The quantitative structure activity relationship (QSAR) study is the most cited and reliable computational technique used for decades to obtain information about a substituent's physicochemical property and biological activity. There is step-by-step development in the concept of QSAR from 0D to 2D. These models suffer various limitations that led to the development of 3D-QSAR. There are large numbers of literatures available on the utility of 3D-QSAR for drug design. Three-dimensional properties of molecules with non-covalent interactions are served as important tool in the selection of bioactive confirmation of compounds. With this view, 3D-QSAR has been explored with different advancements like COMFA, COMSA, COMMA, etc. Some reports are also available highlighting the limitations of 3D-QSAR. In a way, to overcome the limitations of 3D-QSAR, more advanced QSAR approaches like 4D, 5D and 6D-QSAR have been evolved. Here, in this present review we have focused more on the present and future of more predictive models of QSAR studies. The review highlights the basics of 3D to 6D-QSAR and mainly emphasizes the advantages of one dimension over the other. It covers almost all recent reports of all these multidimensional QSAR approaches which are new paradigms in drug discovery.

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A series of 6-amino-4-substituted-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles 5a–j were synthesized via one-pot, four-component condensation reactions of aryl aldehydes 1a–j, propanedinitrile (2), hydrazine hydrate (3) and ethyl acetoacetate (4) under solvent-free conditions. We report herein the use of the Brønsted acid ionic liquid (BAIL) triethylammonium hydrogen sulphate [Et3NH][HSO4] as catalyst for this multi-component synthesis. Compared with the available reaction methodology, this new method has consistent advantages, including excellent yields, a short reaction time, mild reaction conditions and catalyst reusability. Selected synthesized derivatives were evaluated for in vitro anticancer activity against four human cancer cell lines viz. melanoma cancer cell line (SK-MEL-2), breast cancer cell line(MDA-MB-231), leukemia cancer cell line (K-562) and cervical cancer cell line (HeLa). Compounds 5b, 5d, 5g, 5h and 5j exhibited promising anticancer activity against all selected human cancer cell lines, except HeLa. Molecular docking studies also confirmed 5b and 5d as good lead molecules. An in silico ADMET study of the synthesized anticancer agents indicated good oral drug-like behavior and non-toxic nature.

A facile, highly efficient, and greener method for the synthesis of new 1,4-disubstituted-1,2,3-triazoles was conducted using [Et 3 NH][OAc] as a medium by the implementation of ultrasound irradiation via click chemistry, affording excellent yields. The present synthetic method exhibited numerous advantages such as mild reaction conditions, excellent product yields, minimal chemical waste, operational simplicity, shorter reaction time, and a wide range of substrate scope. The synthesized compounds were further evaluated for in vitro antifungal activity against five fungal strains, and some of the compounds displayed equivalent or greater potency than the standard drug. A molecular docking study against the modelled three-dimensional structure of cytochrome P450 lanosterol 14a-demethylase was also performed to understand the binding affinity and binding interactions of the enzyme. Furthermore, the synthesized compounds were evaluated for DPPH radical scavenging activity and antitubercular activity against Mycobacterium tuberculosis H37Rv strain. Fig. 2 1,2,4-Triazole-based marketed antifungal drugs.Scheme 1 Synthesis of alkynes 2a-c and 2-azido-N-phenylacetamides 5a-g. Reagents and conditions: (a) propargyl bromide, K 2 CO 3 , DMF, 2 h, 90-95%; (b) chloroacetyl chloride, NEt 3 , CH 2 Cl 2 , 0 C to rt, 3-5 h, 85-95%; (c) NaN 3 , toluene, reflux, 5-7 h, 88-96%. Scheme 2 Standard model reaction. This journal isScheme 3 Synthesis of 1,4-disubstituted-1,2,3-triazole 6a via the one-pot three-component click reaction. This journal isScheme 4 Synthesis of 1,4-disubstituted-1,2,3-triazole derivatives 6a-g, 7a-g, and 8a-g.22084 | RSC Adv., 2019, 9, 22080-22091This journal is Fig. 4 Binding pose and molecular interactions in the active sites of C. albicans lanosterol 14a-demethylase: (a) 8f and (b) 8g.22086 | RSC Adv., 2019,9,[22080][22081][22082][22083][22084][22085][22086][22087][22088][22089][22090][22091] This journal is

A series of new 1,2,3-triazole-tethered coumarin conjugates linked by N-phenylacetamide was efficiently synthesized via the click chemistry approach in excellent yields. The synthesized conjugates were evaluated for their in vitro antifungal and antioxidant activities. Antifungal activity determination was carried out against fungal strains such as Candida albicans, Fusarium oxysporum, Aspergillus flavus, Aspergillus niger and Cryptococcus neoformans. Compounds 7b, 7d, 7e, 8b and 8e displayed higher potency than the standard drug miconazole, with lower minimum inhibitory concentration values. Also, compound 7a exhibited potential radical scavenging activity as compared with the standard antioxidant butylated hydroxytoluene. In addition, a molecular docking study of the newly synthesized compounds was carried out, and the results showed a good binding mode at the active site of the fungal (C. albicans) P450 cytochrome lanosterol 14α-demethylase enzyme. Furthermore, the synthesized compounds were also tested for ADME properties, and they demonstrated potential as good candidates for oral drugs.