Progesterone receptor (PR) agonists represent pivotal agents in trapping breast cancer cells through modulating the expression of estrogen receptor (ER). The present investigation aimed to test three novel thiadiazolecontaining compounds as antibreast cancer agents. Test compounds were synthesized and abbreviated as 2-{(5-amino-1, 3, 4-thiazole-2-yl) amino}-4-(4-chloro-3methylphenyl)-4-oxobutanoic acid (TAB), 4-(4-chloro-3methylphenyl)-4-oxo 2-[(5-sulfanyl-1, 3, 4-thiadiazol-2-yl)] sulfanyl-butanoic acid (TSB) and 4-(4-chloro-3methylphenyl)-4-oxo 2-[(5-sulfanyl-1, 3, 4-thiadiazol-2-yl)] sulphonyl-botanic acid (TSSB). Molecular docking of the test compounds with PR was simulated. The IC 50 of the test compounds against both Michigan cancer foundation-7 (MCF-7) and HepG2 was determined. Ehrlich solid tumor (EST) was grown in the right thigh of the mouse as a model of breast cancer in vivo. Hepatic and renal functions, besides hematological indicators, were tested. The expression of ER and ER genes in EST was determined using real-time PCR. Immunohistochemistry was carried out for the determination of Ki-67 and cyclindependent kinase 1 (CDK-1) in EST. Our results revealed that TAB, TSB and TSSB reduced Ehrlich tumor size by 48, 64 and 52%, respectively, compared to the EST control group. The docking scores achieved by TAB, TSB and TSSB with PR were −9.29, −9.41 and −9.24 kcal/mol, respectively. The most potent compound against MCF-7 was TSB, with an IC 50 of 3.9 g/ml. The administration of test compounds suppressed Ki-67 and CDK1, and the best effect was observed at TSB. Our findings suggest that test compounds are applicants to be antibreast cancer agents.