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. 2024 May 22;14(23):16584-16599.
doi: 10.1039/d4ra02271h. eCollection 2024 May 15.

Some pyrimidohexahydroquinoline candidates: synthesis, DFT, cytotoxic activity evaluation, molecular docking, and in silico studies

Sayed K Ramadan  1 , Hisham S M Abd-Rabboh  2 , Amal A Abdel Hafez  2 , Wael S I Abou-Elmagd  1
Affiliations

Some pyrimidohexahydroquinoline candidates: synthesis, DFT, cytotoxic activity evaluation, molecular docking, and in silico studies

Sayed K Ramadan et al. RSC Adv. .

Abstract

Some hexahydroquinoline candidates were prepared by reacting 2-amino-3-cyano-1-cyclohexylhexahydroquinoline with oxalyl chloride and triethyl orthoformate. The computational chemical approach agreed with the product-testing results. The produced substances were examined in vitro for their antiproliferative activity against liver carcinoma (HepG2), breast adenocarcinoma (MCF7), prostate cancer (PC3), and colon cancer (HCT116) cell lines. The highest potency against the four cell lines was exhibited by hydrazide, thiosemicarbazide, and thiazolidinone derivatives. The best docking score was presented by thiosemicarbazide and thiazolidinone derivatives as they showed the highest binding to the Mcl-1 enzyme with binding energies of -8.97 and -8.90 kcal mol-1, respectively, which were higher than that of the co-crystallized ligand (LC3) with a binding energy of -8.74 kcal mol-1. Besides, the modeling pharmacokinetics disclosed their desirable drug-likeness and oral bioavailability characteristics.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1. Structures of some quinoline-containing drugs.
Fig. 2
Fig. 2. Rationale and design of the structures of some anticancer agents (including quinoline core) and the target substances.
Scheme 1
Scheme 1. Synthesis of β-enaminonitrile 4 and its reactions with triethyl orthoformate and oxalyl chloride.
Scheme 2
Scheme 2. A plausible mechanism for the formation of enaminonitrile 4.
Fig. 3
Fig. 3. E HOMO and ELUMO of reactant materials 1–3.
Scheme 3
Scheme 3. A probable mechanism for the condensation of 4 with oxalyl chloride.
Fig. 4
Fig. 4. Space models of both compounds obtained 6 and the intermediate [X].
Scheme 4
Scheme 4. Treating acid chloride 6 with 4-aminopyridine and hydrazine hydrate.
Scheme 5
Scheme 5. Reaction of hydrazide 8 with indolin-2,3-dione and phenyl isothiocyanate.
Fig. 5
Fig. 5. Optimized configurations (left), HOMO (middle), and LUMO (right) for substrates 4–11. Atom color index: white H, grey C, blue N, red O, and green Cl (see all substrates in the ESI†).
Fig. 6
Fig. 6. SAR of the most potent substances.
See this image and copyright information in PMC

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