Letters in Organic Chemistry - Volume 19, Issue 2, 2022

The 1-(4-hydroxy-6-methyl-2H-pyran-2-on-3-yl)-3-aryl-2-propenones, chalcone analogs derived from dehydroacetic acid (DHA), play a significant role in synthetic organic chemistry and proved to be an important intermediate for the wealth of multifarious biologically active molecules especially heterocyclic compounds. The review is an attempt to compile the transformations of DHA-chalcones to various classes of products.

A series of novel amide and Schiffs base functionalized novel pyrido[1,2-a] pyrimidin- 4-one derivatives was prepared starting from 6-(thiophen-2-yl)/phenyl-4-(trifluoromethyl) pyridin- 2-amine 1a and 1b. These compounds on reacting with EMME afford compounds 2a and 2b, followed by cyclization to afford compounds 3a and 3b. Treatment of compounds 3a and 3b with hydrazine hydrate gave compounds 4a and 4b, which further reacted with different substituted aromatic aldehydes to give Schiff’s base derivatives 5a-j. In another way, compounds 3a, 3b by reacting with aliphatic amines give amide derivatives 6a-f. All the compounds, 5a-j and 6a-f, were screened against four human cancer cell lines (HeLa, COLO205, Hep G2, and MCF 7). Among all the derivatives, compounds 5c, 5e, 6a, and 6b showed promising anticancer activity.

Human serum albumin (HSA) was found to catalyze the asymmetric nitroaldol reaction of biphenyl aldehydes with nitromethane to afford the corresponding optically active 2-nitro alcohols. Careful optimization of the conditions for the reaction of 4-phenylbenzaldehyde with nitromethane in water at a neutral pH improved both the reactivity and the enantioselectivity. Finally, the reaction of 4-phenylbenzaldehyde (56 mg, 0.30 mmol) in nitromethane (2.8 mL) and water (1.1 mL) using HSA (68 mg) at 5 °C for 240 h gave (R)-1-([1,1'-biphenyl]-4-yl)-2-nitroethanol in 71% yield (52 mg), with an ee up to 85% ee. Subsequent recrystallization improved the ee up to 95%. The reaction was useful in a preparative-scale operation, and the biocatalyst could be reused several times. The procedure was also applicable to other substrates with different substitution patterns. Although the nitroaldol reaction of 2-phenylbenzaldehyde with nitromethane proceeded with low enantioselectivity to afford the corresponding (R)-2-nitroalcohols (35% ee), the reactions of the substrates bearing Br, Me, OMe, or CN group at the 4'-position of the benzene ring gave the corresponding optically active compounds with high enantioselectivities (80-88% ee).

Imidazole and triazine derivatives act as antimicrobial and antitubercular agents. 2D-QSAR determination estimates the pharmacological activity based on the thermodynamic properties of the structure. The structural arrangements and thermodynamic properties of the imidazole derivatives are necessary for the enhancement of pharmacological activity. So, imidazole-triazine clubbed derivatives were designed based on molecular modeling 2DQSAR study on antitubercular activity. PLSR method is applied for 2D-QSAR determination of the (Z)-5-ethylidene-3-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-2-phenyl-3,5- dihydro-4H-imidazol-4-one (B1-B10). The designed compounds were synthesized and spectrally evicted by IR, ¹H NMR, ¹C NMR, and mass spectra data as well as biologically screened against the different antitubercular and antimicrobial species. Compounds B4, B6, and B7 were found potent against the different antimicrobial species. Compound B3 was more effective against the M. tuberculosis H37Rv. Statistically significant QSAR model generated by PLSR methods showed external r²=0.9775 and internal q²=0.2798 predictive abilities. Furthermore, the model also incorporated three parameters, Polar Surface Area Excluding Pand S, Mom Inertia Y, and SsCH3 count, with their corresponding values for each molecule. The 2DQSAR study revealed that antitubercular activity was directly proportional to the total surface area of the polar atoms having molecules and the moment of inertia on the Y-axis. At the same time, antitubercular activity was inversely proportional to the methyl group joined with a single bond. The present study afforded favorable results, which were further used to generate lead target molecules.

A simple and novel protocol for the facile synthesis of bicyclic hybrid molecular framework of morpholinopyrimidines having six-membered pyrimidine ring fused with the morpholine unit is established. The method has been successfully employed to synthesize both regioisomers of the morpholinopyrimidine derivatives in good to high yields. The strategy is further extended successfully to synthesize bicyclic pyrimidooxazapine derivatives bearing the six-membered aromatic pyrimidine unit fused with seven-membered aliphatic oxazapine fragment.

As a part of our ongoing interest to identify bioactive microbial secondary metabolites, the Red Sea tunicate derived Penicillium commune DY004 was investigated. A new dipeptide, penicillizine A (1) together with cyclo(L-Pro-L-Phe) (2), meleagrin (3), α-cyclopiazonic acid (4) and N-(4-hydroxyphenethyl)acetamide (5) was isolated from the ethyl acetate extract of the cultures of the fungus. The structural determinations of 1-5 were supported by interpretation of their oneand two-dimensional nuclear magnetic resonance (NMR) and mass spectrometry (MS) data. In the evaluation of the compounds for their effects against three human tumorous cell lines, meleagrin (3) and α-cyclopiazonic acid (4) displayed the highest and potent activity against HeLa, U373 glioblastoma and MDA-MB-231 cell lines down up to 3.1 μg/mL. These results suggest that marine fungi are a copious source of drug leads with therapeutic potential. Meleagrin and α-cyclopiazonic acid could be used as potential scaffolds for the development of new and more effective drug leads.

An efficient synthesis of amidoalkyl naphthols from the multicomponent reaction of 2- naphthol, aromatic aldehydes, and benzamide derivatives using PEG-400 as an environmentally friendly solvent is described. The main advantage of this protocol is that the benzamide derivatives with low reactivity, such as 4-nitro benzamide, can react effectively. Also, the molecular structure, IR, and ¹³C NMR spectra of the synthesized compounds are also investigated theoretically. Density functional theory (DFT) calculations at the B3LYP level of theory are carried out to locate optimized geometries and calculate vibrational normal modes and ¹³C NMR chemical shifts. These calculations enable us to assign the observed FT-IR and ¹³C NMR peaks to the corresponding vibrational motions and ¹³C atoms, respectively.

Tuberculosis remains a highly infectious disease across the world. In the identification of new antitubercular agents, coumarin clubbed thiadiazole amides have been synthesized and evaluated for in vitro antitubercular activity. Owing to the growing concern of chemicals and their impact on the environment, greener and faster reaction conditions needed to be incorporated. Therefore, we used TBTU as a coupling reagent for efficient and facile synthesis of substituted-N-(5-((7- methyl-2-oxo-2H-chromes-4-yl)-methyl)-1,3, 4 - thiadiazol-2-yl)-benzamide 4a-j with good yields up to 95% in mild reaction conditions. All the synthesized compounds were evaluated in vitro for anti-tubercular activity against the H37Rv strain of M.Tuberculosis. Compounds 4c, 4f, and 4j were found active at 25 μg/mL against M. tb H37Rv. Electron withdrawing substituents present on aromatic side chains showed promising anti-tubercular activity.

Three polycyclic aromatic hydrocarbons derived from benzo[c]phenanthrene have been synthesized through a one-step procedure involving palladium Suzuki coupling and are characterized by ¹H and ¹³C NMR, MS and HRMS spectroscopies. UV-vis absorption and fluorescence properties of these π-conjugated compounds have been evaluated in solutions and strong emission in the blue region of the visible spectrum was noted. The optical spectra of these small polycyclic aromatic compounds are unusual since absorption is entirely in the UV region (λmax = 281-285 nm), yet fluorescence occurs at 410-422 nm. This equates to a Stokes shift of 1.32-1.39 eV (10756- 11256 cm⁻¹) and is among the large Stokes shifts that have been reported for small molecules, making them promising candidates for optoelectronic applications.