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Abstract
The pharmacophore hybridization approach is widely used for the design of drug-like small molecules with anticancer properties. In the present work, a “cost-effective” approach to the synthesis of the novel non-condensed pyrazoline-bearing hybrid molecule with 1,3,4-thiadiazole and dichloroacetic acid moieties is proposed. The 5-amino-1,3,4-thiadiazole-2-thiol was used as a starting reagent, and the synthetic strategy includes stepwise alkylation of the sulfur atom and acylation of the nitrogen atom to obtain the target title compound. The structure of the synthesized 2,2-dichloro-N-[5-[2-[3-(4-methoxyphenyl)-5-phenyl-3,4-dihydro-2H-pyrazol-2-yl]-2-oxoethyl]sulfanyl-1,3,4-thiadiazol-2-yl]acetamide (yield 90%) was confirmed by 1H, 13C, 2D NMR and LC-MS spectra. Anticancer activity in “60 lines screening” (NCI DTP protocol) was studied in vitro for the title compound.
Highlights
The pharmacophore hybridization approach plays a key and leading role in the modern medicinal chemistry of anticancer agents [1,2]
The pharmacophore hybridization approach is widely used for the design of drug-like small molecules with anticancer properties
Pyrazoline-based molecules are available in the pharmaceutical market as approved drugs targeted at different types of cancer diseases: crizotinib—inhibitor of the receptor tyrosine kinases c-MET, ALK and ROS1 [12,13,14]; ruxolitinib—JAK 1 and 2 inhibitor [15,16]; encorafenib—selective BRAF inhibitor (BRAFi) [17]; darolutamide—androgen receptor (AR) antagonist [18]. 1,3,4Thiadiazole derivatives demonstrate in vitro and/or in vivo efficacy across the cancer models [19,20] and are currently at different stages of clinical trials as prospective inhibitors of carbonic anhydrase [21], glutaminase [22], inosine monophosphate dehydrogenase [23], and kinesin spindle protein (KSP, Eg5) [24]
Summary
The pharmacophore hybridization approach plays a key and leading role in the modern medicinal chemistry of anticancer agents [1,2]. DCA and some bioisosteres are intensively studied and evaluated in the synergistic conditions/experiments with other anticancer agents of synthetic and natural origin for the optimization of anticancer potency [25,26]. DCA and some bioisostere2s oafre intensively studied and evaluated in the synergistic conditions/experiments with other anticancer agents of synthetic and natural origin for the optimization of anticancer poategnaciyns[t2s5o,2m6]e. DCA and some bioisosteres are Molbank 2022, 2022, M1328 intensively studied and evaluated in the synergistic conditions/experiments with other anticancer agents of synthetic and natural origin for the optimization of anticancer2pofo7-. NMR spectrum of compound 3, the characteristic signals of all protons are presented. Carbons of aromatic methines resonated in the range from 114.5 to 159.0 ppm and overlapped with each other, as well with the carbonyl group carbon (C-30) signal. The molecular ion peak observed at an m/z value of 538.0 [M + H]+ in the positive ionization mode in the mass spectrum confirmed the formation of the title compound 3
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