Triazolopyrimidine Derivatives Research Articles

Advancements in the Synthesis of Triazolopyrimidines

: The triazolopyrimidine scaffold indeed holds a prominent place in medicinal chemistry due to its versatile pharmacological properties. Researchers have explored the scaffold and its derivatives for various therapeutic applications. The unique structure of triazolopyrimidine has made it a valuable template for designing medicinally active molecules. The literature is full of studies showcasing the synthesis and biological activities of compounds containing the triazolopyrimidine ring, either fused or coupled with other heterocycles. The aim of this review is to provide a comprehensive and general summary of the recent advancements in the synthesis of triazolopyrimidine derivatives (Year 2021 to present).

Design, synthesis, and structure−activity relationship studies of triazolo-pyrimidine derivatives as WRN inhibitors for the treatment of MSI tumors

Werner syndrome RecQ helicase (WRN), a member of the RecQ helicase family, has recently been identified as a synthetic lethal target in microsatellite instability (MSI) tumors. The triazolo-pyrimidine compound HRO761 is the first WRN inhibitor to enter clinical trials, but research on this scaffold remains limited. Here, we designed a series of derivatives to systematically study the structure-activity relationship (SAR) of triazolo-pyrimidine scaffolds, leading to the discovery of compound S35. S35 exhibited excellent WRN helicase inhibitory activity (ADP-Glo kinase assay IC50 = 16.1 nM, fluorometric helicase assay IC50 = 23.5 nM). Additionally, S35 exhibited excellent cellular selectivity, with antiproliferative activity against multiple MSI cell lines (GI50 = 36.4−306 nM), while the GI50 values for multiple microsatellite stability (MSS) cell lines were greater than 20,000 nM. Furthermore, we observed that compound S35 induced DNA damage and caused G2/M cell cycle arrest in MSI cells, which did not occur in MSS cells. S35 demonstrated favorable oral pharmacokinetic properties, with oral administration resulting in dose-dependent tumor growth inhibition in the SW48 xenograft model. These findings provide a promising outlook for the development of WRN inhibitors for the treatment of MSI tumors.

Discovery of Triazolopyrimidine Derivatives as Selective P2X3 Receptor Antagonists Binding to an Unprecedented Allosteric Site as Evidenced by Cryo-Electron Microscopy.

The P2X3 receptor (P2X3R), an ATP-gated cation channel predominantly expressed in C- and Aδ-primary afferent neurons, has been proposed as a drug target for neurological inflammatory diseases, e.g., neuropathic pain, and chronic cough. Aiming to develop novel, selective P2X3R antagonists, tetrazolopyrimidine-based hit compound 9 was optimized through structure-activity relationship studies by modifying the tetrazole core as well as side chain substituents. The optimized antagonist 26a, featuring a cyclopropane-substituted triazolopyrimidine core, displayed potent P2X3R-antagonistic activity (IC50 = 54.9 nM), 20-fold selectivity versus the heteromeric P2X2/3R, and high selectivity versus other P2XR subtypes. Noncompetitive P2X3R blockade was experimentally confirmed by calcium influx assays. Cryo-electron microscopy revealed that 26a stabilizes the P2X3R in its desensitized state, acting as a molecular barrier to prevent ions from accessing the central pore. In vivo studies in a rat neuropathic pain model (spinal nerve ligation) showed dose-dependent antiallodynic effects of 26a, thus presenting a novel, promising lead structure.

Triazolopyrimidine Derivatives: An Updated Review on Recent Advances in Synthesis, Biological Activities and Drug Delivery Aspects.

Molecules containing triazolopyrimidine core showed diverse biological activities, including anti-Alzheimer's, anti-diabetes, anti-cancer, anti-microbial, anti-tuberculosis, anti-viral, anti-malarial, anti-inflammatory, anti-parkinsonism, and anti-glaucoma activities. Triazolopyrimidines have 8 isomeric structures, including the most stable 1,2,4-triazolo[1,5- a] pyrimidine ones. Triazolopyrimidines were obtained by using various chemical reactions, including a) 1,2,4-triazole nucleus annulation to pyrimidine, b) pyrimidines annulation to 1,2,4-triazole structure, c) 1,2,4-triazolo[l,5-a] pyrimidines rearrangement, and d) pyrimidotetrazine rearrangement. This review discusses synthetic methods, recent pharmacological actions and drug delivery perspectives of triazolopyrimidines.

Application of the aza‐Wittig reaction for efficient synthesis of diversely substituted benzo[f]Chromeno[2,3‐d]pyrimidine and benzo[f]chromeno[2,3‐d][1,2,4]triazolopyrimidine derivatives

AbstractAn efficient synthesis of novel benzo[f]Chromeno[2,3‐d]pyrimidine and unknown benzo[f]chromeno[2,3‐d][1,2,4]triazolopyrimidine derivatives is described utilizing ethyl‐2‐amino‐4‐phenyl‐4H‐benzo[f]chromene‐3‐carboxylate as precursor via aza‐Wittig reaction. The process proved to be simple, high‐yielding, and efficient.

In Silico Exploration of few TriazoloPyrimidine Derivatives as Virtual Inhibitors against SARS-CoV-2 : A Comprehensive Analysis Integrating Molecular Docking and ADME-Toxicity Evaluation

This ground-breaking research delves into the potential of novel triazolopyrimidine derivatives as inhibitors of SARS-CoV, employing a robust in-silico approach that integrates molecular docking studies, molecular dynamics simulations, and comprehensive ADMET parameter assessments. The overarching goal is to identify compounds that exhibit both robust binding affinity and favourable pharmacokinetic profiles, laying the foundation for potential antiviral drug development. The methodology begins with the meticulous selection of triazolo pyrimidine derivatives based on their structural characteristics. Molecular docking studies are then conducted, focusing on a specific binding site on the SARS-CoV target. Subsequent molecular dynamics simulations provide a dynamic perspective on the stability of the binding interactions over time. ADMET parameter assessments are employed to evaluate drug-likeness and safety, crucial factors in determining the compounds' viability as potential drug candidates. The findings of this research underscore promising interactions between the triazolo pyrimidine derivatives and the targeted viral site, suggesting their potential as inhibitors of SARS-CoV. Importantly, the ADMET assessments contribute valuable insights into the pharmacokinetic properties of the compounds, informing their overall safety and suitability for further development. Notably, molecular docking studies include a comparative analysis with the standard antiviral drug remdesivir, revealing that the triazolo pyrimidine derivatives exhibit energy scores surpassing those of remdesivir. This finding signifies a potential advantage in terms of binding affinity and effectiveness against SARS-CoV. The implications of this research are profound, extending beyond the identification of potential inhibitors for SARS-CoV to contributing essential knowledge for the development of therapeutics against coronaviruses in general. This study serves as a crucial stepping stone for subsequent experimental validation and optimization of the identified compounds, propelling future drug discovery endeavours in the fight against coronaviral infections.

Insight into the Inhibitory Mechanism of Embryonic Ectoderm Development Subunit by Triazolopyrimidine Derivatives as Inhibitors through Molecular Dynamics Simulation.

Inhibition of the Embryonic Ectoderm Development (EED) subunit in Polycomb Repressive Complex 2 (PRC2) can inhibit tumor growth. In this paper, we selected six experimentally designed EED competitive Inhibitors of the triazolopyrimidine derivatives class. We investigated the difference in the binding mode of the natural substrate to the Inhibitors and the effects of differences in the parent nuclei, heads, and tails of the Inhibitors on the inhibitory capacity. The results showed that the binding free energy of this class of Inhibitors was close to or lower compared to the natural substrate, providing an energetic basis for competitive inhibition. For the Inhibitors, the presence of a strong negatively charged group at the 6-position of the parent nucleus or the 8'-position of the head would make the hydrogen atom on the head imino group prone to flip, resulting in the vertical movement of the parent nucleus, which significantly decreased the inhibitory ability. When the 6-position of the parent nucleus was a nonpolar group, the parent nucleus would move horizontally, slightly decreasing the inhibitory ability. When the 8'-position of the head was methylene, it formed an intramolecular hydrophobic interaction with the benzene ring on the tail, resulting in a significant increase in inhibition ability.

Synthesis, biological activity, and molecular dynamic studies of new triazolopyrimidine derivatives

New series of triazolopyrimidine derivatives were designed, synthesized and fully characterized by spectroscopic tools. The new compounds were investigated as antimicrobial agents against two bacterial and two fungal strains. The antimicrobial results revealed that the triazolopyrimidine derivative 3b exhibited excellent antibacterial and antifungal activity higher than the standard drug (Neomycin). Additionally, we studied the antiviral activity of the three compounds against two different viruses (Corona Virus 229E, and herpes). The fluoro triazolopyrimidine derivatives 3a,b showed significant antiviral activity against low pathogenic Corona virus (229E) with selective index of 25.87 and 18.15 respectively. The same compounds showed good antiviral activity against human herpes type 2 with selective index of 17.7 and 11. The molecular dynamics simulation (MD) studies were also implemented to assign the interaction as well as the stability of the protein–ligand complex in motion.

The Effects of Novel Triazolopyrimidine Derivatives on H2S Production in Lung and Vascular Tonus in Aorta

Introduction: Hydrogen sulfide (H2S), known as a third gasotransmitter, is a signaling molecule that plays a regulatory role in physiological and pathophysiological processes. Decreased H2S levels were reported in inflammatory respiratory diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary hypertension. H2S donors or drugs that increase H2S have emerged as novel treatments for inflammatory respiratory diseases. We previously showed that resveratrol (RVT) causes vascular relaxation and antioxidant effects by inducing H2S production. In the current study, we synthesized a new molecule Cpd2, as an RVT analog. We examined the effect of Cpd2 and its precursor chalcone compound (Cpd1) on H2S formation under both healthy and oxidative stress conditions in the lung, as well as vascular relaxation in the aorta. Methods: Cpd2 synthesized from Cpd1 with microwaved in basic conditions. H2S formation was measured by H2S biosensor in the mice lungs under both healthy and pyrogallol-induced oxidative stress conditions in the presence/absence of H2S synthesis inhibitor aminooxyacetic acid (AOAA). The effect of compounds on vascular tonus is investigated in mice aorta by DMT myograph. Results: RVT and Cpd2 significantly increased l-cysteine (l-cys) induced-H2S formation in the lung homogenates of healthy mice, but Cpd1 did not. Superoxide anion generator pyrogallol caused a decrease in H2S levels in mice lungs and Cpd2 restored it. Inhibition of Cpd2-induced H2S formation by AOAA confirmed that Cpd2 increases endogenous H2S formation in both healthy and oxidative stress conditions. Furthermore, we found that both Cpd1 and Cpd2 (10−8–10−4 M) caused vascular relaxation in mice aorta. Discussion and Conclusion: We found that Cpd2, a newly synthesized RVT analog, is an H2S-inducing molecule and vasorelaxant similar to RVT. Since H2S has antioxidant and anti-inflammatory effects, Cpd2 has a potential for the treatment of respiratory diseases where oxidative stress and decreased H2S levels are present.

Design, Synthesis and Biological Evaluation of Novel Pyrazolotriazolopyrimidine Derivatives as Potential Anticancer Agents

Three novel pyrazolo-[4,3-e][1,2,4]triazolopyrimidine derivatives (1, 2, and 3) were designed, synthesized, and evaluated for their in vitro biological activity. All three compounds exhibited different levels of cytotoxicity against cervical and breast cancer cell lines. However, compound 1 showed the best antiproliferative activity against all tested tumor cell lines, including HCC1937 and HeLa cells, which express high levels of wild-type epidermal growth factor receptor (EGFR). Western blot analyses demonstrated that compound 1 inhibited the activation of EGFR, protein kinase B (Akt), and extracellular signal-regulated kinase (Erk)1/2 in breast and cervical cancer cells at concentrations of 7 and 11 µM, respectively. The results from docking experiments with EGFR suggested the binding of compound 1 at the ATP binding site of EGFR. Furthermore, the crystal structure of compound 3 (7-(4-bromophenyl)-9-(pyridin-4-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine) was determined by single crystal X-ray analysis. Our work represents a promising starting point for the development of a new series of compounds targeting EGFR.

Identification of a herbicide-resistant biotype of Echinochloa crus-galli in Ukraine

Ukraine is one of the world’s guarantors of food security and has the potential to further increase agricultural production. However, the vast majority of herbicides used on crops are acetolactate synthase (ALS) inhibitors, which poses a threat of herbicide-resistant weed species. The emergence and spread of herbicide-resistant weed biotypes can significantly increase the cost of growing crops to the point of loss of profitability. Herbicide resistance in barnyardgrass (Echinochloa crus-galli var. crus-galli) has been studied in long-term field and greenhouse experiments. Resistance of E. crus-galli to the ALS herbicide triazolopyrimidine derivative ‒ penoxsulam was identified. Expressed resistance was observed in weed plants grown from seeds collected under production conditions in Kherson region in 2015–2016 and 2020–2021. Cross resistance was observed for imidazolinone and sulfonylurea derivatives. It should be noted that the level of cross resistance to ALS herbicides was slightly higher for plants derived from weed seeds harvested in 2020–2021 compared to those harvested in 2015–2016. The introduction of a herbicidal composition of a herbicide mixture ‒ an inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD) (an enzyme in plants in the chain of carotenoid synthesis) ‒ mesotrione with an ALS-inhibitor (nicosulfuron) allowed effective control of the weed, which indicates the absence of multiple resistance to herbicides ‒ inhibitors of carotenoid synthesis. The high efficiency of E. crus-galli control was established by the application of herbicides ‒ inhibitors of fatty acid synthesis (graminicides). The highest level of efficiency in the experiments was observed with the application of fluazifop-butyl and somewhat less ‒ with pinoxaden. A tendency to reduce phytotoxicity to barnyardgrass from the south of Ukraine was observed with the introduction of tepraloxydim and quizalofop-ethyl. A lower level of phytotoxicity of fenoxaprop-p-ethyl on E. crus-galli should be noted compared to the effect of pinoxaden. No multiple resistance was observed with glyphosate (5-enolpyruvylshikimate-3-phosphate synthase inhibitor) and reglone (photosystem I inhibitor), allowing control of vegetative weeds at the beginning and end of the growing season. It has been established that monocot weed species have significantly increased their presence and harmfulness in agrophytocenoses in Ukraine and in the world since the 1950s with the widespread introduction of selective dicotyledonous species control with aryloxyphenoxyacetic, propionic and benzoic acid derivatives. This trend has been maintained until recently ‒ barnyardgrass is one of the dominant weed species in modern agrophytocenoses of Ukraine. Therefore, the identification of the ALS-resistant biotype of barnyardgrass complicates weed control in the following crops in rotations in the southern regions of the country: in maize crops with cross resistance to nicosulfuron, in sunflower ‒ to imidazolinones (imazamox, imazapyr), and also makes it impossible to use penoxsulam in rice production. Traditionally, the use of synthetic auxins, phenoxyacetic acid derivatives, etc. is used to control ALS-resistance. However, in Kherson region of Ukraine, already in the third year of application of rinskor (florpyrauxifen-benzyl), some weed plants were found on rice fields affected by ALS-resistant barnyardgrass, which recovered after the use of synthetic auxin. Therefore, the control of ALS-resistance (penoxsulam, etc.) in E. crus-galli with the application florpyrauxifen-benzyl in the Kherson region of Ukraine is already limited. An obvious and economically feasible preventive measure against the emergence of resistant weed biotypes is the implementation of GAP (Good Agricultural Practice, FAO) approaches: in particular, the use of high quality seeds without weed impurities, increasing the proportion of agrotechnical weed control measures, restoring and expanding crop rotations with mandatory rotation of herbicides with different modes of action, introducing dicotyledonous/leguminous crops into rotations, and using herbicides with different modes of action in crops separately or in mixtures. At the same time, agrotechnical measures and the preservation of biodiversity in agrophytocenoses should be the main factor in controlling resistance in weeds. The use of herbicides and their mixtures with different modes of action is of secondary importance. The identification of highly damaging ALS-resistant E. crus-galli in southern Ukraine indicates the insufficient effectiveness of weed control exclusively with herbicides with a single mechanism of action and requires a significant revision of the principles of crop rotation and ways of weed control in the country to maintain high levels of profitability and productivity of agrophytocenoses. Solving this problem is urgent for the preservation of Ukraine's potential as one of the guarantors of global food security.

1,2,4-Triazole and benzimidazole fused dihydropyrimidine derivatives: Design, green synthesis, antibacterial, antitubercular, and antimalarial activities.

This study reports the design and synthesis of novel 1,2,4-triazolo/benzimidazolo-pyrimidine linked 1-benzyl-4-[(p-tolyloxy)methyl]-1,2,3-triazole derivatives as potent antimicrobial agents according to their in vitro antibacterial, antifungal, antitubercular as well as antimalarial activities. An efficient, ecologically benign, and facile multicomponent synthesis wasemployed to synthesize these derivatives. The synthesis is accelerated with the mild and eco-friendly organocatalyst tetrabutylammonium bromide, providing a yield of 82%-96% within the short reaction time of 0.5-1.5 h. Compared with the MIC values of ciprofloxacin and ampicillin on the respective strains, compound d2 showed better activity against Escherichia coli and Streptococcus pyogenes and compound d8 showed better MIC against Staphylococcus aureus. Additionally, compounds d3, d4, and d5 showed potent MIC values against Pseudomonas aeruginosa. All triazolo-pyrimidine derivatives d1-d8 showed potent inhibitory action against Gram-positive strains. Compound e3 showed good potency against Mycobacterium tuberculosis H37Rv. The IC50 values of d3 and e2 indicated better activity against Plasmodium falciparum. Collectively, these derivatives depict potent multifaceted activity and provide promising access for further antimicrobial and antimalarial investigations.

Experimentally Validated Novel Factor XIIa Inhibitors Identified by Docking and Quantum Chemical Post-processing.

Antithrombotic agents based on factor XIIa inhibitors can become a new class of drugs to manage conditions associated with thrombosis. Herein, we report identification of two novel classes of factor XIIa inhibitors. The first one is triazolopyrimidine derivatives designed on the basis of the literature aminotriazole hit and identified using virtual screening of the focused library. The second class is a spirocyclic furo[3,4-c]pyrrole derivatives identified by virtual screening of a large chemical library of drug-like compounds performed in a previous study but confirmed in vitro here. In both cases, the prediction of inhibitory activity is based on the score of the SOL docking program, which uses the MMFF94 force field to calculate the binding energy. For the best ligands selected in virtual screening of the large chemical library, postprocessing with the PM7 semiempirical quantum-chemical method was used to calculate the enthalpy of protein-ligand binding to prioritize 16 compounds for testing in enzymatic assay, and one of them demonstrated micromolar activity. For triazolopyrimidine library, 21 compounds were prioritized for the testing based on docking scores, and visual inspection of docking poses. Of these, 4 compounds showed inhibition of factor XIIa at 30 μM.

Design, Synthesis, and Evaluation of Anticonvulsant Activities of New Triazolopyrimidine Derivatives.

Epilepsy, a severe brain disease affecting a large population, is treated mainly by antiepileptic drugs (AEDs). However, toxicity, intolerance, and low efficiency of the available AEDs have prompted the continual attempts in the discovery of new AEDs. In this study, we discovered a skeleton of triazolopyrimidine for the development of new AEDs. The design, synthesis, in vivo anticonvulsant activity evaluation of triazolopyrimidines (3a–3i and 6a–6e), and pyrazolopyrimidines (4a–4i) are reported. We found that most triazolopyrimidines showed anticonvulsive activity in the maximal electroshock (MES) and pentetrazol (PTZ)-induced seizure models. On the contrary, pyrazolopyrimidines (4a–4i) showed weak or no protective effects. Among the tested derivatives, compound 6d, holding a median effective dose (ED50) of 15.8 and 14.1 mg/kg against MES and PTZ-induced seizures, respectively, was found to be the most potent one. Moreover, the protection index (PI) value of 6d was significantly higher than that of the available AEDs such as valproate, carbamazepine, and diazepam. The antiepileptic efficacy of compound 6d was also observed in the 3-mercaptopropionic acid and bicuculline-induced seizure models. Antagonistic effects of flumazenil and 3-MP for the anticonvulsive activity of 6d and also the radioligand-binding assay confirmed the involvement of GABA receptors, at least benzodiazepine (BZD) receptor, in the anticonvulsant activity of compound 6d. The docking study of compounds 4e and 6d with GABAA receptor confirmed and explained their affinity to the BZD receptors.

Recent Trend in the Chemistry of Triazolopyrimidines and their Applications

: This review deals with the synthetic methods, chemical reactions, and applications of triazolopyrimidine derivatives. The synthetic methods and chemical reactions are subdivided into groups according to the junction between triazole and pyrimidine moieties for instance [1,2,4]triazolo[1,5-a]pyrimidine, [1,2,4]triazolo[1,5-c]pyrimidine, [1,2,3]triazolo[1,5-a]pyrimidine, [1,2,3]triazolo[1,5-c]pyrimidine, [1,2,4]triazolo[4,3-c]pyrimidine, and [1,2,4]triazolo[4,3-a]pyrimidine. Pharmacological activity of triazolopyrimidins is also reported.

Identification of Pax protein inhibitors that suppress target gene expression and cancer cell proliferation

The Pax family of developmental control genes are frequently deregulated in human disease. In the kidney, Pax2 is expressed in developing nephrons but not in adult proximal and distal tubules, whereas polycystic kidney epithelia or renal cell carcinoma continues to express high levels. Pax2 reduction in mice or cell culture can slow proliferation of cystic epithelial cells or renal cancer cells. Thus, inhibition of Pax activity may be a viable, cell-type-specific therapy. We designed an unbiased, cell-based, high-throughput screen that identified triazolo pyrimidine derivatives that attenuate Pax transactivation ability. We show that BG-1 inhibits Pax2-positive cancer cell growth and target gene expression but has little effect on Pax2-negative cells. Chromatin immunoprecipitation suggests that these inhibitors prevent Pax protein interactions with the histone H3K4 methylation complex at Pax target genes in renal cells. Thus, these compounds may provide structural scaffolds for kidney-specific inhibitors with therapeutic potential.

Synthesis, anticancer activity and molecular docking of new triazolo[4,5-d]pyrimidines based thienopyrimidine system and their derived N-glycosides and thioglycosides

A series of new substituted triazolo[4,5-d]pyrimidine derivatives linked to thienopyrimidine ring system were prepared as a hybrid heterocyclic systems, as possible nucleobases analogs, starting from the key carboxamide derivative 2 and its azide precursor via heterocyclization reactions and their structures were characterized. Glycosylation of the prepared triazolopyrimidine derivatives was performed and afforded, regioselctively, the corresponding thienopyrimidine-triazolopyrimidine hybrid N 1-glycosides and their thioglycoside analogues in good yields. The synthesized glycosyl heterocycles were studied for their cytotoxic activity against HepG-2 and MCF-7 human cancer cells and significant results were obtained. Compounds 7a, 8 b, 9 b, 9a and 7 b demonstrated promising activities comparable to the activity of the doxorubicin for (HepG-2) cell line. Furthermore, a number of the afforded triazolopyrimidine glycosides were found potent against cancer cells (MCF-7). Furthermore, docking simulation the promising thienopyrimidine analogues 7-13 was done against EGFR kinase to provide a binding model that could serve in discovery of further anticancer agents.

Design, Synthesis and Biological Evaluation of Novel Pyrazolo[1,2,4]triazolopyrimidine Derivatives as Potential Anticancer Agents.

Three novel pyrazolo-[4,3-e][1,2,4]triazolopyrimidine derivatives (1, 2, and 3) were designed, synthesized, and evaluated for their in vitro biological activity. All three compounds exhibited different levels of cytotoxicity against cervical and breast cancer cell lines. However, compound 1 showed the best antiproliferative activity against all tested tumor cell lines, including HCC1937 and HeLa cells, which express high levels of wild-type epidermal growth factor receptor (EGFR). Western blot analyses demonstrated that compound 1 inhibited the activation of EGFR, protein kinase B (Akt), and extracellular signal-regulated kinase (Erk)1/2 in breast and cervical cancer cells at concentrations of 7 and 11 µM, respectively. The results from docking experiments with EGFR suggested the binding of compound 1 at the ATP binding site of EGFR. Furthermore, the crystal structure of compound 3 (7-(4-bromophenyl)-9-(pyridin-4-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine) was determined by single crystal X-ray analysis. Our work represents a promising starting point for the development of a new series of compounds targeting EGFR.

The high-resolution X-ray structure of vinca-domain inhibitors of microtubules provides a rational approach for drug design.

Tubulin vinca-domain ligands can inhibit microtubule polymerization, causing cell death in mitosis, and their potential against multiple cancer types has been demonstrated. However, due to drug resistance and toxicities, development of novel vinca-domain ligands is still needed. In this study, we determined the high-resolution crystal structures of vinorelbine, YXD, and Phomopsin A in complex with tubulin at 2.5Å. Additionally, we recapitulated all previously published high-resolution crystal structures of the vinca binding site to reveal critical residues and the molecular mechanism of vinca-domain ligands interacting with tubulin. Furthermore, we designed putatively novel triazolopyrimidine derivatives by introducing secondary amine groups to establish salt-bridge and H-bond interactions with Asp179β1 and Asn329α2 . Our studies provided the structural basis for designing novel tubulin vinca-domain ligands.

Recent Development in the Chemistry of Bicyclic 6+5 Systems, Part II: Chemistry of Triazolopyrimidine Derivatives

This review describes the synthesis and reactions of substituted triazolopyrimidines as building blocks toward polyfunctionalized heterocyclic compounds with pharmacological interest.