Synthesis and antibacterial activity evaluation of metronidazole–triazole conjugates

Synthesis and antibacterial activity of metronidazole–triazole conjugates are reported. Total 21 hybrid compounds have been synthesized with different substitution pattern on the triazole ring in order to study their influence on the antibacterial activity. These compounds demonstrated potent to weak antibacterial activity against Gram-positive, and Gram-negative bacteria. Six compounds have shown equal or better antibacterial activity against Gram-negative strains than the reference compound.     

Synthesis,characterization and antineoplastic activity of bis-aziridinyl dimeric naphthoquinone – A novel class of compounds with potent activity against acute myeloid leukemia cells

The synthesis, characterization and antileukemic activity of rationally designed amino dimeric naphthoquinone (BiQ) possessing aziridine as alkylating moiety is described. Bis-aziridinyl BiQ decreased proliferation of acute myeloid leukemia (AML) cell lines and primary cells from patients, and exhibited potent (nanomolar) inhibition of colony formation and overall cell survival in AML cells. Effective production of reactive oxygen species (ROS) and double stranded DNA breaks (DSB) induced by bis-aziridinyl BiQ is reported. Bis-dimethylamine BiQ, as the isostere of bis-aziridinyl BiQ but without the alkylating moiety did not show as potent anti-AML activity. Systemic administration of bis-aziridinyl BiQ was well tolerated in NSG mice.     

Synthesis and biological evaluation of novel 7-hydroxy-4-phenylchromen-2-one–linked to triazole moieties as potent cytotoxic agents

A new series of novel 7-hydroxy-4-phenylchromen-2-one (1a)–linked 1,2,4-triazoles were synthesised using a click chemistry approach. All derivatives were subjected to 3-(4,5-dimethylthiazol-yl)-diphenyl tetrazolium bromide (MTT) cytotoxicity screening against a panel of six different human cancer cell lines (AGS, MGC-803, HCT-116, A-549, HepG2, and HeLa) to assess their cytotoxic potential. Among the tested molecules, some of the analogues showed better cytotoxic activity than that shown by the 7-hydroxy-4-phenylchromen-2-one (1a). Of the synthesised 1,2,4-triazoles,the 7-((4-(4-Chlorophenyl)-4H-1,2,4-triazol-3-yl)methoxy)-4-phenyl-2H-chromen-2-one (4d) showed the best activity, with an IC₅₀ of 2.63?±?0.17?µM against AGS cells. Further flow cytometry assays demonstrated that compound 4d exerts its antiproliferative effects by arresting cells in the G2/M phase of the cell cycle and by inducing apoptosis. Collectively, our results indicate that the 1,2,4-triazole derivatives have a significantly stronger antitumour activity than 1,2,3-triazole derivatives. Most of the compounds exhibited better antitumour activity than the positive control drug 5-fluorouracil.     

Synthesis and evaluation of novel α-substituted chalcones with potent anti-cancer activities and ability to overcome multidrug resistance

A series of forty α-substituted chalcones were synthesized and screened for their antiproliferative activities against HCT116 (colorectal) and HCC1954 (breast) cancer cell lines. Compounds 5a and 5e were found to be the most potent compounds with GI₅₀ values of 0.63 µM and 0.725 µM in HCC1954 cell line and 0.69 µM and 1.59 µM in HCT116 cell line, respectively. Both compounds induced a G2/M cell cycle arrest and caused apoptotic cell death in HCT116 cells as shown by the induction of PARP cleavage. The compounds also stabilized p53 in a dose-dependent manner in HCT116 cells following 24-hour treatment. Furthermore, both 5a and 5e were able to overcome multidrug resistance in two MDR-1 overexpressing multidrug resistant cell lines.     

Synthesis and antibacterial activity of 4″,11-di-O-arylalkylcarbamoyl azithromycin derivatives

A series of new 4″,11-di-O-arylalkylcarbamoyl azithromycin derivatives were designed, synthesized and evaluated for their in vitro antibacterial activities. Some derivatives exhibited greatly improved activity against erythromycin-resistant bacteria. Among them, compounds 5f and 5k were found to have potent activity against erythromycin-resistant Streptococcus pneumoniae whose resistance was encoded by the erm or mef gene.     

Hapivirins and diprovirins: novel θ-defensin analogs with potent activity against influenza A virus

θ-Defensins are cyclic octadecapeptides found in nonhuman primates whose broad antiviral spectrum includes HIV-1, HSV-1, severe acute respiratory syndrome coronavirus, and influenza A virus (IAV). We previously reported that synthetic θ-defensins called retrocyclins can neutralize and aggregate various strains of IAV and increase IAV uptake by neutrophils. This study describes two families of peptides, hapivirins and diprovirins, whose design was inspired by retrocyclins. The goal was to develop smaller partially cyclic peptides that retain the antiviral activity of retrocyclins, while being easier to synthesize. The novel peptides also allowed for systemic substitution of key residues to evaluate the role of charge or hydrophobicity on antiviral activity. Seventy-two hapivirin or diprovirin peptides are described in this work, including several whose anti-IAV activity equals or exceeds that of normal α- or θ-defensins. Some of these also had strong antibacterial and antifungal activity. These new peptides were active against H3N2 and H1N1 strains of IAV. Structural features imparting strong antiviral activity were identified through iterative cycles of synthesis and testing. Our findings show the importance of hydrophobic residues for antiviral activity and show that pegylation, which often increases a peptide's serum t(1/2) in vivo, can increase the antiviral activity of DpVs. The new peptides acted at an early phase of viral infection, and, when combined with pulmonary surfactant protein D, their antiviral effects were additive. The peptides strongly increased neutrophil and macrophage uptake of IAV, while inhibiting monocyte cytokine generation. Development of modified θ-defensin analogs provides an approach for creating novel antiviral agents for IAV infections.     

Synthesis of novel β-carbolines with efficient DNA-binding capacity and potent cytotoxicity

A series of water-soluble β-carbolines, bearing a flexible amino side chain, was prepared and evaluated in vitro against a panel of human tumor cell lines. The N⁹-arylated alkyl substituted β-carbolines represented the most interesting cytotoxic activities, and compound 7b was found to be the most potent antitumor agent with IC₅₀ values lower than 10 μM against eight human tumor cell lines. The results confirmed that the N⁹-arylated alkyl substituents of β-carboline nucleus played an important role in the modulation of the cytotoxic potencies. In addition, these compounds were found to exhibit significant DNA-binding affinity.     

Synthesis and biological evaluation of novel N-arylidenequinoline-3-carbohydrazides as potent β-glucuronidase inhibitors

Thirty N-arylidenequinoline-3-carbohydrazides (1–30) have been synthesized and evaluated against β-glucuronidase inhibitory potential. Twenty four analogs showed outstanding β-glucuronidase activity having IC₅₀ values ranging between 2.11 ± 0.05 and 46.14 ± 0.95 than standard d-saccharic acid 1,4 lactone (IC₅₀ = 48.4 ± 1.25 μM). Six analogs showed good β-glucuronidase activity having IC₅₀ values ranging between 49.38 ± 0.90 and 80.10 ± 1.80. Structure activity relationship and the interaction of the active compounds and enzyme active site with the help of docking studies were established. Our study identifies novel series of potent β-glucuronidase inhibitors for further investigation.     

Synthesis and antibacterial activity of catecholate–ciprofloxacin conjugates

The development of an efficient route to obtain artificial siderophore–antibiotic conjugates active against Gram-negative bacteria is crucial. Herein, a practical access to triscatecholate enterobactin analogues linked to the ciprofloxacin along with their antibacterial evaluation are described. Two series of conjugates were obtained with and without a piperazine linker which is known to improve the pharmacokinetics profile of a drug. A monocatecholate–ciprofloxacin conjugate was also synthesized and evaluated. The antibacterial activities against Pseudomonas aeruginosa for some conjugates are related to the iron concentration in the culture medium and seem to depend on the bacterial iron uptake systems.     

Synthesis and biological activity of 4″-O-acyl derivatives of 14- and 15-membered macrolides linked to ω-quinolone-carboxylic unit

The synthesis and antimicrobial activity of a new class of macrolide antibiotics which consist of a macrolide scaffold and a quinolone unit covalently connected by an appropriate linker are described. Optimization of several synthetic steps and structural properties of lead compound 26 are discussed. Promising antibacterial properties of this compound and some of its analogues are reported.     

Synthesis and antibacterial evaluation of amino acid–antibiotic conjugates

Amino acid conjugates of quinolone, metronidazole and sulfadiazine antibiotics were synthesized in good yields using benzotriazole methodology. All the conjugates were screened for their antibacterial activity using methods adapted from the Clinical and Laboratory Standards Institute. Antibiotic conjugates were tested for activity in four medically relevant organisms; Staphylococcus aureus (RN4220), Escherichia coli (DH5α), Pseudomonas aeruginosa (PAO1), and Bacillus subtilis (168). Several antibiotic conjugates show promising results against several of the strains screened.     

Synthesis and antibacterial activity of a series of novel 9-O-acetyl- 4′-substituted 16-membered macrolides derived from josamycin

A series of novel 9-O-acetyl-4′-substituted 16-membered macrolides derived from josamycin has been designed and synthesized by cleavage of the mycarose of josamycin and subsequent modification of the 4′-hydroxyl group. These derivatives were evaluated for their in vitro antibacterial activities against a panel of Staphylococcus aureus and Staphylococcus epidermidis. 15 (4′-O-(3-Phenylpropanoyl)-9-O-acetyl-desmycarosyl josamycin) and 16 (4′-O-butanoyl-9-O-acetyl-desmycarosyl josamycin) exhibited comparable activities to josamycin against S. aureus (MSSA) and S. epidermidis (MSSE).     

Synthesis and structure–activity relationship of dicationic diaryl ethers as novel potent anti-MRSA and anti-VRE agents

A series of dicationic diaryl ethers have been synthesized and evaluated for in vitro antibacterial activities, including drug resistant bacterial strains. Most of these compounds have shown potent antibacterial activities. Several compounds, such as piperidinyl and thiomorpholinyl compounds 9e and 9l, improved the antimicrobial selectivity and kept potent anti-MRSA and anti-VRE activity. The most potent bis-indole diphenyl ether 19 exhibited anti-MRSA MIC value of ?0.06 μg/mL and enhanced antimicrobial selectivity.     

Synthesis of novel β-carboline based chalcones with high cytotoxic activity against breast cancer cells

A series of novel β-carboline based chalcones was synthesized and evaluated for their cytotoxic activity against a panel of human cancer cell lines. Among them we found that two of the compounds 7c and 7d, showed marked anti-proliferative activity in a panel of solid tumor cell lines with highest effect in breast cancer. The compounds 7c and 7d showed an IC₅₀ of 2.25 and 3.29 μM, respectively against human breast cancer MCF-7 cell line. Further, the compound 7c markedly induced DNA fragmentation and apoptosis in breast cancer cells.     

Synthesis and biological evaluation of 4-styrylcoumarin derivatives as inhibitors of TNF-α and IL-6 with anti-tubercular activity

A series of 4-styrylcoumarin have been synthesized by Knoevenagel condensation between substituted 4-methylcoumarin-3-carbonitrile and different heterocyclic or aromatic aldehydes. 4-Methylcoumarin-3-carbonitrile has been synthesized by the base catalyzed reaction between substituted 2-hydroxyacetophenone and ethyl cyanoacetate. The structures of the newly synthesized compounds were confirmed by ¹H NMR, IR and mass spectral analysis. All the compounds were evaluated for their anti-inflammatory activity (against TNF-α and IL-6) and anti-tubercular activity. Compounds 6a, 6h and 6j exhibited promising activity against IL-6 with 72-87% inhibition and compound 6v showed potent activity against TNF-α with 73% inhibition at 10 μM concentration. Whereas compounds 6n, 6o, 6r and 6u showed very good anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain at <6.25 μM.     

4″-O-(ω-Quinolylamino-alkylamino)propionyl derivatives of selected macrolides with the activity against the key erythromycin resistant respiratory pathogens

Four macrolides—6-O-methyl-8a-aza-8a-homoerythromycin, clarithromycin, azithromycin and azithromycin 11,12-cyclic carbonate, have been selected for the construction of a series of new quinolone derivatives. The quinolone moiety is connected to the macrolide scaffold via a diaminoaklyl 4″-O-propionyl ester chain of varying length. At the terminus the linker is attached via one of the nitrogen atoms in the linker at C(6) or C(7) of the quinolone. Many of compounds described, particularly clarithromycin derivative 37, and azithromycin derivatives 48 and 55, exhibited excellent antibacterial activity against a wide range of clinically relevant macrolide-resistant organisms, with profiles superior to that of telithromycin, an enhanced spectrum ketolide.     

Synthesis and structure–activity relationships of novel furazan-3,4-diamide analogs as potent anti-cancer agents

This study describes the synthesis and structure–activity relationships of a series of furazan-3,4-diamide analogs. 1,2,5-Oxadiazole ring and electron-withdrawing substituent on the phenyl ring are proposed to be the important elements which contribute to a significant extent maximal potency of anti-proliferation effect.     

Synthesis and evaluation of novel phenoxypropanolamine derivatives containing acetanilides as potent and selective β3-adrenergic receptor agonists

In the search for potent and selective human β3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of phenoxypropanolamine derivatives containing acetanilides were prepared and their biological activities were evaluated at the human β3-, β2-, and β1-ARs. Several of the analogues (21a, 21b, and 27a) exhibited potent agonistic activity at the β3-AR. Among the compounds described herein, the N-methyl-1-benzylimidazol-2-ylacetanilide derivative (21b) was found to be the most potent and selective β3-AR agonist, with an EC₅₀ value of 0.28 μM and no agonistic activity for either the β1- or β2-AR. In addition, 21b showed significant hypoglycemic activity in a rodent diabetic model.     

Synthesis and biological evaluation of novel γ-carboline analogues of Dimebon as potent 5-HT6 receptor antagonists

Synthesis, biological evaluation and structure–activity relationships for a series of novel γ-carboline analogues of Dimebon^? are described. Among the studied compounds, γ-carbolines 3{8} and 3{14} have been identified as potent small molecule antagonists of histamine H₁ (IC₅₀ = 0.1 μM) and serotonin 5-HT₆ (IC₅₀ = 0.37 μM) receptors, respectively.     

Design and synthesis of cell selective α/β-diastereomeric peptidomimetic with potent in vivo antibacterial activity against methicillin resistant S. Aureus

Design of therapeutically viable antimicrobial peptides with cell selectivity against microorganisms is an important step towards the development of new antimicrobial agents. Here, we report four de novo designed, short amphipathic sequences based on a α-helical template comprising of Lys, Trp and Leu or their corresponding D-and/or β-amino acids. Sequence A-12 was protease susceptible whereas its α/β-diastereomeric analogue UNA-12 was resistant to trypsin and proteinase K up to 24 h. A-12 and UNA-12 exhibited broad-spectrum antibacterial activity (MIC: 2–32 µg/mL) against pathogens including methicillin resistant S. aureus (MRSA) and methicillin-resistant S. epidermidis (MRSE). Interestingly, A-12 was found to be most toxic (>50% haemolytic at 250 µg/mL) whereas UNA-12 was found to be non cytotoxic among the all analogues against hRBCs and human keratinocytes. Interaction studies with artificial membranes by tryptophan fluorescence and acrylamide quenching assay demonstrated A-12 interacted equally in bacterial as well as mammalian mimic membrane whereas UNA-12 was found to be more selective towards bacterial mimic membrane. Further microscopic tool has revealed membrane damaging ability of A-12 and UNA-12 with bactericidal mode of action against MRSA. Encouragingly, peptidomimetics analogue UNA-12 showed remarkable safety and efficacy against MRSA in in-vivo neutropenic mice thigh infection model. In summary, simultaneous replacement of the natural amino acids with D-/β-congeners is a promising strategy for designing of potent, cell selective and protease stable peptide based antibiotics.