(2Z)-3-Hydroxy-3-(4-R-Phenyl)-Prop-2-Enedithioic Acids as New Antituberculosis Compounds

Figures & data

Figure 1 Examples of compounds that both contain a thio scaffold and exhibit biological activity.

Scheme 1 Synthetic route to compounds 11a–j.

Table 1 Anti-M. tuberculosis Effects and Cytotoxicity Levels of Compounds 11a–j

Compound	R	REMA-Determined MIC100 (μg/mL)	REMA-Determined MBC (μg/mL)	MTT-Determined IC50, in Vero Cells (μg/mL)	Selectivity Index (SI)
11a	-H	62.5	ND	216	3.46
11b	-CH3	250	ND	221	0.88
11c	-OCH3	62.5	ND	100	1.60
11d	-OH	15.6	ND	101	6.47
11e	-NO2	7.8	31.25	255	32.69
11f	-CN	62.5	ND	>50	0.80
11g	-F	62.5	ND	443	7.09
11h	-Cl	15.6	ND	110	7.05
11i	-Br	62.5	ND	ND	ND
11j	-I	500	ND	381	0.762
Rifampin	–	0.06	ND	>1000	>16,666

Notes: Mtb: M. tuberculosis H37Rv ATCC 27294 reference strain. SI= IC₅₀/MIC_100.

Abbreviations: MIC₁₀₀, minimal inhibition concentration; REMA, resazurin microtiter assay; MBC, minimal bactericidal activity; IC₅₀, inhibitory concentration 50 (MTT assay in Vero cells).

Table 2 REMA-Determined MIC₁₀₀ Values of 11e Against Virulent, Non-Virulent and RIF-Resistant M. tuberculosis Strains

Compound	MIC100 μg/mL in H37Rv 27294	MIC100 μg/mL in H37Ra	MIC100 μg/mL in Mtb-209
11e	7.8	7.8	15.6
Rifampin	0.06	0.008	320

Notes: M. tuberculosis H37Rv ATCC 27294 reference strain: M. tuberculosis H37Ra: non-virulent strain. M. tuberculosis-209: RIF-resistant clinical isolate of M. tuberculosis.

Table 3 Calculated Physicochemical Properties of Compounds 11a-j

Compound	MW	logP	logD	logSw	tPSA	RB	HBD	HBA	HA	PAINS
11a	196.29	2.42	1.64	−2.67	72.22	2	1	1	12	NO
11b	210.32	2.78	2.16	−2.96	72.22	2	1	1	13	NO
11c	226.32	2.39	1.49	−2.74	81.45	3	1	2	14	NO
11d	212.29	2.06	1.33	−2.53	92.45	2	2	2	13	NO
11e	241.29	2.25	4.97	−2.76	113.76	3	1	4	15	NO
11f	221.3	2.13	1.5	−2.63	96.01	2	1	2	14	NO
11g	214.28	2.52	1.79	−2.85	72.22	2	1	1	13	NO
11h	230.73	3.04	2.25	−3.28	72.22	2	1	1	13	NO
11i	275.19	3.11	2.41	−3.6	72.22	2	1	1	13	NO
11j	322.19	3.07	2.57	−3.86	72.22	2	1	1	13	NO

Abbreviations: Cmpd, compound; MW, molecular weight; logP, logarithm of the partition coefficient between n-octanol and water; logD, logP of the physiological pH; logSw, logarithm of the water solubility of the compound; RB, numbers of rotatable bonds; HBD, hydrogen bond donors; HBA, hydrogen bond acceptors; HA, heavy atoms in the compound; PAINS, pan-assay interference compounds.

Table 4 Predicted Toxicities of the Synthesized Compounds 11a-j

Compound	Mutagenicity (AMES Test)	Cardiotoxicity (hERG Blocker)	Mitochondrial Toxicity (MMP)	Hepatotoxicity	DILI	Cytotoxicity	AO
11a	−	−	−	−	+	−	III
11b	−	−	−	−	+	+	III
11c	−	−	−	−	−	−	III
11d	−	−	−	−	−	−	II
11e	+	−	−	+	+	−	III
11f	−	−	−	+	+	−	II
11g	−	−	−	−	+	−	III
11h	−	−	−	+	+	−	III
11i	−	−	−	−	+	+	III
11j	−	−	−	−	+	−	III

Notes: no risk (−); high risk (+).

Abbreviations: Cmpd, compound; hERG, human ether-à-go-go-related gene; MMP, mitochondrial membrane potential; DILI, drug-induced liver injury; AO, acute oral toxicity category.

Table 5 Calculated Binding Free Energy (ΔG) from Molecular Docking Results of the Two Tautomeric Forms (Keto and Enol) of 11a-j Compounds Within HadAB Active Site

Compound	ΔG (kcal/mol)
	Keto	Enol
11a	−5.96	−5.74
11b	−6.36	−6.62
11c	−5.78	−5.91
11d	−6.02	−5.91
11e	−6.03	−5.45
11f	−7.24	−6.55
11g	−5.90	−6.10
11h	−6.40	−6.72
11i	−6.69	−6.52
11j	−6.61	−6.94
HCC	−8.32

Figure 2 Nonbonding interactions between the active site of HadAB and (A) the 11d enolic tautomer, (B) 11e enolic tautomer, and (C) 11e ketonic tautomer.