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The novel (1-(4-aryl)-1H-1,2,3-triazol-4-yl)methyl, substituted phenyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives were synthesized by the click reaction of the dihydropyrimidinones, bearing a terminal alkynyl group, with various substituted aryl azides at room temperature using a catalytic amount of Cu(OAc)2 and sodium ascorbate in a 1:2 ratio of acetone and water as a solvent. The newly synthesized compounds were characterized by a number of spectroscopic techniques, such as infrared, liquid chromatography-mass spectrometry, 1H, and 13C nuclear magnetic resonance along with single crystal X-ray diffraction. The current procedure for the synthesis of 1,2,3-triazole hybrids with dihydropyrimidinones is appropriate for the synthesis of a library of analogs 7a-l and the method accessible here is operationally simple and has excellent yields. The title compounds 7a-l were evaluated for their in vitro antitubercular activity against H37RV and multidrug-resistant strains of Mycobacterium tuberculosis by resazurin microplate assay plate method and it was found that compound 7d was promising against H37RV and multidrug-resistant strains of M. tuberculosis at 10 and 15 μg/mL, respectively.

To identify the appropriate target for potent BNTZ compounds from the series, molecular modeling studies revealed the multiple strong binding of several BNTZs with mycobacterium lysine-ɛ-aminotransferase and decaprenylphosphoryl-β-D-ribose 2'-oxidase. The interaction is derived by forming favorable hydrogen bonds and stacking interactions. This new class of BNTZ compounds gave promising antitubercular actions in the low micromolar range, and can be further optimized on a structural basis to develop promising, novel, BNTZ pharmacophore-based anti-tubercular drugs.

A series of trisubstituted indolizine analogues has been designed as a result of a fragment-based approach to target the inhibition of mycobacterial enoyl-acyl carrier protein reductase. Anti-tuberculosis (TB) screening of the characterized compounds by a resazurin microplate assay method revealed that ethyl group at second position of indolizine nucleus exhibited activity against susceptible and multidrug-resistant strains of Mycobacterium tuberculosis at concentration of 5.5 and 11.3 μg/mL, respectively. A molecular docking study was also conducted to evaluate the stability of the active compounds, and compound with ethyl substitution at second position of indolizine nucleus showed the highest free binding energy of ΔG -24.11 (kcal/mol), a low clash score of 3.04, and high lipo score of -13.33. Indolizine analog with ethyl substitution at second position demonstrated Molecular Mechanics/Generalized Born Surface Area (-23.85 kcal/mol). Two molecular dynamics studies were computed (100 ps and 50 ns) to calculate the relationship between the potential and kinetic energies of the active anti-TB compound with time and temperature. The discovery of this lead may have a positive impact on anti-TB drug discovery.

Novel series of diversely substituted indolizines were designed, synthesized, and evaluated for their in vitro anti-mycobacterial activity against H37Rv and multi-drug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB). Many compounds exhibited significant inhibitory activity against MTB H37Rv strains. Indolizines 2d, 2e, and 4 were also found to be active against MTB clinical isolates with multi-resistance to rifampicin and isoniazid. Indolizine 4 was identified as the most promising anti-mycobacterial agent, displaying minimum inhibitory concentration (MIC) values of 4 and 32 μg/mL against H37Rv and MDR strains, respectively. Furthermore, an in silico study was carried out for prospective molecular target identification and revealed favorable interactions with the target enzymes CYP 121, malate synthase, and DNA GyrB ATPase. None of the potent molecules presented toxicity against peripheral blood mononuclear (PBM) cell lines, demonstrating their potentiality to be used for drug-sensitive and drug-resistant tuberculosis therapy.

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Background: This research project is designed to identify the anti-diabetic effects of the newly synthesized compounds to conclude the perspective of consuming one or more of these new synthetic compounds for diabetes management. Introduction: A series of dihydropyrimidine (DHPM) derivative bearing electron releasing and electron withdrawing substituent’s on phenyl ring (a-j) were synthesized and screened for anti-hyperglycemic(anti-diabetic) activity on streptozotocin (STZ) induced diabetic rat model. The newly synthesized compounds were characterized by using FT-IR, melting point, 1H and 13C NMR analysis. The crystal structure and supramolecular features were analyzed through single-crystal X-ray study. Anti-diabetic activity testing of newly prepared DHPM scaffolds was mainly based on their relative substituent on the phenyl ring along with urea and thiourea. Among the synthesized DHPM scaffold, the test compound c having chlorine group on phenyl ring at the ortho position to the hydropyrimidine ring with urea and methyl acetoacetate derivative shows moderate lowering of glucose level.However, the title compounds methyl 4-(4-hydroxy-3-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(g) and ethyl 4-(3-ethoxy-4-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(h)having methoxy and ethoxy substituents on phenyl ring show significant hypoglycemic activity compared to the remaining compounds from the scheme-1. Method: The experimental rat models for the study were divided into 13 groups (n = 10); group 1 animals were treated with 0.5% CMC (0.5mL) (vehicle); group 2 were considered the streptozotocin (STZ)/nicotinamide diabetic control group (DC) and untreated, group 3 diabetic animals were administered with gliclazide 50 mg/kg and act as a reference drug group. The remaining groups of the diabetic animals were administered with the newly synthesized dihydropyrimidine compounds in a single dose of 50 mg/kg orally using the oral gauge, daily for 7 days continuously. The blood glucose level was measured before and 72 hrs after nicotinamide-STZ injection, for confirmation of hyperglycemia and type 2 diabetes development. Results: Blood glucose levels were significantly (p<0.05) reduced after treatment with these derivatives. The mean percentage reduction for gliclazide was 50%, while that of synthesized compounds were approximately 36%. Conclusion: Our result suggests that the synthesized new DHPM derivative containing alkoxy group on the phenyl ring shows a significant lowering of glucose level compared to other derivatives.

Background and Purpose: Tuberculosis has been reported to be the worldwide leading cause of death resulting from a sole infectious agent. The emergence of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis has made the battle against the infection more difficult since most currently available therapeutic options are ineffective against these resistant strains. Therefore, novel molecules need to be developed to effectively treat tuberculosis disease. Preliminary docking studies revealed that tetrahydropyrimidinone derivatives have favorable interactions with the thymidylate kinase receptor. In the present investigation, we report the synthesis and the mycobacterial activity of several pyrimidinones and pyrimidinethiones as potential thymidylate kinase inhibitors. Methods: The title compounds (1a-d) and (2a-b) were synthesized by a one-pot three-component Biginelli reaction. They were subsequently characterized and used for whole-cell anti-TB screening against H37Rv and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) by the resazurin microplate assay (REMA) plate method. Molecular modeling was conducted using the Accelry's Discovery Studio 4.0 client program to explain the observed bioactivity of the compounds. The pharmacokinetic properties of the synthesized compounds were predicted and analyzed. Results: Of the compounds tested for anti-TB activity, pyrimidinone 1a and pyrimidinethione 2a displayed moderate activity against susceptible MTB H37Rv strains at 16 and 32 µg/mL, respectively. Only compound 2a was observed to exert modest activity at 128 µg/mL against MTB strains with cross-resistance to rifampicin and isoniazid. The presence of the trifluoromethyl group was essential to retain the inhibitory activity of compounds 1a and 2a. Molecular modeling studies of these compounds against thymidylate kinase targets demonstrated a positive correlation between the bioactivity and structure of the compounds. The in-silico ADME (absorption, distribution, metabolism, and excretion) prediction indicated favorable pharmacokinetic and drug-like properties for most compounds. Conclusion: Pyrimidinone 1a and pyrimidinethione 2a were identified as the leading compounds and can serve as a starting point to develop novel anti-TB therapeutic agents.