Molecular Engineering of Tetracyclic 2,3‐Dihydro‐1H‐benzo[2,3]‐benzofuro[4,5‐e][1,3]oxazine Derivatives: Evaluation for Potential Anticancer Agents

Abstract

Water-mediated one-pot Mannich type condensation of dibenzo[b,d]furan-2-ol with different amines resulted in a large library of novel 2,3-dihydro-1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazine derivatives in moderate to excellent yields. The ortho-aminomethylation of the dibenzofuranols proceeded smoothly in the presence of various aromatic/aliphatic amines and paraformaldehyde, followed by cyclization. All the newly synthesized tetracyclic 2,3-dihydro-1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazine derivatives were chemically characterized and screened for their cytotoxicity activity by cell viability assay (MTT test) against three human cancer cell lines and antibacterial activity by determining the minimum inhibitory concentration (MIC) against four bacterial strains. Among all the derivatives, MCV-24 showed promising anticancer activity by inhibiting the cell proliferation of an ovarian cancer cell line (SKOV3) with an IC value at 7.5 µM, whereas MCV-24 to MCV-30 derivatives showed moderate activity against a lung cancer cell line (A549) with an IC value ranging from 11 to 15.9 µM. Besides MCV-29, -30, and -31 also exhibited broad-spectrum antibacterial activity. Among all new compounds, MCV-24-30 showed promising anticancer and MCV-29-31 antibacterial activity.

Anticancer Activity of Mannich Bases: A Review of Recent Literature

“…[119] The members of a library of over thirty oxazines 101 (Figure 12), that were obtained through the Mannich reaction of dibenzo[b,d]furan-2ol with aromatic and aliphatic primary amines, exhibited broad antiproliferative activity against A549, SK-OV-3 and MCF-7 cancer cell lines that varied from good to poor. [120] The most potent compounds in this library were those with R = n-C 3 H 7 (IC 50 = 11 μM for A549 cells, IC 50 = 17.5 μM for MCF-7 cells) and R = 2,4,5-F 3 C 6 H 2 CH 2 (IC 50 = 7.5 μM for SK-OV-3 cells). Mannich reaction of ten phenolic substrates with ferrocenemethylamines as amine reagents afforded oxazines 102 (Figure 12), but only a few candidates having a basic substituent (R 1 = CH 2 N(CH 3 ) 2 ) on the ferrocene showed moderate cytotoxicity (IC 50 between 11.0 and 31.0 μM) against the hormone-independent, triple-negative breast cancer cell line HCC70.…”

“…Aminomethylation of phenoxodiol with benzylamine under particular reaction conditions afforded bis‐oxazine 100 , whose anticancer activity was comparable to that of the related benzyl‐substituted mono‐oxazine 98 (IC 50 =5.3 μM for MDA‐MB‐231 cells and IC 50 =5.7 μM for SHEP cells) [119] . The members of a library of over thirty oxazines 101 (Figure 12), that were obtained through the Mannich reaction of dibenzo[ b , d ]furan‐2‐ol with aromatic and aliphatic primary amines, exhibited broad antiproliferative activity against A549, SK‐OV‐3 and MCF‐7 cancer cell lines that varied from good to poor [120] . The most potent compounds in this library were those with R= n ‐C 3 H 7 (IC 50 =11 μM for A549 cells, IC 50 =17.5 μM for MCF‐7 cells) and R=2,4,5‐F 3 C 6 H 2 CH 2 (IC 50 =7.5 μM for SK‐OV‐3 cells).…”

1,3‐Oxazine as a Promising Scaffold for the Development of Biologically Active Lead Molecules

“…Also, compounds 30 to 36 (Figure 7) showed moderate activity against lung cancer cell line with IC 50 values ranging from 11 to 15.9 μM. SAR studies indicated that N‐alkyl substituted compounds have higher affinity for biological activity than aromatic substituent [30] …”

“…SAR studies indicated that N-alkyl substituted compounds have higher affinity for biological activity than aromatic substituent. [30] Kakkerla et al reported the synthesis of 3,4-dihydro-8-methoxy-3-(3-methylisoxazol-5-yl)-2H-benzo[e] [1,3]oxazine derivatives in 2017 using 5-amino-3-methylisoxazole which was treated with different salicylaldehydes in methanol and refluxing to give desired derivatives. The synthesized derivatives were evaluated for in vitro cytotoxicity against three different human cancer cell lines HeLa, MCF-7 and A549 taking cisplatin as reference drug.…”

Antiproliferative Activity of (−)‐Isopulegol‐based 1,3‐Oxazine, 1,3‐Thiazine and 2,4‐Diaminopyrimidine Derivatives

“…On the other hand, 1,3‐thiazine derivatives, an important class of heterocyclic compounds, have a wide range of biological properties[ 66 , 67 ] including antiproliferative,[ 68 , 69 , 70 , 71 , 72 ] analgesic, [73] anticonvulsant,[ 74 , 75 ] anti‐inflammatory, [76] antibiotic, [77] antimicrobial,[ 75 , 78 , 79 , 80 ] antimalarial, [81] and antihypertensive [82] properties. A literature survey revealed that also 1,3‐oxazine moieties exhibit a broad range of pharmacological activities,[ 83 , 84 ] such as anticancer,[ 85 , 86 , 87 , 88 , 89 ] antimicrobial[ 90 , 91 ] and anti‐inflammatory[ 92 , 93 ] effects, which showed their potential value in developing new therapeutic agents.…”