Pyrimidine Hybrids Research Articles

Ultrasound-assisted synthesis and structure elucidation of novel quinoline-pyrazolo[1,5-a]pyrimidine hybrids for anti-malarial potential against drug-sensitive and drug-resistant malaria parasites and molecular docking

Ultrasound-assisted synthesis and structure elucidation of novel quinoline-pyrazolo[1,5-a]pyrimidine hybrids for anti-malarial potential against drug-sensitive and drug-resistant malaria parasites and molecular docking

A promising class of Antiprotozoal agents, design and synthesis of novel Pyrimidine–Cinnamoyl Hybrids

Malaria, caused by parasitic protozoans of the Plasmodium genus, continues to be one of the greatest global health crises, especially in Africa. The emergence of antimalarial drug resistance continues to be a health problem necessitating an urgent need for alternative and cost-effective antimalarials. Using a molecular hybridization approach, we report the design and synthesis of an efficacious novel class of antiprotozoal agents; (E)-1-(4-(4,6-diphenylpyrimidin-2-yl)piperazin-1-yl)-3-phenyl prop-2-en-1-one derivatives (8a-r). The in vitro inhibitory activity of the synthesized compounds was evaluated against the NF54 chloroquine-sensitive strain of Plasmodium falciparum. From the antiprotozoal screening, three compounds displayed propitious activity with IC50 values (0.18-0.21μM), using quinine and chloroquine as standard antimalarials. Compounds 8o and 8l emerged as the most potent candidates with IC50 values of 0.18 ± 0.02 μM and 0.21 ± 0.001 μM with an associated good safety index of 18.59 and 16.75 to human kidney epithelial (HEK293) cells, respectively. The synthesized analogues present a new chemical architecture structurally unrelated to the current regime of antimalarial drugs, representing a valid strategy to combat resistance in P. falciparum species to current commercial drugs. We further investigated the binding affinities of the compounds against recombinant forms of two P. falciparum heat shock protein 70 homologues; PfHsp70-1 and PfHsp70-z, both of which are essential and promising druggable candidates. Compound 8l exhibited the highest binding affinity for both PfHsp70s. Furthermore, molecular docking revealed that compounds 8k, 8l, 8m, and 8o exhibited better fitness to PfHsp70-1, with compounds 8l and 8o showing the highest binding affinity of 10.5 kcal/mol and 10.1 kcal/mol, respectively. Therefore, it can be speculated that PfHsp70-1 may be a possible target of some of the inhibitors tested in this study. The presence of electron-donating groups on the phenyl ring of 4,6-pyrimidine moiety and cinnamoyl group demonstrated a positive correlation between the observed computational data and the biological activity. Taken together, this paper demonstrates the importance of using the molecular hybridization approach in the development of newer cinnamoyl clubbed with 4,6-diphenyl pyrimidine hybrids as potential antiprotozoal agents.

Current scenario of pyrazole hybrids with anti-breast cancer therapeutic applications.

Breast cancer stands as the leading cause of cancer-related deaths among women globally, but current therapy is restricted to the serious adverse effects and multidrug resistance, necessitating the exploration of novel, safe, and efficient anti-breast cancer chemotherapeutic agents. Pyrazoles exhibit excellent potential for utilization as effective anti-breast cancer agents due to their ability to act on various biological targets. Particularly, pyrazole hybrids demonstrated the advantage of targeting multiple pathways, and some of them, which are exemplified by larotrectinib (pyrazolo[1,5-a]pyrimidine hybrid), can be applied for breast cancer therapy. Thus, pyrazole hybrids hold great promise as useful therapeutic interventions for breast cancer. The aim of this review is to summarize the current scenario of pyrazole hybrids with in vitro and/or in vivo anti-breast cancer potential, along with the modes of action and structure-activity relationships, covering articles published from 2020 to the present, to streamline the development of rational, effective and safe anti-breast cancer candidates.

Potential MRSA inhibitory activity of some new benzofuran-pyrazolo[1,5-a]pyrimidine hybrids attached to arene units via methylene or azo linkage

MRSA, a resistant bacteria causing severe infections, is targeted by researchers developing new anti-resistance compounds. The study aimed to investigate the MRSA inhibitory activity of two series of benzofuran-pyrazolo[1,5-a]pyrimidines 1 and 2, attached to arene units via methylene or azo linkage, respectively. The desired products were prepared, in 82–92% yields, by reacting benzofuran-based enaminone 4 with the appropriate 1H-pyrazole-3,5-diamines 5 in pyridine at reflux for 5–6 h. The new hybrids showed a wide spectrum of antibacterial activity against different ATCC strains. Products with azo linkage and para-substituted arene units with electron-releasing groups demonstrated higher antibacterial activity. 3-((4-Methoxyphenyl)diazenyl)-linked pyrazolo[1,5-a]pyrimidine 2e demonstrates activity that exceeded the reference ciprofloxacin with MIC/MBC values of 1.8/3.6 µM against S. aureus and E. coli strains. Also, it demonstrated more effective MRSA inhibitory activity than the reference linezolid, with MIC/MBC values of 3.6/14.4 and 1.8/7.2 µM against MRSA ATCC:33591 and ATCC:43300 strains, respectively.

New Diaryl-1,2,4-triazolo[3,4-a]pyrimidine Hybrids as Selective COX-2/sEH Dual Inhibitors with Potent Analgesic/Anti-inflammatory and Cardioprotective Properties.

COX-2-selective drugs were withdrawn from the market just a few years after their development due to cardiovascular side effects. As a result, developing a selective COX-2 inhibitor as an anti-inflammatory agent with cardioprotective characteristics has become a prominent objective in medicinal chemistry. New 15 diaryl-1,2,4-triazolo[3,4-a]pyrimidine hybrids 8a-o were synthesized and investigated in vitro as dual COX-2/sEH inhibitors. Compounds 8b, 8m, and 8o have the highest potency and selectivity as COX-2 inhibitors (IC50 = 15.20, 11.60, and 10.50 μM, respectively; selectivity index (COX-1/COX-2) = 13, 20, and 25, respectively), compared to celecoxib (COX-2; IC50 = 42 μM; SI = 8). The 5-LOX inhibitory activity of compounds 8b, 8m, and 8o was further examined in vitro. Compounds 8m and 8o, the most effective COX-2 selective inhibitors, demonstrated stronger 5-LOX inhibitory action than the reference quercetin, with IC50 values of 2.90 and 3.05 μM, respectively. Additionally, compounds 8b, 8m, and 8o were the most potent dual COX-2/sEH inhibitors, with IC50 values against sEH of 3.20, 2.95, and 2.20 nM, respectively, and were equivalent to AUDA (IC50 = 1.2 nM). In vivo investigations also demonstrated that these compounds were the most efficacious as analgesic/anti-inflammatory derivatives with a high cardioprotective profile against cardiac biomarkers and inflammatory cytokines. The docking data analysis inquiry helped better understand the binding mechanisms of the most active hybrids within the COX-2 active site and supported their COX-2 selectivity. Compounds 8b, 8m, and 8o exhibited a similar orientation to rofecoxib and celecoxib, with a larger proclivity to enter the selectivity side pocket than the reference compounds.

Pyrazolo - Pyrimidines as Targeted Anticancer Scaffolds - A Comprehensive Review.

Globally, cancer is the leading cause of death, which causes 10 million deaths yearly. Clinically, several drugs are used in treatment but due to drug resistance and multidrug resistance, there occurs a failure in the cancer treatment. The present review article is a comprehensive review of pyrazole and pyrimidine hybrids as potential anticancer agents. The review comprises more than 60 research works done in this field. The efficiency of the reported pyrazolopyrimidine fused heterocyclic with their biological data and the influence of the structural aspects of the molecule have been discussed. This review highlighted pyrazolo-pyrimidines as targeted anticancer agents with effect on multiple targets. The review will be helpful for the researchers involved in targeted drugs for cancer therapy for designing new scaffolds with pyrazolo-pyrimidine moieties.

Design, synthesis, computational study and cytotoxic evaluation of some new quinazoline derivatives containing pyrimidine moiety

Quinazoline derivatives, as an important category of heterocyclic compounds, have received much attention for the design and development of new drugs due to their various pharmacological properties. Besides, there is a great deal of evidence showing pyrimidine analogs as anticancer agents. Thus, in the present study, for the design of new target compounds with cytotoxic activity, we focused on various quinazolinone and pyrimidine hybrids. A new series of quinazoline-pyrimidine hybrid derivatives (6a-6n) have been designed and synthesized as novel antiproliferative agents. All the synthesized compounds characterized based on their IR, NMR and Mass spectroscopic data. Antiproliferative activities of the new compounds were evaluated against three human cancer cell lines (MCF-7, A549, SW-480). The compounds were found to have appropriate potential with IC50 values ranging from 2.3 ± 5.91 to 176.5 ± 0.7 μM against the tested cell lines. Compound 6n exerted the highest antiproliferative activity with IC50 values of 5.9 ± 1.69 μM, 2.3 ± 5.91 μM and 5.65 ± 2.33 μM against A549, SW-480 and MCF-7 respectively. The results indicated that 6n could induce apoptosis in A549 cell line in a dose dependent manner and arrest in the S phase of cell cycle. Docking studies were also done to investigate the detailed binding pattern of the synthesized compounds against EGFR. Furthermore, molecular dynamic simulation and binding free energy calculation have been done to rescore initial docking pose of the synthesized compounds using ensemble-based MMGB/PBSA free energy method. According to the results, free energy calculation confirmed biological activity of compounds and also, Arg 817 and Lys 721 residues had the pivotal role in the high potency of 6n. Finally, the drug likeness and in silico ADME study were also predicted.

Synthesis and anti-microbial studies of new series of 1,2,3,4-tetrazole integrated thieno[2,3-d]pyrimidine derivatives

The present study describes synthesis of a novel series of 1,2,3,4-tetrazole integrated thieno[2,3-d]-pyrimidine hybrid 11a-l. Further, in vitro anti-microbial activities of the synthesized analogues 11a-l were evaluated against Gram-positive bacteria and Gram-negative bacteria, and fungal pathogens respectively. As a result, the analogues 11d and 11l were shown potent anti-bacterial activities 0.09–0.48 µg/mL and 0.07–0.51 µg/mL, respectively against tested pathogens and compared with standard Ciprofloxacin (0.08–0.34 µg/mL). As well, the compounds 11 h and 11l have also shown highest inhibition zones (ZOIs) ranging from 13.20 ± 0.57 to16.70 ± 0.50; and 17.00 ± 0.00 to 17.50 ± 1.04 mm, respectively against nominated fungal pathogens. Subsequently, the conducted molecular docking studies with the active site of DNA gyrase of Staphylococcue aureus and Esterase of Aspergillus niger were shown that all the synthesized derivatives 11a-l exhibited good docking scores of between -9.2 and -8.8 kcal/mol and were better as compared with standard drugs.

Discovery of pyrimidine-tethered benzothiazole derivatives as novel anti-tubercular agents towards multi- and extensively drug resistant Mycobacterium tuberculosis

In this study, new benzothiazole–pyrimidine hybrids (5a–c, 6, 7a–f, and 8–15) were designed and synthesised. Two different functionalities on the pyrimidine moiety of lead compound 4 were subjected to a variety of chemical changes with the goal of creating various functionalities and cyclisation to further elucidate the target structures. The potency of the new molecules was tested against different tuberculosis (TB) strains. The results indicated that compounds 5c, 5b, 12, and 15 (MIC = 0.24–0.98 µg/mL) are highly active against the first-line drug-sensitive strain of Mycobacterium tuberculosis (ATCC 25177). Thereafter, the anti-tubercular activity was evaluated against the two drug-resistant TB strains; ATCC 35822 and RCMB 2674, where, many compounds exhibited good activity with MIC = 0.98–62.5 3 µg/mL and 3.9–62.5 µg/mL, respectively. Compounds 5c and 15 having the highest anti-tubercular efficiency towards sensitive strain, displayed the best activity for the resistant strains by showing the MIC = 0.98 and 1.95 µg/mL for MDR TB, and showing the MIC = 3.9 and 7.81 µg/mL for XDR TB, consecutively. Finally, molecular docking studies were performed for the two most active compounds 5c and 15 to explore their enzymatic inhibitory activities.

Recent Advances on Pyrazole-Pyrimidine/Fused Pyrimidine Hybrids with Anticancer Potential (A Review)

Recent Advances on Pyrazole-Pyrimidine/Fused Pyrimidine Hybrids with Anticancer Potential (A Review)

Novel topoisomerase II/EGFR dual inhibitors: design, synthesis and docking studies of naphtho[2′,3′:4,5]thiazolo[3,2-a]pyrimidine hybrids as potential anticancer agents with apoptosis inducing activity

Topoisomerases II are ubiquitous enzymes with significant genotoxic effects in many critical DNA processes. Additionally, epidermal growth factor receptor (EGFR) plays pivotal role in tumour growth and angiogenesis. A novel series of naphtho[2',3':4,5]thiazolo[3,2- a ]pyrimidine hybrids have been designed, synthesised and evaluated for their topo IIα/EGFR inhibitory and apoptotic inducer activities. Cytotoxicity of the synthesised hybrids was evaluated against MCF-7, A549 and HCT-116 cell lines. Of the synthesised hybrids, 6i, 6a and 6c experienced superior cytotoxic activity compared to doxorubicin and erlotinib against the tested cancer cells. The molecular mechanism of these hybrids revealed their ability to successfully inhibit topo IIα and EGFR activities in micromolar concentration and may serve as topo II catalytic inhibitor. Moreover, these hybrids significantly arrested cell cycle at G2/M phase together with increased p53, caspae-7, caspase-9 levels and Bax/Bcl-2 ratio. The synthesised hybrids showed efficient binding pattern in molecular docking study and have acceptable drug likeness characters.

Synthesis of 5-(arylmethylideneamino)-4-(1H-benzo[d]imidazol-1-yl)pyrimidine hybrids: synthetic sequence and the molecular and supramolecular structures of two intermediates and three final products.

A concise and versatile synthesis of 5-(arylmethylideneamino)-4-(1H-benzo[d]imidazol-1-yl)pyrimidines has been developed, starting from 4-(1H-benzo[d]imidazol-1-yl)pyrimidines, and we report here the synthesis and spectroscopic and structural characterization of three such products, along with those of two intermediates in the reaction pathway. The intermediates 4-[2-(4-chlorophenyl)-1H-benzo[d]imidazol-1-yl]-6-methoxypyrimidine-2,5-diamine, (II), and 4-[2-(4-bromophenyl)-1H-benzo[d]imidazol-1-yl]-6-methoxypyrimidine-2,5-diamine, (III), crystallize as the isostructural monohydrates C18H15ClN5O·H2O and C18H15BrN5O·H2O, respectively, in which the components are linked into complex sheets by O-H...N and N-H...O hydrogen bonds. In the product (E)-4-methoxy-5-[(4-nitrobenzylidene)amino]-6-[2-(4-nitrophenyl)-1H-benzo[d]imidazol-1-yl]pyrimidin-2-amine, which crystallizes as a 1:1 solvate with dimethyl sulfoxide, C25H18N8O5·C2H6OS, (IV), inversion-related pairs of the pyrimidine component are linked by N-H...N hydrogen bonds to form cyclic centrosymmetric R22(8) dimers to which pairs of solvent molecules are linked by N-H...O hydrogen bonds. (E)-4-Methoxy-5-[(4-methylbenzylidene)amino]-6-[2-(4-methylphenyl)-1H-benzo[d]imidazol-1-yl]pyrimidin-2-amine, C27H24N6O, (V), crystallizes with Z'= 2 and the molecules are linked into a three-dimensional framework structure by a combination of N-H...N, C-H...N and C-H...π(arene) hydrogen bonds. The analogous product (E)-4-methoxy-5-[(4-chlorobenzylidene)amino]-6-[2-(4-methylphenyl)-1H-benzo[d]imidazol-1-yl]pyrimidin-2-amine, C26H21ClN6O, (VI), crystallizes from dimethyl sulfoxide in two forms: one, denoted (VIa), is isostructural with (V), and the other, denoted (VIb), crystallizes with Z'= 1, but as an unknown solvate in which the pyrimidine molecules are linked by N-H...N hydrogen bonds to form a ribbon containing two types of centrosymmetric ring.

Synthesis and Antiprotozoal Activity of Azabicyclo-Nonane Pyrimidine Hybrids

2,4-Diaminopyrimidines and (dialkylamino)azabicyclo-nonanes possess activity against protozoan parasites. A series of fused hybrids were synthesized and tested in vitro against pathogens of malaria tropica and sleeping sickness. The activities and selectivities of compounds strongly depended on the substitution pattern of both ring systems as well as on the position of the nitrogen atom in the bicycles. The most promising hybrids of 3-azabicyclo-nonane with 2-aminopyrimidine showed activity against P. falciparum NF54 in submicromolar concentration and high selectivity. A hybrid with pyrrolidino substitution of the 2-azabicyclo-nonane as well as of the pyrimidine moiety exhibited promising activity against the multiresistant K1 strain of P. falciparum. A couple of hybrids of 2-azabicyclo-nonanes with 2-(dialkylamino)pyrimidines possessed high activity against Trypanosoma brucei rhodesiense STIB900 and good selectivity.

Synthesis of Pyrimidine Hybrids Based on 4H-Pyran and 4H-Chromene Privileged Structures

Abstract: A combinatorial library of pyrimidine hybrids based on 4H-chromene and 4H-pyran privileged structures has been developed by reacting phenyl isothiocyanate with chromene derivatives 1a-j and pyranopyrazoles 2a-f in refluxing dry pyridine, respectively. Thus, the target pyrimidine hybrids 3a-j and 4a-f were obtained in good yields with a simple reaction strategy.

Efficient Synthesis with Green Chemistry Approach of Novel Pharmacophores of Imidazole-Based Hybrids for Tumor Treatment: Mechanistic Insights from In Situ to In Silico.

Simple SummaryHere, we report the eco-friendly synthesis and antitumor potential of the imidazole hybrids of pyrimidine. The results showed that all the compounds possess excellent inhibition of tumors, promoting enzymes hCA-IX and hCA-II. Furthermore, the selectivity index showed that compounds 7, 10, and 11 are selective inhibitors of hCA-IX, while compound 2 is a selective inhibitor of hCA-IX. More importantly, all the active inhibitors are toxic to the breast cancer cell line and non-cytotoxic for the normal breast cell line. These compounds would be a suitable choice to investigate in the in vivo models to check their efficacy against these particular targets. These newly identified human carbonic anhydrase inhibitors have potential to be considered as therapeutic leads for the treatment of CA-related diseases, especially for breast and lung tumors and glaucoma. Furthermore, lead optimization and preclinical and clinical investigations of these compounds are necessary to develop potential drug entities for the treatment of cancer.Imidazole-based pyrimidine hybrids are considered a remarkable class of compounds in pharmaceutical chemistry. Here, we report the anticancer bioactivities of eleven imidazole-based pyrimidine hybrids (1–11) that specifically target cytosolic carbonic anhydrase (CAs) isoenzymes, including human CA-II and human CA-IX (hCA-II, and hCA-IX). A highly eco-friendly aqueous approach was used for the formation of a carbon–carbon bond by reacting aromatic nitro group substitution of nitroimidazoles with carbon nucleophiles. The in vitro results indicate that this new class of compounds (1–11) includes significant inhibitors of hCA IX with IC50 values in the range of 9.6 ± 0.2–32.2 ± 1.0 µM, while hCA II showed IC50 values in range of 11.6 ± 0.2–31.1 ± 1.3 µM. Compound 2 (IC50 = 12.3 ± 0.1 µM) showed selective inhibition for hCA-II while 7, 8, and 10 (IC50 = 9.6–32.2 µM) were selective for hCA-IX. The mechanism of action was investigated through in vitro kinetics studies that revealed that compounds 7, 3, 11, 10, 4, and 9 for CA-IX and 1, 2, and 11 for CA-II are competitive inhibitors with dissociation constant (Ki) in the range of 7.32–17.02 µM. Furthermore, the in situ cytotoxicity of these compounds was investigated in the human breast cancer cell line MDA-MB-231 and compared with the normal human breast cell line, MCF-10A. Compound 5 showed excellent anticancer/cytotoxic activity in MDA-MB-231 with no toxicity to the normal breast cells. In addition, in silico molecular docking was employed to predict the binding mechanism of active compounds with their targets. This in silico observation aligned with our experimental results. Our findings signify that imidazole-based hybrids could be a useful choice to design anticancer agents for breast and lung tumors, or antiglaucoma compounds, by specific inhibition of carbonic anhydrases.

Novel ferrocene-pyrazolo[1,5-a]pyrimidine hybrids: A facile environment-friendly regioselective synthesis, structure elucidation, and their antioxidant, antibacterial, and anti-biofilm activities

Novel ferrocene-pyrazolo[1,5-a]pyrimidine hybrids: A facile environment-friendly regioselective synthesis, structure elucidation, and their antioxidant, antibacterial, and anti-biofilm activities

Conjugates of Lupane Triterpenoids with Arylpyrimidines: Synthesis and Anti-inflammatory Activity

Semisynthetic triterpenoid betulonic acid is of significant interest due to its biological activity and synthetic application. In this study, we report the synthesis of hybrid compounds, containing betulonic acid carboxamide and arylpyrimidine fragments. A total of 15 conjugates were prepared using the cyclocondensation reaction of new terpenoid alkynyl ketones with amidinium salts. The main synthetic approach to betulonic acid amide-derived alkynylketones was based on the cross-coupling reaction of N-(4-ethynylphenyl)- or N-(2-(4-ethynylphenyl)-1-(methoxycarbonyl)ethyl)- substituted betulonic acid carboxamide with aroylchlorides. Cyclocondensation of alkynones with amidine or guanidine hydrochlorides by reflux in MeCN in the presence of K2CO3 led to the formation of terpenoid pyrimidine hybrids in 52-89% isolated yield. Anti-inflammatory properties of new type of triterpenoid-pyrimidine conjugates were studied using the histamine- and concanavalin A- induced mouse paw edema models. In a model of acute inflammation betulonic acid amide-arylpyrimidines containing a 4-fluorophenyl substituent at the C-6 position of pyrimidine ring exhibited significant and selective anti-inflammatory activity. Compounds containing the 4-bromophenyl- substituent in the pyrimidine ring revealed selective anti-inflammatory activity in the model of immunogenic inflammation (concanavalin-A model). It should be noted that the methoxycarbonyl substituted ethane link between pharmacophore ligands (betulonic acid carboxamide and arylpyrimidine) has a significant effect on anti-inflammatory activity in both in vivo models of inflammation. It was shown by molecular docking that the new derivatives are incorporated into the binding site of the protein Keap1 Kelch-domain by their pyrimidine substituent with the formation of more non-covalent bonds.

Synthesis, computational study and biological evaluation of 9-acridinyl and 1-coumarinyl-1,2,3-triazole-4-yl derivatives as topoisomerase II inhibitors

Topoisomerase (IIB) inhibitors have been involved in the therapies of tumour progression and have become a major focus for the development of anticancer agents. New three-component hybridised ligands, 1,4-disubstituted-1,2,3-triazoles (8–17), were synthesised via a 1,3-dipolar cycloaddition reaction of 9-azidoacridine/3-azidocoumarin with N/O-propargyl small molecules under click reaction conditions. Cancer cell growth inhibition of the synthesised triazoles was tested against human cell-lines in the NCI-60-cell-panel, and the most active compounds tested against topoisomerase (IIB)-enzymes. The acridinyl ligands (8–10) revealed 60–97% cell growth inhibition in six cancer cell-panels. Cell-cycle analysis of MCF7 and DU-145 cells treated with the active acridinyl ligands exhibited cell-cycle arrest at G2/M phase and proapoptotic activity. In addition, compound 8 displayed greater inhibitory activity against topoisomerase (IIB) (IC50 0.52 µM) compared with doxorubicin (IC50 0.83 µM). Molecular dynamics simulation studies showed the acridine–triazole–pyrimidine hybrid pharmacophore was optimal with respect to protein–ligand interaction and fit within the binding site, with optimal orientation to allow for intercalation with the DNA bases (DG13, DC14, and DT9).

The Antibacterial Activity of 1,2,3-triazole- and 1,2,4-Triazole-containing Hybrids against Staphylococcus aureus: An Updated Review (2020- Present).

Staphylococcus aureus (S. aureus), a prominent, highly contagious nosocomial and community- acquired bacterial pathogen, can cause a broad spectrum of diseases. Antibiotic-resistant S. aureus strains, which pose potential causes of morbidity and mortality, have continuously emerged in recent years, calling for novel anti-S. aureus agents. 1,2,3-triazole and 1,2,4-triazole, the bioisostere of amides, esters, and carboxylic acids, are potent inhibitors of DNA gyrase, topoisomerase IV, efflux pumps, filamentous temperature-sensitive protein Z, and penicillin-binding protein. In particular, 1,2,3-triazole- and 1,2,4-triazole-containing hybrids have the potential to exert dual or multiple antibacterial mechanisms of action. Moreover, 1,2,3-triazole-cephalosporin hybrid cefatrizine, 1,2,3- triazole-oxazolidinone hybrid radezolid, and 1,2,4-triazolo[1,5-a]pyrimidine hybrid essramycin, have already been used in clinical practice to treat bacterial infections. Hence, 1,2,3-triazole- and 1,2,4- triazole-containing hybrids possess promising broad-spectrum antibacterial activity against diverse clinically significant organisms, including drug-resistant forms. This review is an update on the latest development of 1,2,3-triazole- and 1,2,4-triazole-containing hybrids with anti-S. aureus activity, covering articles published between January 2020 and July 2021.

Synthesis, antitubercular activity and molecular docking study of substituted [1,3]dioxino[4,5-d]pyrimidine derivatives via facile CAN catalyzed Biginelli reaction

We have developed a simple and convenient method for the synthesis of substituted-aryllidine-2,2-dimethyl-7-thioxo/oxo-4H-[1,3]dioxino[4,5-d]pyrimidine derivatives (4a-g) via one-pot Biginelli reaction of Meldrum’s acid (1), indole-3-carbaldehyde/thiophene-2-carbaldehyde/2-chloro-quinoline-3-carbaldehyde (2) and amines (3) in aqueous ethanol in the presence of a catalytic amount of CAN. The obtained pyrimidine hybrids were screened for their antimycobacterial activity against Mycobacterium tuberculi H37RV strain. The antimycobacterial results showed that compounds 4a and 4b exhibited excellent activity with MIC value of 1.6 µg/mL, four-fold greater than the standard streptomycin (6.24 µg/mL), while compounds (4c-g) showed lower efficacy. To study the interaction between the synthesized compounds and receptor, the compounds 4a, 4b, 4c, and 4d were studied for molecular docking on the enzyme enoyl-acyl carrier protein reductase (enoyl-ACP reductase) and the compounds 4a and 4b have emerged as active antitubercular agents with least binding energy –9.4 kcal/mol and −9.3 kcal/mol respectively.