Ivanka Stankova

Synthesis of thiazole, imidazole and oxazole containing amino acids for peptide backbone modification.

Novel 5‐ring heterocyclic building blocks are synthesized. These can be incorporated into analogs of peptide antibiotics such as microcin B17, which is a potent DNA‐gyrase inhibitor that exhibits eight thiazole and oxazole moieties. In particular, the syntheses of imidazole and bisoxazole amino acids as novel peptidomimetics are reported, this includes a new procedure for the oxidative conversion of the intermediates oxazoline, imidazoline as well as oxazole–oxazoline into the corresponding heteroaromatic compounds. A mixture of 1,8‐diazabicyclo‐[5.4.0.]‐undec‐7‐ene/carbon tetrachloride/acetonitrile and pyridine proved to be a very effective and mild agent. Copyright

Synthesis, antioxidative and antiviral activity of hydroxycinnamic acid amides of thiazole containing amino acid

The synthesis and the biological (antioxidant and antiviral) activities of novel hydroxycinnamic acid amides of a thiazole containing TFA.valine-4-carboxylic acid ethyl ester are reported. The amides have been synthesized from p-coumaric, ferulic and sinapic acids with the corresponding TFA.valine-thiazole-4-carboxylic acid ethyl ester using the coupling reagent N-ethyl-N′-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and 4-(dimethylamino) pyridine (DMAP) as a catalyst. The antioxidant properties of the newly synthesized amides have been studied for then antioxidative activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH)* test. The newly synthesized compounds have been tested against the replication in vitro of influenza virus A (H3N2) and human herpes virus 1 and 2 (HSV-1 and HSV-2).

Amino acid and peptide esters of abacavir: synthesis and activity against human immunodeficiency virus type 1 in cell culture

Abacavir (ABC) is clinically associated with hypersensitivity reactions, risk for cardiovascular disease, etc. A possible way to minimize side effects is by modifying chemical structure. Three esters of ABC containing amino acid (glycine) and dipeptide esters (glycyl-glycine) were synthesized and their activity on HIV-1 III B replication in MT-4 cells was evaluated. One of the newly synthesized esters—Gly-ABC—demonstrates low-cytotoxicity and high-anti-HIV-1 activity in MT-4 cells, as well as low-mitochondrial toxicity and high-genetic barrier to resistance.

Cinnamic Esters of Acyclovir-Synthesis and Biological Activity

In the present study we have synthesized esters of acyclovir (2–4) with cinnamic acids (p-coumaric, ferulic, and sinapic acids) and evaluated them for their antiviral and antioxidant potential. The antiviral activity of the newly synthesized compounds has been tested against human herpes virus 1 (HSV-1) in vitro. The results indicate that none of the synthesized compounds inhibits the tested virus strain. The antioxidant properties have been studied using 2,2-diphenyl-1-picrylhydrazyl (DPPH)* test.

Hydroxycinnamic acid amides with oxazole-containing amino acid: synthesis and antioxidant activity.

Three hydroxycinnamic acid derivatives conjugated with glycine-containing oxazole were synthesized. The prepared compounds were tested for their antioxidant activity using the 1,1-diphenyl-2-picrylhydrazyl (DPPH・) test. Among the tested hydroxycinnamic acid amides the highest DPPH scavenging activity has been found for the sinapic acid amide.

New analogues of acyclovir--synthesis and biological activity.

New acyclovir esters with peptidomimetics were synthesized and evaluated in vitro for their antiviral activity against the replication of Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). The infl uence of peptidomimetics containing oxazole and thiazolyl-thiazole moieties on the antiviral activity is also reported. The esters were synthesized using the coupling reagents N-ethyl-N’-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and N,N-dimethyl-4-aminopyridine (DMAP) as a catalyst.

Synthesis and Anti-Virus Activity of Some Nucleosides Analogues

New 3’-, 5’-, 5-bromo-2’-deoxyuridine (3 a-g) and 3’-, 5’-thymidine (4 a-i) analogues with amino acid and peptide residues were synthesized and evaluated for antiviral activity. The influence of long peptide chains, essential amino acids and the effect of this structural modification on the antiviral activity has been also reported. Three 5-bromo-2’-deoxyuridine derivatives containing glycyl-, glycyl-glycyl-and glycyl-gly-cyl-glycyl-residues (3a, 3b, 3c) showed a strong activity against the herpes virus PsRV and a moderate one vs. HSV-1. The corresponding thymidine analogues were considerably less effective, and only compounds 4d and 4h showed a borderline effect against PsRV

Tailoring acyclovir prodrugs with enhanced antiviral activity: rational design, synthesis, human plasma stability and in vitro evaluation

Bile acid prodrugs have served as a viable strategy for refining the pharmaceutical profile of parent drugs through utilizing bile acid transporters. A series of three ester prodrugs of the antiherpetic drug acyclovir (ACV) with the bile acids cholic, chenodeoxycholic and deoxycholic were synthesized and evaluated along with valacyclovir for their in vitro antiviral activity against herpes simplex viruses type 1 and type 2 (HSV-1, HSV-2). The in vitro antiviral activity of the three bile acid prodrugs was also evaluated against Epstein–Barr virus (EBV). Plasma stability assays, utilizing ultra-high performance liquid chromatography coupled with tandem mass spectrometry, in vitro cytotoxicity and inhibitory experiments were conducted in order to establish the biological profile of ACV prodrugs. The antiviral assays demonstrated that ACV-cholate had slightly better antiviral activity than ACV against HSV-1, while it presented an eight-fold higher activity with respect to ACV against HSV-2. ACV-chenodeoxycholate presented a six-fold higher antiviral activity against HSV-2 with respect to ACV. Concerning EBV, the highest antiviral effect was demonstrated by ACV-chenodeoxycholate. Human plasma stability assays revealed that ACV-deoxycholate was more stable than the other two prodrugs. These results suggest that decorating the core structure of ACV with bile acids could deliver prodrugs with amplified antiviral activity.

Molecular Docking of Amino Acid Analogues of Rimantidine

M2 channel is a 97-residue single-pass membrane protein with its N-and C-termini directed toward the outside and inside of the virion, re-spectively; it is a homotetramer in its native state. The four TM helicesform a channel in which His37 is the pH sensor and Trp41, the gate. Theadamantane-based drugs, amantadine and rimantadine, which target theM2 channel, have been used as rst-choice antiviral drugs against commu-nity outbreaks of inuenza A viruses for many years, but resistance to theadamantanes has recently become widespread. To overcome this dierentanalogues of rimantidine have been synthesized. The aim of this study isto predict the biological activity of amino acid analogues of rimantidinewith a help of docking studies in order to synthesize only promising can-didates. Twenty analogues of rimantidine with natural amino acids wereused. Docking was performed with the M2 channel as it is very impor-tant in the replicative cycle of inuenza A virus. Crystal structure of thechannel was obtained from RCSB (PDB id: 2rlf). Docking was performedwith GOLD 5.2 using GoldScore tness function. The complexes of riman-tidine analogues with M2 channel were analyzed and their total energieswere calculated in Molegro Molecular Viewer. Total energy of the com-plex rimantidine/M2 channel is -29.437 kJ/mole. All complexes of aminoacid analogues of rimantidine with the channel have lower energies, butthe lowest are the energies of the complexes of Asn-Rim/M2 channel andHis-Rim/M2 channel with -72.475 and -76.440 kJ/mole, respectively. Fromthe energetically point of view complexes will be more stables. This meansthat all rimantidine analogues will block the M2 channel thus will aectthe viral replication cycle. Docking studies are an useful tool for predictionof biological eect of dierent type of compounds and could be applied inshortening the drug design process.