Thiazolopyrimidine Derivatives Research Articles

Biological properties and in silico studies of thiazolopyrimidine derivatives active against visceral and cutaneous Leishmania spp. amastigote forms

Biological properties and in silico studies of thiazolopyrimidine derivatives active against visceral and cutaneous Leishmania spp. amastigote forms

Thiazolopyrimidine derivatives as novel class of small molecule tyrosinase inhibitor

Tyrosinase, the rate-limiting enzyme of melanogenesis, plays a crucial role in hyperpigmentation. As a result, in this study, a novel class of thiazolopyrimidine derivatives was developed and synthesized as tyrosinase inhibitor. The structure of derivatives was characterized using various spectroscopy techniques, including FTIR, Mass, 1H-NMR, and 13C-NMR. Next, the inhibitory activities of all derivatives were examined against tyrosinase, and, 6a as the most potent compound, exhibited an IC50 value of 28.50 µM. Furthermore, the kinetic study of 6a was performed to better understand the inhibitory mechanism and its type of inhibition. The UV/Vis spectra analysis was also executed to provide valuable evidence supporting the inhibitory mechanism of compound 6a in the context of tyrosinase inhibition. Also, molecular docking and dynamic molecular study of 6a were executed to study its interactions within the enzyme’s binding site.

Synthesis, antifungal evaluation, and molecular docking studies of steroidal thiazolopyrimidines.

A series of steroidal thiazolopyrimidine derivatives were developed and evaluated for their antifungal properties against Candida species using steroid as the basic skeletonand a thiazolopyrimidine heterocycle as a pharmacophore in the D-ring. Dehydroepiandrosterone, aromatic aldehydes, and 2-aminothiazole were used in a one-pot multicomponent reaction with silica sulphuric acid to generate the target molecules. Additionally, molecular docking studies were conducted to determine how synthesized steroidal derivatives interacted with the amino acid residues of CYP51 ofCandida albicans.

Insights into the crystal structure and computational studies of newly synthesized thiazolopyrimidine derivatives against adenosine receptor (Thermostabilised HUMAN A2a)

Efficient synthesis of biologically active molecules is one of the main objectives of organic and medicinal chemistry. In this context, thiazolopyrimidine derivatives were synthesized in good yield (average 84%). The molecular docking studies suggest that the two derivatives 3a and 3b of the thiazolopyrimidines have good binding affinity towards adenosine receptors (ARs) (Thermostabilised HUMAN A2a) complex. To probe intermolecular interactions DFT (NBO/NLO/QTAIM) calculations were performed. In addition, an ADMET analysis has been performed and discussed for both compounds. The results suggest that both compounds could exhibit a strong binding affinity for the thermostabilized human A2a receptor complex.

Design, synthesis, docking, and anticancer evaluations of new thiazolo[3,2-a] pyrimidines as topoisomerase II inhibitors

New thiazolopyrimidine derivatives 2, 3a-d, 4a-c, 5, 6a-c, and 7a,b were synthesised. All prepared compounds were evaluated by MTT cytotoxicity assay against three human tumour cell lines. Compounds 3c, 3d, 4c, 6a, 6b, and 7b exhibited potent to strong anticancer activity that was nearly comparable or superior to Doxorubicin. Compounds exhibiting significant cytotoxicity were further selected to study their inhibitory activity on the Topo II enzyme. Compound 4c was the most potent Topo II inhibitor with an IC50 value of 0.23 ± 0.01 µM, which was 1.4-fold and 3.6-fold higher than the IC50 values of Etoposide and Doxorubicin. Furthermore, compound 4c showed significant cell cycle disruption and apoptosis on A549 cells compared to control cells. Molecular docking of the most active compounds illustrated proper fitting to the Topo II active site, suggesting that our designed compounds are promising candidates for the development of effective anticancer agents acting through Topo II inhibition.

Design, synthesis, in vitro – In vivo biological evaluation of novel thiazolopyrimidine compounds as antileishmanial agent with PTR1 inhibition

The leishmaniasis are a group of vector-borne diseases caused by a protozoan parasite from the genus Leishmania. In this study, a series of thiazolopyrimidine derivatives were designed and synthesized as novel antileishmanial agents with LmPTR1 inhibitory activity. The final compounds were evaluated for their in vitro antipromastigote activity, LmPTR1 and hDHFR enzyme inhibitory activities, and cytotoxicity on RAW264.7 and L929 cell lines. Based on the bioactivity results, three compounds, namely L24f, L24h and L25c, were selected for evaluation of their in vivo efficacy on CL and VL models in BALB/c mice. Among them, two promising compounds, L24h and L25c, showed in vitro antipromastigote activity against L. tropica with the IC50 values of 0.04 μg/ml and 6.68 μg/ml; against L. infantum with the IC50 values of 0.042 μg/ml and 6.77 μg/ml, respectively. Moreover, the title compounds were found to have low in vitro cytotoxicity on L929 and RAW264.7 cell lines with the IC50 14.08 μg/ml and 21.03 μg/ml, and IC50 15.02 μg/ml and 8.75 μg/ml, respectively. LmPTR1 enzyme inhibitory activity of these compounds was determined as 257.40 μg/ml and 59.12 μg/ml and their selectivity index (SI) over hDHFR was reported as 42.62 and 7.02, respectively. In vivo studies presented that L24h and L25c have a significant antileishmanial activity against footpad lesion development of CL and at weight measurement of VL group in comparison to the reference compound, Glucantime®. Also, docking studies were carried out with selected compounds and other potential Leishmania targets to detect the putative targets of the title compounds. Taken together, all these findings provide an important novel lead structure for the antileishmanial drug development.

Design, synthesis and chemoinformatic studies of new thiazolopyrimidine derivatives as potent anticancer agents via phosphodiesterase-5 inhibition and apoptotic inducing activity

Inhibition of phosphodiesterase-5 (PDE5) has been validated as possible new therapeutic approach for cancer. To further explore this concept, three series of thiazolopyrimidine containing compounds has been designed and synthesized as PDE5 inhibitors. All the compounds were evaluated against PDE5 inhibitory effect in addition to their antiproliferative activities against three different cancer cell lines (colorectal carcinoma colon cancer; HCT-116, mammary gland breast cancer; MCF-7 and human prostate cancer; PC3) in addition to normal cell line (human lung fibroblast; WI38). Among the synthesized compounds, three compounds (3c, 4a and 5a) significantly inhibit PDE5 with IC50 0.046 nM, 0.323 nM, and 0.546 nM, respectively in comparison to sildenafil (IC50 0.689 nM). Moreover, compounds 3a, 3c, 3f, 3g, 3h were found to have potent cytotoxic activities against MCF-7 cancer cell line with IC50 ranging from 5.47±0.4 to 9.92±0.9 µM. Apoptosis cytometric assay showed that compound 5a induced pronounced increase in the total percent of apoptotic HCT116 cells (15.87%) compared to 3c (12.43%), mainly during late stage. Additionally, compounds 3c and 5a were evaluated against proapoptotic Bax, and anti-apoptotic Bcl-2 expression levels that revealed that both compounds expressively enhanced Bax 7.68 and 5.42 folds, respectively compared to untreated control. Also, both compounds 3c and 5a down regulate Bcl-2 with 2.94 and 2.354 ng/mL, respectively. From the docking study, it was concluded that compounds 3c and 5a interact in a similar pattern to sildenafil in the binding site of PDE5. Finally, logP and in silico ADMET assessment were calculated to determine the lipohpilcity metric and ADMET properties for these candidates.

Synthesis, Characterization and Antifungal Activity of Novel Thiazolo-Pyrimidine Fused Heterocycles

In medicinal chemistry, nitrogen and sulphur containing heterocyclic compounds are well known for their therapeutic properties.(1) Among them thiazole and pyrimidine derivatives possess diverse pharmaceutical activities.(2,3) More particularly thiazolo-pyrimidine fused shows various therapeutically activities like, anticancer, antimicrobial, antibacterial effects, antiviral ,etc (4-7). Such type of fused heterocycles containing furan and naphthalene moieties has not been developed. Thus, the aim of the present work to study the novel fused thiazolo-pyrimidine derivatives, their characterization and antifungal activity. (scheme-1).

MOLECULAR DOCKING STUDIES OF THIAZOLOPYRIMIDINE DERIVATIVES AS ANTIMICROBIAL AGENTS

Antimicrobial agents are essential drugs for the health of humans and animals as they cure infectious diseases produced by several contagious strains (bacteria, fungi, parasites, and viruses). Antibiotics efficacy is restricted by an increased number of antibiotic-resistant bacteria. Computational chemistry is crucial in the development of novel potential therapeutics. In this study, the objective was to integrate the two separately bioactive molecules, i.e., thiazoles and pyrimidines into one molecule to produce compounds with better pharmacological activity. Various thiazolo-pyrimidine derivatives were planned through a suitable synthetic scheme and were docked on DNA gyrase subunit B and dihydrofolate reductase, which are established targets for microbial infection. The results were studied and the findings were compared to two known medications as well as potential inhibitors. The result recognizes few thiazolo-pyrimidine derivatives with increased binding efficiency leading to enhanced potency.

Synthesis and Anticancer Activity of New Pyrimidine and Oxadiazole Acyclic Nucleoside Analogs and Thiazolopyrimidine Derivatives

Synthesis and Anticancer Activity of New Pyrimidine and Oxadiazole Acyclic Nucleoside Analogs and Thiazolopyrimidine Derivatives

Efficient L-Proline catalyzed synthesis of some new (4-substituted-phenyl)-1,5-dihydro-2H-pyrimido[4,5-d][1,3]thiazolo[3,2a]-pyrimidine-2,4(3H)-diones bearing thiazolopyrimidine derivatives and evaluation of their pharmacological activities

In the present study, a simple and efficient protocol has been developed to synthesize a series of new (4-substituted-phenyl)-1,5-dihydro-2H-pyrimido[4,5-d][1,3]thiazolo[3,2a]-pyrimidine-2,4(3H)-dione derivatives (4a-g) through L-proline-catalyzed reaction of 2-amino-4-(4-substituted-phenyl)thiazole (1), substituted benzaldehyde (2), and barbituric/thiobarbituric acid (3) at a refluxed temperature in aqueous ethanol under mild and metal-free conditions. The obtained compounds were evaluated for in vitro cytotoxicity and anti-inflammatory effects. The in silico docking studies provided the probable interactions of synthesized compounds with P38 MAP kinase and MMP-9 proteins. The structures of all the synthesized compounds were confirmed using analytical and spectroscopic techniques. The in vitro cytotoxicity studies revealed the potential cytotoxic effects of the compounds 4f and 4g. The anti-inflammatory studies suggested the prominent anti-inflammatory effects of the compounds 4a and 4g. The SAR studies showed the importance of electron-withdrawing groups in enhancing the potency among the tested compounds. The results of in silico studies supported our findings from in vitro analysis in terms of drug-likeness of the synthesized compounds and their effective interactions with P38 MAP kinase and MMP-9 proteins envisaging their use as prominent therapeutic agents.

Silica-supported sodium carbonate: an efficient heterogeneous catalyst for the synthesis of new thiazolopyrimidine derivatives

Silica-supported sodium carbonate: an efficient heterogeneous catalyst for the synthesis of new thiazolopyrimidine derivatives

Synthesis and spectral characterization of some new thiazolopyrimidine derivatives

Thiazolopyrimidnes are considered one of the most interesting classes in heterocyclic chemistry due to their pharmaceutical importance. Herein, we report the synthesis of some new heterocyclic compounds containing thiazolopyrimidine starting from compound (1) which was previously prepared in literature. The starting compound was allowed to react with different alkylating agents such as chloroacetone, chloroacetyl chloride, and phenacyl bromide to afford derivatives (2-4). Compound (5), benzylidene derivative, was obtained by the reaction of compound (2) with benzaldehyde while amino-dicarbonitrile compound (6) can be obtained by the reaction of compound (5) and malononitrile. Acetylation of amino group in compound (6) with chloroacetyl chloride led to formation of compound (7). Nucleophilic substitution of chlorine in compound (7) by aniline gave compound (8) which further subjected the Munich reaction to form compound (9). All new synthesized compounds were characterized using different elemental and spectral analysis.

Synthesis and Crystal Structure of Thiazolopyrimidine Derivatives: Insights into Weak Interactions

Synthesis and Crystal Structure of Thiazolopyrimidine Derivatives: Insights into Weak Interactions

New thiazolopyrimidine as anticancer agents: Synthesis, biological evaluation, DNA binding, molecular modeling and ADMET study

In the present study, new series of thiazolopyrimidine derivatives was synthesized as purine analogs. The structures of the products were confirmed through spectroscopic techniques such as NMR and mass spectrometry. In addition, the synthesized compounds were evaluated as antitumor active agent through NCI screening protocol against 60 different cell lines under 9 different panels. Furthermore, DNA binding activity of the compounds was also evaluated. The results revealed that compound 35 proved to be the most active member of the tested series and it is promoted to the 5-dose testing where it gives GI50, TGI and LC50 values of 1.07, 6.61, 34.7 μM respectively. Furthermore, it also proved to have a good DNA binding activity with value that is comparable with that produced by doxorubicin which was used as positive standard. In addition, compound 27 was proved to be the most active DNA binding agent with binding affinity 28.38 ± 1.1. The pharmacokinetic properties were also calculated. Molecular docking studies suggested binding mode of compounds 27 and 35 to DNA minor groove via hydrogen bonding interaction. The anticancer activity of compounds 27 and 35 may be attributed to DNA binding.

Design, synthesis, and in vitro biological evaluation of novel thiazolopyrimidine derivatives as antileishmanial compounds.

A series of thiazolopyrimidine derivatives was designed and synthesized as a Leishmania major pteridine reductase 1 (LmPTR1) enzyme inhibitor. Their LmPTR1 inhibitor activities were evaluated using the enzyme produced by Escherichia coli in a recombinant way. The antileishmanial activity of the selected compounds was tested in vitro against Leishmania sp. Additionally, the compounds were evaluated for cytotoxic activity against the murine macrophage cell line RAW 264.7. According to the results, four compounds displayed not only a potent in vitro antileishmanial activity against promastigote forms but also low cytotoxicity. Among them, compound L16 exhibited an antileishmanial activity for both the promastigote and amastigote forms of L. tropica, with IC50 values of 7.5 and 2.69 µM, respectively. In addition, molecular docking studies and molecular dynamics simulations were also carried out in this study. In light of these findings, the compounds provide a new potential scaffold for antileishmanial drug discovery.

Synthesis and Structure of Thiazolopyrimidine Derivatives

Three-component condensations of ethyl acetoacetate with 1,3-thiazol-2-amine and aromatic aldehydes in isopropyl alcohol at 20°C under ultrasonic activation lead to the formation of ethyl 5-aryl-7-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylates, ethyl 5-aryl-7-hydroxy-7-methyl-6,7-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylates, or ethyl 2-hydroxy-2-methyl-2H-chromene-3-carboxylate, depending on the position and nature of substituents in the aldehyde component. The structure of the isolated compounds was determined by one- and two-dimensional NMR and IR spectroscopy, and a plausible mechanism of their formation was proposed.

Synthesis and Cytotoxic Activity of New Thiazolopyrimidine Sugar Hydrazones and Their Derived Acyclic Nucleoside Analogues.

New thienyl- or chlorophenyl-substituted thiazolopyrimidine derivatives and their derived sugar hydrazones incorporating acyclic d-galactosyl or d-xylosyl sugar moieties in addition to their per-O-acetylated derivatives were synthesized. Heterocyclization of the formed sugar hydrazones afforded the derived acyclic nucleoside analogues possessing the 1,3,4-oxadiazoline as modified nucleobase via acetylation followed by the cyclization process. The cytotoxic activity of the synthesized compounds was studied against human breast cancer MCF7 and MDA-MB-231 cell lines as well as human colorectal cancer HCT 116 and Caco-2 cell lines. High activities were revealed by compounds 1, 8, 10, 11, and 13 against Caco-2 and MCF7 cells in addition to moderate activities exhibited by other compounds against HCT116 or MDA-MB-231 cells.

The potential antiviral activity of a novel pyrimidine derivative against Herpes Simplex Virus type-1 (HSV-1)

Context: Previous studies and the are trials to find new molecules to help in the war against viruses. We have started preparing new compounds in this field beginning with the nucleus of thiouracil for what is known from its multiple biological activity, including against viruses. objective: Evaluation antiviral activities of new synthetic pyrimidine compounds. materials and methods: Our new target compounds were prepared starting with 2-thiouracil which was hydroxy methylated to give compound 1 which in turn was chloromethylated by thionyl chloride yielding compound 2. This chloromethyl compound was then reacted with three selected aromatic amines namely, p-nitroaniline, p-fluoroaniline and 2-aminopyridine respectively, giving aminomethyl derivatives 3a-c, which were used as starting material for preparing many target compounds by reaction firstly with s-bromopropanoic acid affording pyrimido thiazine derivatives 4a-c. They were cyclocondensed with anthranilic acid giving pyrimido quinazoline derivatives 5a-c. In another pathway, they were reacted with s-amino ethanol affording imidazopyrimidine derivatives 6a-c. Also, they were S-methylated by methyl iodide giving methyl thiopyrimidine derivatives 7a-c alo were cyclocondensed with ethylbromoacetate and/or chloroacetyl chloride giving isomers of thiazolopyrimidine derivatives 8a-c and 9a-c. Finally, they S-alkylated by reaction with chloroacetic acid yielding acetic acid derivatives 10a-c. Results: Compound 3c and 10c exhibited a potent antiviral activity and, they showed insignificant differences as compared with other compounds. In addition, 10c exhibited higher efficacy as compared with acyclovir. Conclusion: The aryl methyl aminopyrimidine was the pharmacophore of these target compounds. Any change in the structure decreases the activity except the introduction of acetic acid moiety which potentiate the antiviral activity.

Antioxidant Properties of Synthesized Bicyclic Thiazolopyrimidine Derivatives as Possible Therapeutic Agents

Oxidant/antioxidant imbalance in the body has been implicated as one of the pathophysiological mechanisms leading to disease development. Therefore, we searched for a good antioxidant candidate that can be used as a therapeutic agent alone or in combination with other reported drugs. Earlier, we reported the A2A receptor antagonist properties of 7-Imino-3-substituted-2-thioxo-3,7-dihydro-2H-thiazolo[4,5-d]pyrimidin-6-yl)-urea derivatives (compounds 1–12) and the neuroprotective effect of compound 2. Therefore, in the present work, the antioxidant potential of compounds 1–12 was studied. Compounds 1–12 were screened using different (red/ox) tests, such as the Ferric Reducing Antioxidant Power (FRAP) assay, to determine total antioxidant activity, redox status tests (with and without prooxidants) such as Advanced Oxidation Protein Products (AOPP) and Total Oxidative Status (TOS) which measures H2O2 and lipid hydroperoxides, Paraoxonase-1 Enzyme Activity (PON1), Total SH-groups content, and Total Antioxidative Status (TAS) for antioxidant determination. The Prooxidative Score, Antioxidative Score, and Oxy Score were also calculated. From the obtained results, compounds 6 (8720 FRAP value and 39.31 Oxy Score) and 12 (7866 FRAP value and 36.41 Oxy Score) were found to possess significant antioxidant activity with reasonable potential for therapeutic activity.