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.

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.

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.

In vitro & in vivo studies on lornoxicam loaded nanoemulsion gels for topical application.

The objective of this work was to increase the solubility, in vitro skin permeability of lornoxicam from semisolid topical formulations and also to investigate the in vivo potential of nanoemulsion formulation. Optimized lornoxicam loaded nanoemulsion was prepared successfully by spontaneous self-emulsification method and the size of the stable formulations was found within the range of 102 to 200 nm. The stable nanoemulsion formulations characterized for viscosity, droplet size, transmission electron microscopy (TEM) and refractive index. In vitro permeation rate of nanoemulsion and conventional gel of lornoxicam (LX) were determined. Prmeability parameters like steady-state flux (Jss), permeability coefficient (Kp), and enhancement ratio (Er) were significantly increased in nanoemulsion NE8 and the nanogel NG8 as compared to conventional gel (LG). In vivo studies revealed a significant increase in anti-inflammatory effects as compared with conventional gel of LX. The anti-inflammatory effects of formulation NG8 showed a significant increase in percent inhibition value when compared with control, this difference was found to be highly significant (p<0.001). This work shows for the first time that lornoxicam can be formulated into nanoemulsions and may show promise in enhancing solubility and permeation.

Solid lipid nanoparticles (SLNs) gels for topical delivery of aceclofenac in vitro and in vivo evaluation.

Solid lipid nanoparticles (SLN) are very potential formulations for topical delivery of anti-inflammatory and anti-arthritic drugs. The solid state of the lipid particles enable efficient drug encapsulation and controlled drug release. In the present study, the evaluation of different formulation parameters based on variation of concentration of lipid and cosurfactant was studied. The SLN gel formulations of the dispersions were compared to the SLN dispersions and with the marketed gel of aceclofenac. The SLNs were prepared by high speed homogenization and ultra-sonication method with fixed amount of aceclofenac (10%) and pluronic F68 (1.5%). The particle size, zeta potential and span of developed formulations was found to be within the range of 123 nm to 323 nm, -12.4 to -18.5 and 0.42 to 0.86 respectively as the lipid concentration was increased from 7.5% to 40%. The highest entrapment efficiency was found to be 75% with the formulation having lipid concentration of 30% and 0.85% of phospholipon 90G. Permeation rate and controlled release property of xanthan gum loaded SLN gel formulations and SLN dispersion was studied through excised pig skin for 24hr. The drug release of SLN gel formulations was better controlled as compare to SLN dispersions. In vivo anti-inflammatory study showed that action of aceclofenac was enhanced for SLN dispersion and gel formulations. The results indicated the superiority of SLN based formulations for topical delivery of aceclofenac.

Solid lipid nanoparticles (SLNs) for topical delivery of aceclofenac by using xanthan gum: Ex vivo and in vivo evaluation.

Solid lipid nanoparticles (SLN) are very potential formulations for topical delivery of anti-inflammatory and anti-arthritic drugs. The solid state of the lipid particle enables efficient drug encapsulation and controlled drug release. In the present study the evaluation of different parameters based on variation of concentration of lipid and co-surfactant was studied. The SLN gel formulation of the same dispersion was compared with the SLN dispersion and with the marketed gel formulation of aceclofenac. At first the solid lipid nanoparticles were prepared by high speed homogenization and ultra-sonication method with fixed amount of aceclofenac (10%) and pluronic F68 (1.5%). The particle size, zeta potential and span was found to be within the range of 123 nm to 323 nm, -12.4 to -18.5 and 0.42 to 0.86 respectively as the lipid concentration was increasing from 7.5% to 40%. The highest entrapment efficiency was found to be 75% with the formulation having lipid concentration of 30% and 0.85% of phospholipon 90G (Phospholipid as co-surfactant). Particle surface morphology was measured by scanning electron microscope (SEM). Permeation rate and controlled release property of xanthan gum loaded SLN gel formulations and SLN dispersion was studied through the excised pig skin for 24hr and it was found that release rate of SLN gel formulation was more controlled as compare to SLN dispersions. In vivo pharmacodynamic study was carried out for 24 hr by injecting 0.1ml (w/v) CFA (Complete Fraud's Adjuvant). From the in vitro and in vivo study it was found that action of aceclofenac was enhanced by prepared SLN dispersion and gel formulations. The results indicated the utility of both SLN dispersion and SLN gel system for transdermal delivery of aceclofenac as excellent and logical.

Antimalarial evaluation and docking studies of hybrid phenylthiazolyl-1,3,5-triazine derivatives: a novel and potential antifolate lead for Pf-DHFR-TS inhibition.

Present communication deals with the docking study of hybrid phenyl thiazolyl-1,3,5-triazine analogues (1a-36d) on three selected different binding site viz., α, ß and γ of wild type Pf-DFHR-TS. In admiration of excellent H-bond scoring, with regard to cycloguanil and to a large extent similar scoring with WR99210, compound 4a, 12b, 21c, 23c, 28d, 29d, 34d, and 35d were selected for in vitro antimalarial activity against 3D7 strain of Plasmodium falciparum. Findings from the study disclose that a significant correlation was exist between in vitro results and in silico prediction (r(2)=0.543). Furthermore, investigation of structure-activity relationships elucidate crucial structural requirement for site specific binding of ligands.

Design, synthesis and SAR exploration of hybrid 4-chlorophenylthiazolyl-s-triazine as potential antimicrobial agents.

Two novel series of hybrid class 4-chlorophenylthiazole-s-triazine were synthesized via nucleophilic substitution of 2,4,6-trichloro-1,3,5-triazine with distinguished alkenyl/alkyl/aryl/hetero alkyl-aryl amino and mercapto nucleophiles under nitrogen atmosphere. We identified that the spectrums of antibacterial activity of all tested compounds reveal promising and significant inhibition of gram-positive and gram-negative micro-organisms and the most active compounds, 31d and 32d, were found to be non-toxic in preliminary cytotoxicity assay. We also report that the Molinspiration and Osiris Property Explorer calculations have found a new lead 32d, which binds preferentially to the nuclear receptor to exhibit antibacterial potency.