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Two series of novel substituted 1,4-dihydropyridine derivatives incorporating nitrogen mustard pharmacophore hybrids without spacer DHP-M (4a–4d) and with ethyl spacer DHP-L-M (8a–8g) were designed and synthesized. They were subjected to in silico ADME prediction study to check their drug-like properties and evaluated for their cytotoxicity against: A 549 (lung), COLO 205 (colon), U 87 (glioblastoma), and IMR-32 (neuroblastoma) human cancer cell lines in vitro using 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay against chlorambucil and docetaxel. Majority of the test compounds exhibited moderate to significant cytotoxic activity. The highest activity in all the investigated cancer cells was displayed by DHP-M (4a). This may be due to the less steric hindrance offered by 4a.

Target drug delivery of nitrogen mustard anticancer agents for a brain tumor is still a challenge due to their high hydrophilicity, poor physicochemical properties, and toxicity to normal tissues. The present study is, therefore, an attempt to investigate the possibility of improving the targeting potential and sustained release of nitrogen mustard alkylating agent to brain by employing reversible redox chemical delivery system approach. Various redox derivatives CDS-L-M (4a–c) based on dihydropyridine ↔ quaternary pyridinium ion redox system were synthesized and characterized by IR, (1H and 13C)-NMR, and CHN elemental studies. The potential of these CDS derivatives (4a–c) to penetrate the blood–brain barrier was computed through an online software program and the values analyzed lay between the ranges those are required for good brain penetration. The results of storage stability study, in vitro chemical oxidation (silver nitrate) and pharmacokinetic studies in human blood, rat blood and brain homogenate for all CDS-L-M (4a–c) demonstrated that all derivatives could be oxidized into corresponding quaternary salts at an adequate rate, which suggested that brain targeting could be possible with more stable CDS-L-M (4c). The in vivo study on rats showed that administration of the CDS-L-M (4c) resulted in the sustained level of the corresponding salt (3c) in the brain, while blood levels of the oxidized metabolite rapidly fell. The in vitro NBP alkylating activity of quaternary salt (3c) of CDS-L-M (4c) was comparable to the known drug chlorambucil among all the synthesized derivatives.

A series of novel substituted aminobenzophenone derivatives containing nitrogen mustard moiety (5a–f) were synthesized and characterized on the basis of their IR, 1H NMR, 13C NMR, CHN, and mass spectral data. All the compounds when evaluated for chemical 4-(4-nitrobenzyl) pyridine alkylating activity proved to be active alkylating agents. All the synthesized compounds were subjected to physicochemical parameters determination required for central nervous system (CNS) activity through computational, online software, and QikProp 3.2. The log P values and other in silico ADME physicochemical descriptors analyzed lay between the ranges those are required for good BBB penetration. The in vitro antiproliferative activity against human cancer cell lines viz. A 549 (lung), COLO 205 (colon), U 87 (glioblastoma), and IMR-32 (neuroblastoma) was investigated. Most of the test compounds showed potent antitumor activity, especially compound (5f) which displayed the highest activity against CNS cancer cell line comparable to that of chlorambucil and docetaxel. The preliminary structure–activity relationship (SAR) revealed that 5-chloroaminobenzophenone-mustard series (5a–c) exhibited better antitumor activity than 5-nitroaminobenzophenone-mustard series (5d–f).

Every year, there are more than two lakhs of population affected with CNS tumor. Nitrogen mustard class of alkylating drugs, used clinically against various types of tumor, is too polar to cross the BBB. The redox chemical drug delivery prodrug approach is one of the most interesting procedures for delivering drugs in a sustained and specific manner to the CNS. The objective of the present study is to investigate the redox drug delivery system for the delivery of bis(2-chloroethyl)amine (nor mustard) as alkylating cytotoxic agent to the brain. Various redox derivatives of CDS-M (4a–d) were synthesized incorporating different alkyl/aryl moieties at ring nitrogen and subjected to in silico physicochemical parameters determination required for CNS activity through computational, online, and QikProp 3.2 software. The results of stability study, in vitro chemical (silver nitrate), and biological oxidation studies in human blood, rat blood, and brain homogenate for all CDS-M (4a–d) have been promising and suggest that brain targeting could be possible with more stable CDS-M (4d). The in vivo study showed that CDS-M (4d) was able to cross the BBB at detectable concentrations, and in vitro NBP alkylating activity of its quaternary salt (3d) was comparable to the known drug chlorambucil among all the synthesized derivatives.