Design and development of novel N-(4-aminobenzoyl)- l-glutamic acid conjugated 1,3,5-triazine derivatives as Pf-DHFR inhibitor: An in-silico and in-vitro study.

In the present work, a library of 120 compounds was prepared using various aliphatic and aromatic amines. Finally, 10 compounds were selected through in silico screening carrying 4-aminobenzoyl-l-glutamic acid and 1,3,5-triazine moiety. The docking results of compounds 4d16 and 4d38 revealed higher binding interaction with amino acids Asp54 (-537.96 kcal/mol) and Asp54, Phe116 (-618.22 kcal/mol) against wild (1J3I) and quadruple mutant (1J3K) type of Pf-DHFR inhibitors and were comparable to standard WR99210. These compounds were developed by facile and microwave-assisted synthesis via nucleophilic substitution reaction and characterized by different spectroscopic methods. In vitro antimalarial assay results also suggested that these two compounds were having higher antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strain out of the ten synthesized compounds with IC50 13.25 µM and 14.72 µM, respectively. These hybrid scaffolds might be useful in the lead discovery of a new class of Pf-DHFR inhibitors.

Implication of in silico studies in the search for novel inhibitors against SARS-CoV-2.

Corona Virus Disease-19 (COVID-19) is a pandemic disease mainly caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It had spread from Wuhan, China, in late 2019 and spread over 222 countries and territories all over the world. Earlier, at the very beginning of COVID-19 infection, there were no approved medicines or vaccines for combating this disease, which adversely affected a lot of individuals worldwide. Although frequent mutation leads to the generation of more deadly variants of SARS-CoV-2, researchers have developed several highly effective vaccines that were approved for emergency use by the World Health Organization (WHO), such as mRNA-1273 by Moderna, BNT162b2 by Pfizer/BioNTech, Ad26.COV2.S by Janssen, AZD1222 by Oxford/AstraZeneca, Covishield by the Serum Institute of India, BBIBP-CorV by Sinopharm, coronaVac by Sinovac, and Covaxin by Bharat Biotech, and the first US Food and Drug Administration-approved antiviral drug Veklury (remdesivir) for the treatment of COVID-19. Several waves of COVID-19 have already occurred worldwide, and good-quality vaccines and medicines should be available for ongoing as well as upcoming waves of the pandemic. Therefore, in silico studies have become an excellent tool for identifying possible ligands that could lead to the development of safer medicines or vaccines. Various phytoconstituents from plants and herbs with antiviral properties are studied further to obtain inhibitors of SARS-CoV-2. In silico screening of various molecular databases like PubChem, ZINC, Asinex Biol-Design Library, and so on has been performed extensively for finding effective ligands against targets. Herein, in silico studies carried out by various researchers are summarized so that one can easily find the best molecule for further in vitro and in vivo studies.

Discovery of novel 1,3,5-triazine as adenosine A2A receptor antagonist for benefit in Parkinson's disease.

Parkinson's disease (PD) is a chronic neuro-degenerative ailment characterized by impairment in various motor and nonmotor functions of the body. In the past few years, adenosine A2 A receptor (A2 AR) antagonists have attracted much attention due to significant relief in PD. Therefore, in the current study, we intend to disclose the development of novel 1,3,5-triazines as A2 AR antagonist. The radioligand binding and selectivity of analogs were tested in HEK293 (human embryonic kidney) and the cells were transfected with pcDNA 3.1(+) containing full-length human A2 AR cDNA and pcDNA 3.1(+) containing full-length human A1 R cDNA, where they exhibit selective affinity for A2 AR. Molecular docking analysis was also conducted to rationalize the probable mode of action, binding affinity, and orientation of the most potent molecule (7c) at the active site of A2 AR. It has been shown that compound 7c form numerous nonbonded interactions in the active site of A2 AR by interacting with Ala59, Ala63, Ile80, Val84 Glu169, Phe168, Met270, and Ile274. The study revealed 1,3,5-triazines as a novel class of A2 AR antagonists.

Discovery of novel pyrazole derivatives as a potent anti-inflammatory agent in RAW264.7 cells via inhibition of NF-ĸB for possible benefit against SARS-CoV-2.

Due to unavailability of a specific drug/vaccine to attenuate severe acute respiratory syndrome coronavirus 2, the current strategy to combat the infection has been largely dependent upon the use of anti-inflammatory drugs to control cytokines storm responsible for respiratory depression. Thus, in this study, we discovered novel pyrazole analogs as a potent nuclear factor kappa B (NF-ĸB) inhibitor. The compounds were assessed for NF-ĸB transcriptional inhibitory activity in RAW264.7 cells after stimulation with lipopolysaccharides (LPS), revealing Compound 6c as the most potent analog among the tested series. The effect of Compound 6c was further investigated on the levels of interleukin-1ß, tumor necrosis factor-α, and interleukin-6 in LPS-stimulated RAW267.4 cells by enzyme immunoassay, where it causes a significant reduction in the level of these cytokines. In Western blot analysis, Compound 6c also causes the inhibition of inhibitor kappa B-α and NF-κB. It was found to be snugly fitted into the inner grove of the active site of NF-ĸB by forming H-bonds and a nonbonded interaction with Asn28 in a docking analysis.

In silico study, synthesis, and evaluation of the antimalarial activity of hybrid dimethoxy pyrazole 1,3,5-triazine derivatives.

Malaria continues to become a major global health problem, particularly in Sub-Saharan Africa, Asia, and Latin America. The widespread emergence of resistance to first-line drugs has further bolstered an urgent need for a new and cost-effective antimalarial(s). Thus, the present study enumerates the synthesis of novel hybrid dimethoxy pyrazole 1,3,5-triazine derivatives 7(a-j) and their in silico results short-listed three compounds with good binding energies and dock scores. Docking analysis shows that hydrogen-bonding predominates and typically involves key residues, such as Asp54, Tyr170, Ile164, and Arg122. The in vitro antimalarial evaluation of three top-ranked compounds (7e, 7g, and 7h) showed half-maximal inhibitory concentration values range from 53.85 to 100 µg/ml against chloroquine-sensitive strain 3D7 of Plasmodium falciparum. Compound 7e may be utilized as a lead for further optimization work in drug discovery due to good antimalarial activity.

Microwave-assisted synthesis of hybrid PABA-1,3,5-triazine derivatives as an antimalarial agent.

The present manuscript deals with the development of novel p-aminobenzoic acid (PABA) associated 1,3,5-triazine derivatives as antimalarial agents. The molecules were developed via microwave-assisted synthesis and structures of compounds were ascertained via numerous analytical and spectroscopic techniques. The synthesized compounds were also subjected to ADMET analysis. In a docking analysis, the title compounds showed high and diverse binding affinities towards wild (-162.45 to -369.38 kcal/mol) and quadruple mutant (-165.36 to -209.47 kcal/mol) Pf-DHFR-TS via interacting with Phe58, Arg59, Ser111, Ile112, Phe116. The in vitro antimalarial activity suggested that compounds 4e, 4b, and 4h showed IC50 ranging from 4.18 to 8.66 µg/ml against the chloroquine-sensitive (3D7) strain of Plasmodium falciparum. Moreover, compounds 4g, 4b, 4e, and 4c showed IC50 ranging from 8.12 to 12.09 µg/ml against chloroquine-resistant (Dd2) strain. In conclusion, our study demonstrated the development of hybrid PABA substituted 1,3,5-triazines as a novel class of Pf-DHFR inhibitor for antimalarial drug discovery.

1,3,5-Triazine: A versatile pharmacophore with diverse biological activities.

1,3,5-Triazine and its derivatives have been the epicenter of chemotherapeutic molecules due to their effective biological activities, such as antibacterial, fungicidal, antimalarial, anticancer, antiviral, antimicrobial, anti-inflammatory, antiamoebic, and antitubercular activities. The present review represents a summarized report of the crucial biological activities possessed by substituted 1,3,5-triazine derivatives, with special attention to the most potent compounds.

Design, facile synthesis, and antibacterial activity of hybrid 1,3,4-thiadiazole-1,3,5-triazine derivatives tethered via -S- bridge.

Some hybrid 1,3,4-thiadiazole-1,3,5-triazine derivatives tethered via -S- bridge were synthesized and characterized with the aid of spectroscopic and elemental analysis. These hybrid conjugates were then investigated for their antibacterial activity against selected Gram-positive and Gram-negative bacteria. Excellent to moderate antibacterial activity was presented by the target compounds.

Design, synthesis, antibacterial activity, and molecular docking studies of novel hybrid 1,3-thiazine-1,3,5-triazine derivatives as potential bacterial translation inhibitor.

Some novel hybrid 1,3-thiazine-1,3,5-triazine derivatives were synthesized and tested for antibacterial activity. Compounds 8c and 8f were found active against Gram positive and Gram negative microorganisms. Molecular docking studies have been performed on eubacterial ribosomal decoding A site (Escherichia coli 16S rRNA A site) to rationalize the probable mode of action, binding affinity, and orientation of the molecules at the active site of receptor. The structures of all these newly synthesized compounds were confirmed by their elemental analyses and spectral data techniques viz. IR, ¹H NMR, ¹³C NMR, and mass.