Synthesis and molecular modeling of antimicrobial active fluoroquinolone-pyrazine conjugates with amino acid linkers.

Novel fluoroquinolone-pyrazine conjugates 7a-h with amino acid linkers were synthesized in good yields utilizing benzotriazole chemistry. Antimicrobial bioassay showed that the synthesized bis-conjugates have antimicrobial properties comparable to the parent drugs. Compound 7h showed superior antibacterial activity against Staphylococcus aureus and Streptococcus pyogenes (MIC=74.6 µM and 149.3 µM, respectively). This matched well with the estimated values obtained from 3D-pharmacophore and 2D-QSAR studies (MIC=67 µM and 92.9 µM, respectively).

Synthesis, antimalarial properties and 2D-QSAR studies of novel triazole-quinine conjugates.

Click chemistry technique led to novel 1,2,3-triazole-quinine conjugates 8a-g, 10a-o, 11a-h and 13 utilizing benzotriazole-mediated synthetic approach with excellent yields. Some of the synthesized analogs (11a, 11d-h) exhibited antimalarial properties against Plasmodium falciparum strain 3D7 with potency higher than that of quinine (standard reference used) through in vitro standard procedure bio-assay. Statistically significant BMLR-QSAR model describes the bio-properties, validates the observed biological observations and identifies the most important parameters governing bio-activity.

Traceless chemical ligation from S-, O-, and N-acyl isopeptides.

Peptides are ubiquitous in nature where they play crucial roles as catalysts (enzymes), cell membrane ion transporters, and structural elements (proteins) within biological systems. In addition, both linear and cyclic peptides have found use as pharmaceuticals and components of various conjugate molecular systems. Small wonder then that chemists throughout the ages have sought to mimic nature by synthesis of the amide polymers known as peptides and proteins. The fundamental reaction in the formation of a peptide bond is condensation of an amine of one amino acid with the activated carbonyl group of another. This "fragment condensation" has been achieved in many ways both in solution and by solid-phase peptide synthesis (SPSS) on resin. The most successful method for in-solution coupling is known as native chemical ligation (NCL), and the technique dates back to the pioneering work of Wieland (1953) and subsequently Kent (1994) among many others. This Account builds on the established principles of NCL as applied specifically to S-, O-, and N-isopeptides, molecules that are generally more soluble and less prone to aggregation than native peptides. This Account also covers NCL of isopeptides containing terminal and nonterminal S-acylated cysteine units, reactions that enable the synthesis of native peptides from S-acyl peptides without the use of auxiliaries. With C-terminal S-acyl isopeptides, NCL was carried out under microwave irradiation in phosphate buffer (pH 7.3) at 50 °C. Intramolecular acyl migration was observed through 5-19-membered transition states with relative rates, as assessed by product analysis, in the order, 5 > 10 > 11 > 14, 16, or 17 > 12 > 13, 15, or 19 > 18 ≫ 9 > 8. The rate/pH profile for the 15-membered TS showed a maximum for ligated product versus transacylation at pH 7.0-7.3 presumably associated with the pKa of the N-nucleophile in the hydrogen-bonded TS. Cysteine occurs at low abundance (1.7%) in natural peptides and is rarely available in a terminal position thus limiting the utility of the method. This Account reports, however, NCL at nonterminal acyl cysteine through 5-, 8-, 11-, and 14-membered TSs with relative rates of ligation in the order, 5 ≫ 14 > 11 ≫ 8, thus paralleling the results with acylated terminal cysteine residues. In an obvious sequel to the work with acylated cysteine, we discuss intramolecular O- to N-acyl shift in O-acyl serine and O-acyl tyrosine isopeptides where the story becomes more complex in terms of viable conditions and optimum size of the cyclic TS. N- to N-acyl migration in acyl tryptophan isopeptides is described, and finally, chemical ligation is applied to the synthesis of cyclic peptides. Conformational analysis and quantum chemical calculations are used to rationalize ligation through a range of cyclic transition states. This Account highlights the fact that NCL of acyl isopeptides is an extremely useful strategy for the synthesis of a wide variety of native peptides in good yields and under mild conditions. Mechanistic aspects of the ligations are not fully resolved, but theoretical studies indicate that hydrogen bonding within the various cyclic transition states plays a major role.

Applications of Chemical Ligation in Peptide Synthesis via Acyl Transfer.

The utility of native chemical ligation (NCL) in the solution or solid phase synthesis of peptides, cyclic peptides, glycopeptides, and neoglycoconjugates is reviewed. In addition, the mechanistic details of inter- or intra-molecular NCLs are discussed from experimental and computational points of view.

Novel antibacterial active quinolone-fluoroquinolone conjugates and 2D-QSAR studies.

Novel, quinolone-fluoroquinolone conjugates 10a-f, 11a-f, 13a-f and 14a-f with amino acid linkers were synthesized in good yields utilizing benzotriazole chemistry. Antibacterial bioassay showed the synthesized bis-conjugates exhibit anti-bacterial properties comparable with the parent drugs.

Synthesis and QSAR study of novel anti-inflammatory active mesalazine-metronidazole conjugates.

Novel, mesalazine, metronidazole conjugates 6a-e with amino acid linkers were synthesized utilizing benzotriazole chemistry. Biological data acquired for all the novel bis-conjugates showed (a) some bis-conjugates exhibit comparable anti-inflammatory activity with parent drugs and (b) the potent bis-conjugates show no visible stomach lesions. 3D-pharmacophore and 2D-QSAR modeling support the observed bio-properties.

Synthesis, molecular docking and anticancer studies of peptides and iso-peptides.

Chiral peptides and iso-peptides were synthesized in excellent yield by using benzotriazole mediated solution phase synthesis. Benzotriazole acted both as activating and leaving group, eliminating frequent use of protection and subsequent deprotection. The procedure was based on the hypothesis that epimerization should be suppressed in solution due to a faster coupling rate than SPPS. All the synthesized peptides complied with Lipinski's Ro5 except for the rotatable bonds. Inhibition of cell proliferation of cancer cell lines is one of the most commonly used methods to study the effectiveness of any anticancer agents. Synthesized peptides and iso-peptides were tested against three cancer cell lines (MCF-7, MDA-MB 231) to determine their anti-proliferative potential. NFkB was also determined. Molecular docking studies were also carried out to complement the experimental results.

Rational design, synthesis and molecular modeling studies of novel anti-oncological alkaloids against melanoma.

3D-pharmacophore and 2D-QSAR modeling studies describe the anti-oncological properties of spiro-alkaloids. The dispiro[2H-indene-2,3'-pyrrolidine-2',3''-[3H]indole]-1,2''(1''H, 3H)-diones 20-38 were prepared via 1,3-dipolar cycloaddition reactions of azomethine ylides (generated in situ via decarboxylative condensation of isatins 7-9 with sarcosine 10) and 2-(arylmethylidene)-2,3-dihydro-1H-inden-1-ones 11-19 in refluxing ethanol. Some of the spiro-alkaloids (21, 22, 29 and 37) revealed potent antitumor properties against melanoma carcinoma cell lines (GaLa, LuPiCi and LuCa) utilizing the in vitro SRB standard method exhibiting potency close to that of the standard reference doxorubicin.

Synthesis, and QSAR analysis of anti-oncological active spiro-alkaloids.

QSAR study describes the anti-neoplastic spiro-alkaloids with relevant molecular descriptors using CODESSA III software. The dispiro[3H-indole-3,2'-pyrrolidine-3',3"-piperidines] 24-48 were synthesized via [3 + 2]-cycloaddition reaction of azomethine ylides, (generated in situ via decarboxylative condensation of isatins 21-23 with sarcosine) and 3E,5E-1-alkyl-3,5-bis(arylmethylidene)-4-piperidones 10-20. Some of the synthesized analogues exhibited promising antitumor properties against HELA (cervical), HEPG2 (liver), T-47D, MCF7 (breast), and HCT116 (colon) human tumor cell lines, demonstrating activity close to or even better than the standard Doxorubicin, based on in vitro Sulfo-Rhodamine-B bio-assay.

Macrocyclic peptidomimetics with antimicrobial activity: synthesis, bioassay, and molecular modeling studies.

Novel, cyclic peptidomimetics were synthesized by facile acylation reactions using benzotriazole chemistry. Microbiological testing of the synthesized compounds revealed an exceptionally high activity against Candida albicans with a minimum inhibitory concentration (MIC) two orders of magnitude lower than the MIC of the antifungal reference drug amphotericin B. A strikingly high activity was also observed against three Gram-negative bacterial strains (Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus vulgaris), two of which are known human pathogens. Thus the discovered chemotype is a potential polypharmacological agent. The toxicity against mammalian tumor cells was found to be low, as demonstrated in five different human cell lines (HeLa, cervical; PC-3, prostate; MCF-7, breast; HepG2, liver; and HCT-116, colon). The internal consistency of the experimental data was studied using 3D-pharmacophore and 2D-QSAR.

A benzotriazole-mediated route to protected marine-derived hetero-2,5-diketopiperazines containing proline.

A procedure for the cyclization of dipeptidoyl benzotriazolides containing proline derivatives promoted by triethylamine under MW activation is introduced. The reaction is general for a variety of dipeptidoyl benzotriazolides and represents a very practical and convenient method for the preparation of Pro- or Hyp-derived 2,5-diketopiperazines (2,5-DKPs) and bis-DKPs with a disulfide linker. This method can be used for the construction of 2,5-DKP compound libraries and for the synthesis of natural products with diketopiperazine cores.

Synthesis and bioactivity of a Goralatide analog with antileukemic activity.

Natural tetrapeptide Goralatide (AcSDKP) is a selective inhibitor of primitive haematopoietic cell proliferation. It is not stable in vivo and decomposes within 4.5min when applied to live cells. In this work we developed an analog of Goralatide that exhibits cytotoxicity towards human myeloid HL-60, HEL, Nalm-6 leukemia cells, endothelial HUVEC, glioblastoma U251 and transformed kidney 293T cells. The Goralatide analog showed significant stability in organic solution with no tendency to degrade oxidatively.

Peptidomimetics via modifications of amino acids and peptide bonds.

Peptidomimetics represent an important field in chemistry, pharmacology and material science as they circumvent the limitations of traditional peptides used in therapy. Self-structural organizations such as turns, helices, sheets and loops can be accessed by chemical modifications of amino acids or peptides. In-depth structural and conformational analysis and structure-activity relationships (SAR) offer a way to establish peptidomimetic libraries. Herein, we review recent developments in peptidomimetics that are formed via heteroatom replacement within the native amino acid backbone. Each sub-section describes structural features, utility and preparative methods.

Long-range chemical ligation from N→N acyl migrations in tryptophan peptides via cyclic transition states of 10- to 18-members.

Chemical ligations to form native peptides from N→N acyl migrations in Trp-containing peptides via 10- to 18-membered cyclic transition states are described. In this study, a statistical, predictive model that uses an extensive synthetic and computational approach to rationalize the chemical ligation is reported. N→N acyl migrations that form longer native peptides without the use of Cys/Ser/Tyr residues or an auxiliary group at the ligation site were achieved. The feasibility of these traceless chemical ligations is supported by the N-C bond distance in N-acyl isopeptides. The intramolecular nature of the chemical ligations is justified by using competitive experiments and theoretical calculations.

One-pot decarboxylative acylation of N-, O-, S-nucleophiles and peptides with 2,2-disubstituted malonic acids.

Monocarbonyl activation of 2,2-disubstituted malonic acids with benzotriazole leads to decarboxylation of one of the carboxy groups and formation of a CH bond. Intermediate carbonyl benzotriazoles then readily acylate nucleophilic reagents and peptides resulting in libraries of conjugates and peptidomimetics.

Tandem deprotection-dimerization-macrocyclization route to C(2) symmetric cyclo-tetrapeptides.

Dimerization-macrocyclization has been a long-standing problem in the cyclization of peptides since, together with the desired cyclic product, many cyclic oligomers and linear polymers may also be formed during the reaction. Therefore, the development of a process that affords the cyclic dimer predominantly is difficult. A novel and versatile strategy for the synthesis of symmetric cyclo-tetrapeptides by palladium-promoted tandem deprotection/cyclo-dimerization from readily available Cbz-dipeptidoyl benzotriazolides is reported (Cbz=carboxybenzyl).

Synthesis of taurine-containing peptides, sulfonopeptides, and N- and O-conjugates.

Taurine-containing water-soluble peptidomimetics were designed and synthesized. N-terminal taurine acylations allowed synthesis of a number of taurine-containing peptides. N-protection of taurine with Cbz and SO2-activation with benzotriazole followed by coupling with various amino esters, dipeptides and nucleophiles provided taurine N- and O-conjugates and sulfonopeptides.

Synthesis and direct C2 functionalization of imidazolium and 1,2,4-triazolium N-imides.

Pd-catalyzed direct C2 arylation and Cu-catalyzed direct one-pot alkynylation/intramolecular cyclization of azolium N-imides are reported. Various acetylenes, aryl iodides, and 1-alkyl substituents were examined. The mild protocol allows direct C2 arylation of azolium N-imides without the use of specialized reagents together with novel one-pot regioselective preparations of imidazole-pyrazolo and pyrazolo-1,2,4-triazole ring systems. The electronic properties of selected examples were examined by fluorescence spectroscopy.

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 characterisation of glucosamine-NSAID bioconjugates.

Strategies to couple non-steroidal anti-inflammatory drugs (NSAIDs) to a glucosamine hydrochloride salt via an amino acid linker are investigated and a series of novel NSAID-glucosamine bioconjugates have been prepared.