A rapid, sustainable and environmental friendly protocol for the catalyst-free synthesis of 2-methyl-5-oxo-hexahydroquinoline-3-carboxylate via ultrasonic irradiation

Ganja H., Robert A.R., Lavanya P., Chinnam S., Maddila S., Jonnalagadda S.B.

A green, facile and multicomponent reaction for the preparation of furo[3,4-b]chromenes using a recoverable and reusable yttria doped hydroxyapatite (Y2O3/HAp) solid material as the heterogeneous catalyst is described. The reaction progresses with mixing the aldehyde, 4-hydroxyfuran-2(5H)-one, 5,5-dimethylcyclohexane-1,3-dione and Y2O3/HAp at R.T. in ethanol solvent media to obtain the desired target molecules in excellent yields (91–98%). The proposed approach shows noteworthy benefits such as ecofriendly, non-toxic solvents, easy handling, short reaction time (10 min), simple workup procedure, avoiding column chromatography and reusability of the catalyst, proving vital green chemistry principles.

Shabalala N.G., Kerru N., Maddila S., van Zyl W.E., Jonnalagadda S.B.

A library of twenty 2-amino-4H-chromene derivatives is reported via a simple, efficient, and environmentally friendly protocol, of which fourteen molecules were novel. This was achieved through a three-component reaction of chosen aliphatic and aromatic aldehydes with isopropyl cyanoacetate and 5,5-dimethyl-1,3-cyclohexanedione in aqueous ethanol under ultrasound irradiation. Excellent yields (95–99%) of the desired derivatives were obtained for rapid reaction times (5–15 min) at room temperature. This method avoids the use of a catalyst, volatile organic solvents, and column chromatography. The present method gives a 95% atom economy and 100% of carbon efficiency.

Maddila S.N., Maddila S., Kerru N., Bhaskaruni S.V., Jonnalagadda S.B.

Nayab R.S., Maddila S., Krishna M.P., Titinchi S.J., Thaslim B.S., Chintha V., Wudayagiri R., Nagam V., Tartte V., Chinnam S., Chamarthi N.R.

Maddila S.N., Maddila S., Bhaskaruni S.V., Kerru N., Jonnalagadda S.B.

• 3% MnO 2 /HAp as highly efficient heterogeneous catalyst. • Three component one-pot synthesis in water. • Nine new pyran-carboxamide derivatives. • Excellent yields (91–98%) in short reaction times (15 min). Three different loadings of MnO 2 on hydroxyapatite (MnO 2 /Hap) were synthesized and the hydroxyapatite supported MnO 2 materials were characterized by several analytical techniques including FT-IR, P-XRD, TEM and SEM analysis. 3% MnO 2 /HAp material proved highly efficient catalyst for the synthesis of a series of ten pyran-carboxamide derivatives (yield 91–98%) in aqueous medium at room temperature (RT) conditions, via one-pot multi-component reaction, of which nine were new moieties. The prominent features of the protocol are excellent yields, high atom efficiency, short reaction times (15 min), recyclable catalyst and no need for column separation.

Xue W., Li X., Ma G., Zhang H., Chen Y., Kirchmair J., Xia J., Wu S.

Due to the occurrence of antibiotic resistance, bacterial infectious diseases have become a serious threat to public health. To overcome antibiotic resistance, novel antibiotics are urgently needed. N-thiadiazole-4-hydroxy-2-quinolone-3-carboxamides are a potential new class of antibacterial agents, as one of its derivatives was identified as an antibacterial agent against S. aureus. However, no potency-directed structural optimization has been performed. In this study, we designed and synthesized 37 derivatives, and evaluated their antibacterial activity against S. aureus ATCC29213, which led to the identification of ten potent antibacterial agents with minimum inhibitory concentration (MIC) values below 1 μg/mL. Next, we performed bacterial growth inhibition assays against a panel of drug-resistant clinical isolates, including methicillin-resistant S. aureus, and cytotoxicity assays with HepG2 and HUVEC cells. One of the tested compounds named 1-ethyl-4-hydroxy-2-oxo-N-(5-(thiazol-2-yl)-1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-3-carboxamide (g37) showed 2 to 128-times improvement compared with vancomycin in term of antibacterial potency against the tested strains (MICs: 0.25-1 μg/mL vs. 1-64 μg/mL) and an optimal selective toxicity (HepG2/MRSA, 110.6 to 221.2; HUVEC/MRSA, 77.6-155.2). Further, comprehensive evaluation indicated that g37 did not induce resistance development of MRSA over 20 passages, and it has been confirmed as a bactericidal, metabolically stable, orally active antibacterial agent. More importantly, we have identified the S. aureus DNA gyrase B as its potential target and proposed a potential binding mode by molecular docking. Taken together, the present work reports the most potent derivative of this chemical series (g37) and uncovers its potential target, which lays a solid foundation for further lead optimization facilitated by the structure-based drug design technique.

Yang Y., Pratap Singh R., Song D., Chen Q., Zheng X., Zhang C., Zhang M., Li Y.

Quinclorac (QNC) is an effective but environmentally persistent herbicide commonly used in rice production. However, few studies have investigated its environmental behavior and degradation. In the present study, we carried out microbial cultures in the presence of QNC to observe changes in soil microbiota and to identify species capable of QNC degradation by using high-throughput sequencing of the 16S rRNA. Pseudomonas was the dominant genus, and Pseudomonas putida II-2 and other species were found to be capable of mineralizing QNC as a source of carbon and energy. However, this degradation rate was slow, only reaching 51.5 ± 1.6% for 7 days at 30 °C on QNC + minimal salt medium. Achromobacter sp. QC36 co-metabolized QNC when rice straw was added into the mineral salt medium containing QNC, and a mixed culture of both strains could mineralize approximately 92% of the 50 mg/L QNC after 5 days of cultivation in the presence of rice straw, at 25-35 °C and pH 6.0-8.0. Non-phytotoxicity of tobacco after degradation of QNC by mixed strains was evidenced in a pot experiment. These results suggest that this mixed culture may be useful in QNC bioremediation and can be used as a bio-formulation for agro-economical and industrial application.

Aly A.A., Sayed S.M., Abdelhafez E.M., Abdelhafez S.M., Abdelzaher W.Y., Raslan M.A., Ahmed A.E., Thabet K., El-Reedy A.A., Brown A.B., Bräse S.

• Synthesis of new pyrazolo-quinoline-2-ones. • NMR spectra as effective tool to elucidate the given structure. • Some compounds showed significant improvement for oxidative stress parameters MDA, SOD, GSH and NOx in comparison with model group and greater than NAC. • Colonic histopathological investigation was performed on all targeted compounds. • H&E sections of some compounds revealed apparent normal colonic cells compared with NAC. • Docking studies with caspase-3 revealed that most of the tested compounds showed good binding with the enzyme. We report the synthesis of new quinoline-2-one/pyrazole hybrids and their antiapoptotic activity. This effect was studied in sight of decreasing tissue damage induced by I/R in colon of rats using N -acetylcysteine (NAC) as anti-apoptotic reference. Compounds 6a , 6c and 6f showed significant improvement for oxidative stress parameters MDA, SOD, GSH and NOx in comparison with model group and greater than the reference NAC ( N -acetylcysteine), whereas compounds 6d and 6e exhibited weaker antioxidant activity when compared with the reference NAC. Moreover, compounds 6a, 6c and 6f showed significant decrease in inflammatory mediators TNFα and CRB greater than NAC when compared to the model group especially compound 6c whose found CRB conc 1.90 (mg/dL) in comparison to NAC of conc 2.13 mg/dL. Additionally, colonic histopathological investigation was performed to all targeted compounds that indicates H&E sections of compounds 6a and 6f revealed apparent normal colonic cells while compound 6e showed dilated blood vessels with more apoptotic cells if compared with NAC. Caspase-3 inhibition assay revealed that compounds 6a , 6b and 6d weaken caspase-3 expression to an extent higher than NAC (1.063, 0.430, 0.731 and 1.115, respectively). Docking studies with caspase-3 revealed that most of the tested compounds showed good binding with the enzyme especially for compound 6d make several interactions better than that of the reference NAC.

Bhaskaruni S.V., Maddila S., Gangu K.K., Jonnalagadda S.B.

The use of mixed oxides is a well-appreciated approach in the fields of material science and synthesis, due to remarkable tunable surface properties such as acidic and basic characteristics, oxidation/reduction capabilities, and high agility of lattice oxygen, which makes them ideal choices as heterogeneous catalysts. The activity of the mixed oxides broadly relies on the nature of support and active material used and on the preparation method, calcination temperatures. Wide range of techniques for preparation of mixed oxide materials are adoptable, viz. sol-gel, co-precipitation, wet impregnation, microwave irradiation and hydrothermal methods. Use of mixed oxides as solid catalysts have gained popularity in many valued organic transformations, via alkylation, oxidation, condensation, dehydration, dehydrogenation, cycloaddition and isomerization. Application of mixed oxides in the area of green organic synthesis is a valuable strategy, which contributed significantly to the design of many novel heterocyclic scaffolds. The chemistry of N-heterocycle scaffolds, which generally possess five and six membered rings, is an interesting area for both synthetic and medicinal chemistry research constituting over 60% organics used in various arenas. The position and number of nitrogen atoms in the rings, distinguish them as pyrroles, pyrazoles, imidazoles, triazoles, pyridines and pyramidines classes. In this review, we focus on the scope, importance and versatile applications of mixed metal oxides and their synergetic effects as heterogeneous catalysts in the synthesis of variety of N-heterocyclic derivatives. The scientific aspects of the mixed oxides as catalytic active materials to design efficient synthetic protocols for the organic transformations is also discussed.

Bhaskaruni S.V., Maddila S., van Zyl W.E., Jonnalagadda S.B.

Nickel oxide loaded on zirconia (NiO/ZrO2) as an expedient catalyst is reported for the synthesis of 18 unsymmetrical 1,4-dihydropyridine derivatives. The Lewis acidic nature of the catalyst proved an excellent choice for the one-pot, four-component fusion reaction with excellent yields of 89-98% and a completion time of 20-45 min. Mechanistic studies show that enamine and imine functionalities are the two possible pathways for the formation of 1,4-dihydropyridines with high selectivity. Crystal structures of two novel compounds (5a, 5c) were reported. The catalyst demonstrated reusability up to six cycles. The reaction at room temperature and ethanol as a solvent make this protocol green and economical.

Maddila S., Abafe O.A., Bandaru H.N., Maddila S.N., Lavanya P., Seshadri N., Jonnalagadda S.B.

A simple and efficient one-pot method has been developed for the synthesis of benzochromenes (4a–k) using V-CaHAp as a heterogeneous catalyst by the condensation of aldehydes, β-naphthol and malononitrile in ethanol as solvent at room temperature for 20 min. The reaction, with this catalyst was carried out under mild reaction conditions with very good to excellent yields (89–98%). The material can be recycled very easily and reused for at least 6 runs without substantial loss in activity, which makes this methodology environmentally benign. We achieved a feasible and cost-effective synthesis by using non-toxic materials and minimal catalyst which is easy to handle.

Maddila S., Gorle S., Jonnalagadda S.B.

Khumalo M.R., Maddila S.N., Maddila S., Jonnalagadda S.B.

Eleven new tetrahydrobenzo[b]pyran derivatives were synthesized via a three component reaction of different aromatic aldehydes, methyl cyanoacetate and 1,3-cyclohexadione, with water as solvent under catalyst-free microwave irradiation. The structures of all the new molecules were well analysed and their structures established by using various spectral techniques (1H NMR, 13C NMR, 15N NMR and HRMS). Various advantages of reported protocol are the ease of preparation, short reaction times (10 min), aqueous solvent and excellent yields (89–98%). Additionally, this method provides a clean access to the desired products by simple workup.

da Silva Júnior E.N., Jardim G.A., Jacob C., Dhawa U., Ackermann L., de Castro S.L.

Naphthoquinones are of key importance in organic synthesis and medicinal chemistry. In the last few years, various synthetic routes have been developed to prepare bioactive compounds derived or based on lapachones. In this sense, this review is mainly focused on the synthetic aspects and strategies used for the design of these compounds on the basis of their biological activities for the development of drugs against the neglected diseases leishmaniases and Chagas disease and also cancer. Three strategies used to develop bioactive quinones are discussed and categorized: (i) C-ring modification, (ii) redox centre modification and (iii) A-ring modification. Framed within these strategies for the development of naphthoquinoidal compounds against T. cruzi. Leishmania and cancer, reactions including copper-catalyzed azide-alkyne cycloaddition (click chemistry), palladium-catalysed cross couplings, C-H activation reactions, Ullmann couplings and heterocyclisations reported up to July 2019 will be discussed. The aim of derivatisation is the generation of novel molecules that can potentially inhibit cellular organelles/processes, generate reactive oxygen species and increase lipophilicity to enhance penetration through the plasma membrane. Modified lapachones have emerged as promising prototypes for the development of drugs against leishmaniases, Chagas disease and cancer.

Yang G., Zhu J., Yin X., Yan Y., Wang Y., Shang X., Liu Y., Zhao Z., Peng J., Liu H.

Inspired by quinine and its analogues, we designed, synthesized, and evaluated two series of quinoline small molecular compounds (a and 2a) and six series of quinoline derivatives (3a-f) for their antifungal activities. The results showed that compounds 3e and 3f series exhibited significant fungicidal activities. Significantly, compounds 3f-4 (EC50 = 0.41 μg/mL) and 3f-28 (EC50 = 0.55 μg/mL) displayed the superior in vitro fungicidal activity and the potent in vivo curative effect against Sclerotinia sclerotiorum. Preliminary mechanism studies showed that compounds 3f-4 and 3f-28 could cause changes in the cell membrane permeability, accumulation of reactive oxygen species, loss of mitochondrial membrane potential, and effective inhibition of germination and formation of S. sclerotiorum sclerotia. These results indicate that compounds 3f-4 and 3f-28 are novel potential fungicidal candidates against S. sclerotiorum derived from natural products.

Mohareb R.M., Mukhtar S., Parveen H., Abdelaziz M.A., Alwan E.S.

Background: A number of research were conducted on the pyran and thiophene derivatives, which were attributed to have a wide range of biological activities, including anti-plasmodial, as well as acting as caspase, hepatitis C and cancer inhibitors. Objective: The multicomponent reactions of the 5-acetyl-2-amino-4-(phenylamino)-thiophene-3-carbonitrile produced biologically active target molecules like pyran and their fused derivatives. Comparison between regular catalytic multi-component reactions and solvent-free ionic liquids immobilized multicomponent was studied. Methods: The multicomponent reactions in this work were carried out not only under the reflux conditions using triethylamine as a catalyst but also in solvent-free ionic liquids immobilized magnetic nanoparticles (MNPs) catalysts. Results: Through this work, thirty-one new compounds were synthesized and characterized and were evaluated toward the six cancer cell lines, namely A549, HT-29, MKN-45, U87MG, and SMMC-7721 and H460. The most active compounds were further screened toward seventeen cancer cell lines classified according to the disease. In addition, the effect of compound 11e on the A549 cell line was selected to make further morphological changes in the cell line. The Molecular docking studies of 11e and 11f were carried and promising results were obtained. Conclusion: The synthesis of heterocyclic compounds derived from thiophene derivatives has been receiving significant attention. After a detailed optimizing study, it has been found that the solvent-free ionic liquids immobilized multi-component syntheses afforded a high yield of compounds, opening a greener procedure for this synthetically relevant transformation. Many of the synthesized compounds can be considered anticancer agents, enhancing further studies

Kumar K.S., Robert A.R., Kerru N., Maddila S.

We report a facile, efficient, and environmentally benign approach for preparing morpholino-linked 1,4-dihydropyridine derivatives. The four-component fusion of morpholin-4-amine, diethyl acetylene dicarboxylate, malononitrile, and chosen substituted benzaldehydes occurred under microwave irradiation under mild conditions in the presence of potassium carbonate as a catalyst. This protocol offers remarkable benefits such as excellent yields (92–98 %), easy handling, simple workup, economy, cleaner reaction profile, green conditions, shorter reaction time (≤10 min), and avoiding column chromatography for purification.

Maddila S., Devi L., Muralidhar P., Nagaraju K., Jonnalagadda S.B.

• Excellent yields (95–97%) in short reaction times (

Prasanna B.L., Rao B.S., Muralidhar P., Nagaraju K., Maddila S.

A novel 4 H -pyran-3-carbonitrile analogues have been synthesized conveniently using a highly efficient protocol via solvent-free, one-pot, multicomponent condensation of malononitrile, various aldehydes, and 5,5-dimethylcyclohexane-1,3‑dione along with TEA as catalyst under simple grinding approach. Simple handling, mild reaction conditions with superb alterations, inexpensive, environmental friendliness, avoiding toxic solvents, short reaction times (10 min), easy workup process, and higher product yields (89–96%) are remarkable benefits of this approach.

Hosseininasab F.S., Memarian H.R.

Various symmetrical and unsymmetrical decahydroacridine-1,8-dione and polyhydroquinoline derivatives were synthesized via two-step cyclocondensation reactions. The advantages of this step-wise addition of reactants in comparison with other one-pot reactions are avoiding the formation of 2 or 3 undesired by-products, therefore allowing cleaner work up of reaction. The important factor of this effective cyclocondensation method is that the prepared β-enaminone component was added dropwise to the solution, in which the Knoevenagel condensation product is slowly being formed by reaction of aldehyde molecule and 1,3-dicarbonyl compounds. The results of the proposed step-wise method are compared and discussed with those obtained in the one-pot reactions.

Muralidhar P., Kumar B.S., Nagaraju K., Maddila S.

A facile, efficient and one-pot two component reaction for the synthesis of 3-aminoindole was performed under green conditions and products were obtained in good to excellent yields. The structure of all the target molecules was characterized and confirmed with FTIR, 1H NMR, 13C NMR and HRMS analysis. Green conditions, easy workup short reaction times with high yield of products and high efficient catalyst are some advantages of presented protocol.

Rao D.J., Nagaraju K., Maddila S.

A swift, environmental-friendly and efficient protocol for the synthesis of isoxazole-5(4 H )-one derivatives through multicomponent reaction of substituted aldehydes, ethylacetoacetate and hydroxylamine is designed by MWI under catalyst-free condition. The noticeable features of this protocol are: simple handling, environmental-benign, catalyst-free, avoid of harmful catalysts, short reaction time (≤ 10), energy conserving, no toxic by-products and excellent yields (93–98%).

Devi L., Nagaraju K., Maddila S., Jonnalagadda S.B.

• A facile, an efficient protocol using ultrasound irradiation. • Synthesis of tetrahydro-1H-pyrazolo-[3,4-b]-quinolin-5(4H)-ones. • One-pot/multi-component green solvent (ethanol) protocol. • Excellent yields (94 to 98%) in short reaction times (< 10 min). A green and efficient protocol for the one-pot, multicomponent, catalyst-free synthesis of tetrahydro-1H-pyrazolo-[3,4-b]-quinolin-5(4H)-ones (4a-j) from the reaction of 5-amino-3-methyl-1-phenylpyrazole, aromatic aldehydes, and dimedone in ethanol as green solvent under ultrasound irradiation is described. This protocol offers several benefits such as simple handling, easy workup process, waste-free, milder reaction conditions, cleaner reaction, environment-friendly, short reaction times, absence of any tedious purification and excellent yields.

Maddila S., Nagaraju K., Jonnalagadda S.B.

A series of novel pyrano[2,3-d]-pyrimidine beared 1,2,3-triazoles (4a-j) was synthesized by using CuSO4 and sodium ascorbate as a catalyst via cycloaddition of alknyl pyranopyrimidinone (3) with various substituted aryl azides. All the synthesized compounds have been confirmed by diverse spectroscopy analyses such as FT-IR, 1HNMR, 13CNMR and HR-MS spectral study. Further, the target molecules were screened for their antibacterial activity against Klebsiella pneumonia, Staphylocouccus aureus, Escherichia coli, and Bacillus subtilis and antifungal activity against Candida albicans and Aspergillus flavus. Molecules 4g and 4h were found to be excellent bacterial and fungal activity compare to the corresponding standard Amoxicillin and Ketoconazole.