents. In addition, interesting ADME properties were found.     

A new class of potential anti-tuberculosis agents: Synthesis and preliminary evaluation of novel acrylic acid ethyl ester derivatives

Novel acrylic acid ethyl ester derivatives were synthesized and evaluated as potential agents against Mycobacterium species. A versatile and efficient copper-catalyzed coupling process was developed and used to prepare a library of substituted acrylic acid ethyl ester analogs. Minimum inhibitory concentration assays indicated that two of these compounds 3 and 4 have greater in vitro activity against Mycobacterium smegmatis than rifampin, one of the current, first-line anti-mycobacterial chemotherapeutic agents. Moreover, members of this new class of compounds appear to exhibit a specific anti-mycobacterial effect and do not inhibit the growth of the other Gram-positive or Gram-negative species tested.     

Design,synthesis and biological activity of novel substituted 3-benzoic acid derivatives as MtDHFR inhibitors

The enzyme dihydrofolate reductase from M. tuberculosis (MtDHFR) has a high unexploited potential to be a target for new drugs against tuberculosis (TB), due to its importance for pathogen survival. Preliminary studies have obtained fragment-like molecules with low affinity to MtDHFR which can potentially become lead compounds. Taking this into account, the fragment MB872 was used as a prototype for analogue development by bioisosterism/retro-bioisosterism, which resulted in 20 new substituted 3-benzoic acid derivatives. Compounds were active against MtDHFR, with IC₅₀ values ranging from 7 to 40 μM, where compound 4e not only had the best inhibitory activity (IC₅₀ = 7 μM), but also was 71-fold more active than the original fragment MB872. The 4e inhibition kinetics indicated an uncompetitive mechanism, which was supported by molecular modeling which suggested that the compounds can access an independent backpocket from the substrate and competitive inhibitors. Thus, based on these results, substituted 3-benzoic acid derivatives have strong potential to be developed as novel MtDHFR inhibitors and also anti-TB agents.     

Synthesis,in vitro antiproliferative activity and kinase profile of new benzimidazole and benzotriazole derivatives

Protein kinase 2 (CK2), a member of the serine/threonine kinase family, has been established as a promising target in anticancer therapy. New derivatives of known CK2 inhibitors 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi) and 4,5,6,7-tetrabromo-1H-benzotriazole (TBBt) bearing azide or substituted triazole groups were synthesized. Their influence on the activity of human recombinant CK2α and cytotoxicity against normal and cancer cell lines were evaluated. TBBi derivatives with triazole substituted with carboxyl substituent (7 and 10) exhibited the most potent inhibitory activity against CK2 with K_i value in the range of 1.96–0.91 μM, respectively. New TBBi derivatives 2, 3, 5 and 9 have demonstrated the EC₅₀, in the range of 12–25 μM and 13–29 μM respectively towards CCRF-CEM and MCF-7 cells. Derivatives TBBi decreased viability of cancer cells more efficiently than BALB cells and the biggest differences were observed for the azide substituted compounds 3 and 5. The effect of the most active compounds on the activity of eight off-target kinases was evaluated. Inhibitory efficiency of CK2-mediated p65 phosphorylation was demonstrated for the TBBi and compound 12.     

Synthesis,molecular docking,and biological activity of 2-vinyl chromones: Toward selective butyrylcholinesterase inhibitors for potential Alzheimer's disease therapeutics

We investigated the biological activity of a series of substituted chromeno[3,2-c]pyridines, including compounds previously synthesized by our group and novel compounds whose syntheses are reported here. Tandem transformation of their tetrahydropyridine ring under the action of activated alkynes yielding 2-vinylsubstituted chromones was used to prepare nitrogen-containing derivatives of a biologically active chromone system. The inhibitory activity of these chromone derivatives against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carboxylesterase (CaE) was investigated using the methods of enzyme kinetics and molecular docking. Antioxidant (antiradical) activity of the compounds was assessed in the ABTS assay. The results demonstrated that a subset of the studied chromone derivatives selectively inhibit BChE but do not exhibit antiradical activity. In addition, the results of molecular docking effectively explained the observed features in the efficacy, selectivity, and mechanism of BChE inhibition by the chromone derivatives.