Synthesis, structure, antimycobacterial and anticancer evaluation of new pyrrolo-phenanthroline derivatives

Figures & data

Figure 1. Dose response curves used to calculate MIC, IC₅₀ and IC₉₀.

Scheme 1. Synthesis of fused pyrrolo derivatives 4, 6 and 7.

Figure 2. X-ray molecular structure of compound 7a with thermal ellipsoids at 50% probability level.

Figure 3. View of supramolecular columnar architecture in the crystal structure of 7a. Only H atoms involved in hydrogen bonding are shown. H-bonds parameters: C10–H⋯O3 [C10–H 0.93 Å, H⋯O3 2.38 Å, C10⋯O3(2 − x, 1 − y, −z) 3.308(4) Å, C10–H⋯O3 175.8 °]; C3–H⋯O3 [C3–H 0.93 Å, H⋯O3 2.49 Å, C3⋯O3(2 − x, 1 − y, −z) 3.419(4) Å, C10–H⋯O3 173.0°]; C14–H⋯O3 [C14–H 0.97 Å, H⋯O3 2.44 Å, C14⋯O3(−1 + x, y, z) 3.299(4) Å, C10–H⋯O3 148.0°].

Scheme 2. Synthesis of fused pyrrolo derivatives 8, 9, 10 and 11.

Figure 4. The X-ray molecular structure of compound 11f with the thermal ellipsoids at 50% probability level.

Figure 5. View of supramolecular columnar architecture in the crystal structure of 11f. Only H atoms involved in hydrogen bonding are shown. H-bonds parameters: C7–H⋯O1 [C7–H 0.93 Å, H…O1 2.48 Å, C7⋯O1(1 + x, y, z) 3.158(5) Å, C10–H⋯O3 129.8 °].

Scheme 3. Design in the class of pyrrolo[2,1-c][4,7]phenanthroline derivatives.

Table 1. Solubility in microbiological medium and antimycobacterial activity of compounds 4a–d and 6a–d against M. tuberculosis H37Rv under aerobic conditions.

				Compound solubility
Compounds	IC50 (µM)	IC90 (µM)	MIC (µM)	Starting concentration (µM)	Lowest insoluble concentration (µM)
4a	>200	>200	>200	200	12.5
4b	>50	>50	>50	100	12.5
4c	>100	>100	>100	20	10
4d	>50	>50	>50	50	12.5
6a	>50	>50	>50	20	20
6b	>20	>20	>20	200	N/A
6c	>50	>50	>50	200	100
6d	>200	>200	>200	200	N/A
Control*
Rifampicin	0.0036	0.0061	0.0055	0.04	N/A

N/A means the compound was soluble at the highest concentration.

*Each experiment runs included and other control compounds: metoprolol tartrate, phenytoin, haloperidol, simvastatin, diethylstilbestrol and tamoxifen.

Bold values indicate moderate active compounds.

Table 2. Percentage growth inhibition (PGI, μM) data of compounds 4a, 4c, 6c and 6d against an NCI 60 human tumour cell lines (selection).

Panel/Cell line	Compound 4a, PGI	Compound 4c, PGI	Compound 6c, PGI	Compound 6d, PGI
CNS Cancer
SF-SNB-19	84.77	95.43	74.19	86.66
Melanoma
M14	77.14	88.38	95.18	99.07
Renal Cancer
UO-31	81.49	84.21	58.02	76.07
Breast Cancer
MCF7	84.73	92.59	93.10	56.64
T-47D	80.69	81.09	86.01	70.76

The number reported for the one-dose assay, percentage growth inhibition (PGI), is growth relative to the no-drug control and relative to the time zero number of cells. Full results are presented in the SM.

Bold and underlined values indicate active compounds. Underlined values indicates moderate active compounds.